Search

The canine adrenal glands receive blood from the celiac artery, cranial mesenteric artery, caudal phrenic artery, cranial abdominal artery, phrenicoabdominal trunk, abdominal aorta, renal artery and lumbar artery. These are classified into three types: cranial, middle and caudal adrenal branches. It is also known that the adrenal vein flows into the phrenicoabdominal vein. However, individual differences in the branching pattern of adrenal vessels have not been systematically analysed. We evaluated adrenal vessels in dogs that underwent contrast-enhanced abdominal computed tomography (CT). There were 255 arteries travelling to the adrenal glands in 47 cases, with 1-6 arteries travelling per adrenal gland. The arteries included 67 caudal phrenic arteries, 62 aortic arteries, 60 cranial abdominal arteries, 39 renal arteries, 12 phrenicoabdominal trunks, 8 cranial mesenteric arteries, 6 celiac arteries and 1 lumbar artery. Most of the branches were from the aorta and caudal phrenic artery on the left side, and the cranial abdominal and caudal phrenic artery on the right side. A total of 110 adrenal veins were identified. Inflow into the phrenicoabdominal vein and into the right and left renal veins was observed, and we identified no inflow into other veins. This study demonstrated two points: laterality and individual differences in adrenal blood vessels. When evaluating adrenal blood vessels with abdominal contrast-enhanced CT, it is recommended to take images under general anaesthesia with breath-holding and observe them using multiplanar reconstruction.

Background:Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome.Methods:This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome.Results:Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit.Conclusions:These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.

Masataka Otake,1 Shin Ono,1 Yuichiro Watanabe,1 Koichiro Kumagai,1 Koji Matsuzawa,1 Hiroyuki Kasahara,1 Masaya Ootake,1 Takuro Sugai,1,2 Toshiyuki Someya1 1Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan; 2Murakami Hamanasu Hospital, Murakami, Niigata, JapanCorrespondence: Yuichiro Watanabe, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, Chuo-ku, Niigata, 951-8510, Japan, Tel +81-25-227-2213, Fax +81-25-227-0777, Email yuichiro@med.niigata-u.ac.jpPurpose: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia.Patients and Methods: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates.Results: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]).Conclusion: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.Keywords: antipsychotic polypharmacy, body mass index, oral health, tooth loss

Takotsubo cardiomyopathy, a disease that causes transient contractile abnormalities mainly in the left ventricular apex, is rarely reported in children, especially in those with single-ventricle disease. A 4-year-old boy with a single right ventricle was transferred to our hospital following a severe seizure and was diagnosed with takotsubo cardiomyopathy by echocardiography. His cardiac function improved; however, he developed hypoxic-ischemic encephalopathy.

Sufficient left ventricular volume is required for patients with tetralogy of Fallot (TOF) who are going to have biventricular repair. In this study, we investigated the utility of the electrocardiogram to evaluate left ventricular volume in patients with TOF.Patients whose left ventricular (LV) end-diastolic volume was lower than 80% of normal were defined as having a small LV. Seven patients with TOF who had to undergo Blalock-Taussig shunt surgery because of a small LV were assigned to group S. Twenty patients with TOF who had sufficient LV volume were assigned to group G. The amplitudes of the Q wave of V5-7 leads (QV5-QV7), the S wave of V1 lead, and the R wave of the II, III, aVf, and V5-7 leads of the electrocardiogram were evaluated.The amplitude of QV5 was 0 mV in all cases in group S, which was significantly smaller than that in group G (0 vs 0.01 mV, P = 0.028). The frequency of absent QV5 was significantly higher in group S than in group G (100% vs 50%, P = 0.026). Absent QV5 showed 100% sensitivity, 50% specificity, and a negative predictive value of 100% for a small LV.In TOF, the amplitude of the septal Q wave reflects LV volume. In particular, the absence of QV5 suggests a small LV end-diastolic volume, which is lower than 80% of normal.

This study investigated the incidence and risk factors of perioperative clinical seizure and epilepsy in children after operation for CHD. We included 777 consecutive children who underwent operation from January 2013 to December 2016 at Kanagawa Children’s Medical Center, Kanagawa, Japan. Perinatal, perioperative, and follow-up medical data were collected. Elastic net regression and mediation analysis were performed to investigate risk factors of perioperative clinical seizure and epilepsy. Anatomic CHD classification was performed based on the preoperative echocardiograms; cardiac surgery was evaluated using Risk Adjustment in Congenital Heart Surgery 1. Twenty-three (3.0%) and 15 (1.9%) patients experienced perioperative clinical seizure and epilepsy, respectively. Partial regression coefficient with epilepsy as the objective variable for anatomical CHD classification, Risk Adjustment in Congenital Heart Surgery 1, and the number of surgeries was 0.367, 0.014, and 0.142, respectively. The proportion of indirect effects on epilepsy via perioperative clinical seizure was 22.0, 21.0, and 33.0%, respectively. The 15 patients with epilepsy included eight cases with cerebral infarction, two cases with cerebral haemorrhage, and three cases with hypoxic-ischaemic encephalopathy; white matter integrity was not found. Anatomical complexity of CHD, high-risk cardiac surgery, and multiple cardiac surgeries were identified as potential risk factors for developing epilepsy, with a low rate of indirect involvement via perioperative clinical seizure and a high rate of direct involvement independently of perioperative clinical seizure. Unlike white matter integrity, stroke and hypoxic-ischaemic encephalopathy were identified as potential factors for developing epilepsy.

Objective: We conducted this non-randomized prospective interventional study to clarify the relationship between improved attention-deficit hyperactivity disorder (ADHD) symptoms and regional brain activity.Methods: Thirty-one adult patients underwent near-infrared spectroscopy examinations during a go/no-go task, both before and 8 weeks after atomoxetine administration.Results: Clinical symptoms, neuropsychological results of the go/no-go task, and bilateral lateral prefrontal activity significantly changed. A positive correlation was observed between right dorsolateral prefrontal cortex activity and Conners’ Adult ADHD Rating Scales scores. Before atomoxetine administration, no correlations between prefrontal cortex activity and clinical symptoms were observed in all cases. When participants were divided into atomoxetine-responder and non-responder groups, a positive correlation was observed between prefrontal cortex activity and clinical symptoms in the non-responder group before treatment but not in the responder group, suggesting that non-responders can activate the prefrontal cortex without atomoxetine.Conclusions: Individuals with increased ADHD symptoms appear to recruit the right dorsolateral prefrontal cortex more strongly to perform the same task than those with fewer symptoms. In clinical settings, individuals with severe symptoms are often observed to perform more difficultly when performing the tasks which individuals with mild symptoms can perform easily. The atomoxetine-responder group was unable to properly activate the right dorsolateral prefrontal cortex when necessary, and the oral administration of atomoxetine enabled these patients to activate this region. In brain imaging studies of heterogeneous syndromes such as ADHD, the analytical strategy used in this study, involving drug-responsivity grouping, may effectively increase the signal-to-noise ratio.

Owing to the absence of a sub-pulmonary ventricle, the central venous pressure rises in patients with Fontan circulation. During exercise, central venous pressure may rise further to increase the systemic ventricular preload and cardiac output. We performed a single-centre prospective trial of cardiopulmonary exercise test while monitoring peripheral venous pressure which strongly correlates with central venous pressure. The objective of this study was to test the hypothesis that peripheral venous pressure at peak exercise inversely correlates with exercise capacity in patients with Fontan circulation. Seventeen patients following Fontan operation performed cardiopulmonary exercise test while monitoring peripheral venous pressure. Peak oxygen uptake, heart rate reserve, peak oxygen pulse (divided by body surface area), and peripheral venous pressure at peak exercise were measured. Correlations of peripheral venous pressure at peak exercise with the peak oxygen uptake, heart rate reserve, and peak oxygen pulse were evaluated. The peripheral venous pressure at peak exercise inversely correlated with the peak oxygen uptake (R = −0.66, p < 0.01), heart rate reserve (R = −0.6, p < 0.05), and peak oxygen pulse (R = −0.48, p < 0.05). Exercise-induced peripheral venous hypertension correlates with exercise intolerance in patients with Fontan circulation. Peak oxygen uptake is a useful index for evaluating the status of congestion in the daily life of patients with Fontan circulation.

Background In both humans and animals, anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital coronary artery anomaly. In veterinary medicine, ALCAPA is reported to be discovered only during autopsy or necropsy, and diagnostic methods and prognosis remain poorly understood in dogs. Case presentation A 6-month-old Kaninchen Dachshund was diagnosed with functional mitral valve regurgitation and ALCAPA. Echocardiography identified anomalous vessels in the left ventricular wall and abnormal origin of the left coronary artery from the pulmonary artery. Further evaluation with coronary computed tomographic angiography demonstrated the left coronary artery arising from the posterior aspect of the main pulmonary artery together with the characteristic findings of ALCAPA. The right coronary artery was found to be dilated and tortuous. Furthermore, dilated coronary collateral arteries within the ventricular septum and along the epicardial surface were observed. The dog underwent surgery, but the origin of the anomalous artery could not be ligated, and it died from pulmonary edema 5 months after surgery. Conclusion Anomalous origin of the left coronary artery from the pulmonary artery is overlooked in clinical practice due to its rarity. Coronary computed tomographic angiography was useful to definitively diagnose ALCAPA in a low-invasive manner. Antemortem diagnosis of ALCAPA was shown to be possible in dogs for the first time, and presence of unexplained mitral valve regurgitation should raise concern to this anomaly.

After birth, the ductus venosus becomes an important route connecting the pulmonary and systemic venous systems for survival in infracardiac total anomalous pulmonary venous connection. We encountered a fetal case of right atrial isomerism with infracardiac total anomalous pulmonary venous connection and agenesis of ductus venosus. Prenatal echocardiography suggested that the fetus had severe pulmonary venous obstruction; however, no obstructive lesions were detected at the level of the vertical vein that drained into the portal veins. Therefore, we concluded that emergency surgical pulmonary venous obstruction release was the only way for the fetus to survive. However, the saturation level was maintained above 70% due to the abundant communications via the hepatic sinusoid over 1 week after birth. In conclusion, hepatic sinusoids can be a sufficient route for pulmonary venous return and may not cause severe pulmonary venous obstruction in infracardiac total anomalous pulmonary venous connection with agenesis of ductus venosus.

Left ventricle noncompaction (LVNC) is a clinically heterogeneous disorder. Although several genetic mutations have been reported, only a little is known about its genotype–phenotype correlation. We report two cases of LVNC with different mutations and different clinical courses for each. Case 1 was a 15-year-old boy with atrial septum defect and pulmonary valve stenosis. He was diagnosed as LVNC when he was 3 years old, but his cardiac function was maintained and no medication was necessary. A 432 kb deletion in chromosome 8p 23.1, including GATA4, was found. Case 2 was a boy who was referred to our hospital at the age 6 for apparent right ventricle hypertrophy in electrocardiogram carried out for screening. We recognized severe pulmonary hypertension (PH) and LVNC with attenuated cardiac diastolic function and fair systolic function. In spite of medications for both heart failure and PH, the response was poor. A genetic investigation revealed a point mutation at exon 6 of TBX20, c.655-2A>G.

BACKGROUND Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ± .04 mg/kg [mean ± standard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ± .31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ± 32.3 ng/mL in 7 responders and was significantly higher than 29.5 ± 23.9 ng/mL (P

Aims Left ventricular apical pacing (LVAP) has been reported to preserve left ventricular (LV) function in chronically paced children with complete atrioventricular block (CAVB). We sought to evaluate long-term feasibility of LVAP and the effect on LV mechanics and exercise capacity as compared to normal controls. Methods and results Thirty-six consecutive paediatric patients with CAVB and LVAP in the absence (N = 22) or presence of repaired structural heart disease (N = 14, systemic LV in all) and 25 age-matched normal controls were cross-sectionally studied after a median of 3.9 (interquartile range 2.1–6.8) years of pacing using echocardiography and exercise stress testing. Pacemaker implantation was uneventful and there was no death. Probability of the absence of pacemaker-related surgical revision (elective generator replacement excluded) was 89.0% at 5 years after implantation. Left ventricular apical pacing patients had lower maximum oxygen uptake (P = 0.009), no septal to lateral but significant apical to basal LV mechanical delay (P Conclusion Left ventricular apical pacing is technically feasible with a low reintervention rate. Mechanical synchrony between LV septum and free wall is maintained at the price of an apical to basal mechanical delay associated with LV contraction inefficiency as compared to healthy controls. Global LV systolic function is, however, not negatively affected by LVAP.

Diphenyl (α-aminoalkyl)phosphonates act as mechanism-based inhibitors against serine proteases by forming a covalent bond with the hydroxy group of the active center Ser residue. Because the covalent bond was found to be broken and replaced by 2-pyridinaldoxime methiodide (2PAM), we employed a peptidyl derivative bearing diphenyl 1-amino-2-phenylethylphosphonate moiety (Phe(p) (OPh)2 ) to target the active site of chymotrypsin and to selectively anchor to Lys175 in the vicinity of the active site. Previously, it was reported that the configuration of the α-carbon of phosphorus in diphenyl (α-aminoalkyl)phosphonates affects the inactivation reaction of serine proteases, i.e., the (R)-enantiomeric diphenyl phosphonate is comparable to l-amino acids and it effectively reacts with serine proteases, whereas the (S)-enantiomeric form does not. In this study, we evaluated the stereochemical effect of the phosphonate moiety on the selective chemical modification. Epimeric dipeptidyl derivatives, Ala-(R or S)-Phe(p) (OPh)2 , were prepared by separation with RP-HPLC. A tripeptidyl (R)-epimer (Ala-Ala-(R)-Phe(p) (OPh)2 ) exhibited a more potent inactivation ability against chymotrypsin than the (S)-epimer. The enzyme inactivated by the (R)-epimer was more effectively reactivated with 2PAM than the enzyme inactivated by the (S)-epimer. Finally, N-succinimidyl (NHS) active ester derivatives, NHS-Suc-Ala-Ala- (R or S)-Phe(p) (OPh)2 , were prepared, and we evaluated their action when modifying Lys175 in chymotrypsin. We demonstrated that the epimeric NHS derivative that possessed the diphenyl phosphonate moiety with the (R)-configuration effectively modified Lys175 in chymotrypsin, whereas that with the (S)-configuration did not. These results demonstrate the utility of peptidyl derivatives that bear an optically active diphenyl phosphonate moiety as affinity labeling probes in protein bioconjugation. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 521-530, 2016.

Protein-losing enteropathy (PLE) is a life-threatening complication in patients following the Fontan operation. However, PLE also develops in some patients with congenital heart disease (CHD) after biventricular repair (BVR). This study compared clinical profiles of PLE patients following the Fontan operation with those after BVR. We retrospectively reviewed clinical charts of postoperative CHD patients with PLE. The study population comprised 42 PLE patients (14BVR, 28Fontan). Postoperative follow-up period until onset was significantly shorter in the Fontan group than in the BVR group (14 ± 2 vs. 8 ± 1 years, p = 0.02), while there was no difference in PLE onset age between groups. Furthermore, there were no differences in prevalence of clinically relevant arrhythmias, cardiac output, or central venous pressure between the two groups at PLE onset. Percentage of structural lesions (valve regurgitation and/or stenotic lesions) responsible for development of PLE and ventricular end-diastolic pressure were higher in the BVR group than in the Fontan group (93 vs. 50%, p

BACKGROUND Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

Aims Food-derived peptides have been reported to yield a variety of health promoting activities. Pyroglutamyl peptides are contained in the wheat gluten hydrolysate. In the present study, we investigated the effect of pyroglutamyl dipeptides on the lipopolysaccharide (LPS)-induced inflammation in macrophages. Main methods RAW 264.7 macrophages were treated with LPS and various concentrations of pyroglutamyl-leucine (pyroGlu-Leu), -valine (pyroGlu-Val), -methionine (pyroGlu-Met), and -phenylalanine (pyroGlu-Phe). Cell viability/proliferation and various inflammatory parameters were measured by the established methods including ELISA and western blotting. The binding of fluorescein isothiocyanate-labeled LPS to RAW 264.7 cells was also measured fluorescently. Key findings All the tested dipeptides significantly inhibited the secretion of nitric oxide, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 from LPS-stimulated RAW 264.7 macrophages. Above all, pyroGlu-Leu inhibited the secretion of all these inflammatory mediators even at the lowest dose (200 μg/ml). PyroGlu-Leu dose-dependently suppressed IκBα degradation and MAPK (JNK, ERK, and p38) phosphorylation in LPS-stimulated RAW 264.7 cells. On the other hand, it did not affect the binding of LPS to the cell surface. Significance Our results indicated that pyroGlu-Leu inhibits LPS-induced inflammatory response via the blocking of NF-κB and MAPK pathways in RAW 264.7 macrophages.

Risperidone (RIS) is a frequently used efficacious psychotropic drug. However, it prolongs the QTc interval and may cause fatal arrhythmia. Little is known on the determinants of this RIS side effect. RIS is metabolized by CYP2D6, and is subject to drug efflux by P-glycoprotein (P-gp) encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp removes both RIS and its metabolite 9-OH-RIS from cardiac tissue. To investigate the effect of RIS metabolism and ABCB1 gene polymorphisms on QTc, steady-state plasma RIS and 9-OH-RIS levels, and QTc were measured. CYP2D6, ABCB1 C3435T and G2677T/A genotypes were determined in 66 schizophrenia patients on RIS. QTc was significantly longer in patients with ABCB1 3435CT+3435 TT than in those with 3435CC (P=0.006). ABCB1 G2677T/A genotype did not affect QTc. Multiple regression analysis showed that C/T or T/T genotypes at the ABCB1 C3435T locus, lower weight, and older age prolonged QTc. In summary, the T allele of the ABCB1 C3435T genotype should be considered in future diagnostic development efforts for RIS-associated QT.

The purpose of this retrospective study was to describe pre- and postcontrast computed tomographic (CT) characteristics of confirmed nonparenchymal hemangiosarcoma in a group of dogs. Medical records were searched during the period of July 2003 and October 2011 and dogs with histologically confirmed nonparenchymal hemangiosarcoma and pre- and postcontrast CT images were recruited. Two observers recorded a consensus opinion for the following CT characteristics for each dog: largest transverse tumor diameter, number of masses, general tumor shape, character of the tumor margin, precontrast appearance, presence of dystrophic calcification, presence of postcontrast enhancement, pattern of postcontrast enhancement, presence of regional lymphadenopathy, and presence of associated cavitary fluid. A total of 17 dogs met inclusion criteria. Tumors were located in the nasal cavity, muscle, mandible, mesentery, subcutaneous tissue, and retroperitoneal space. Computed tomographic features of nonparenchymal hemangiosarcoma were similar to those of other soft tissue sarcomas, with most tumors being heterogeneous in precontrast images, invasive into adjacent tissue, and heterogeneously contrast enhancing. One unexpected finding was the presence of intense foci of contrast enhancement in 13 of the 17 tumors (76%). This appearance, which is not typical of other soft tissue sarcomas, was consistent with contrast medium residing in vascular channels. Findings indicated that there were no unique distinguishing CT characteristics for nonparenchymal hemangiosarcoma in dogs; however, the presence of highly attenuating foci of contrast enhancement may warrant further investigation in prospective diagnostic sensitivity and treatment outcome studies.

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.

Aims In Europe and North America, schizophrenia patients treated with antipsychotic agents have a higher prevalence of obesity and metabolic syndrome compared with healthy individuals. In Japan, the prevalence of overweight/obesity in the general population is considerably lower than that in Europe and North America. The purpose of this study was to investigate the prevalence of underweight and overweight/obesity as well as laboratory data in Japanese inpatients with schizophrenia. Methods The subjects were 333 inpatients with schizophrenia and 191 age- and sex-matched healthy volunteers. Overweight/obesity was defined as body mass index (BMI) ≥ 25 kg/m2, standard weight was defined as BMI ≥ 18.5 to

9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.

Objective We examined sex differences in the effect of olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), or quetiapine (QTP) on mean corrected QT (QTc) intervals among 222 patients with schizophrenia. Methods Subjects were patients with schizophrenia who were treated with either OLZ (n = 69), RIS (n = 60), ARP (n = 62), or QTP (n = 31). Electrocardiographic measurements were conducted, and the QT interval was corrected using Bazett's correction formula. Results The mean QTc interval of the QTP group was significantly longer than that of the RIS group (p = 0.002) or ARP group (p = 0.029). The mean QTc interval of the OLZ group was also significantly longer than that of the RIS group (p = 0.006). In female participants, the difference in the mean QTc interval among the four second-generation antipsychotic (SGA) groups was statistically significant (p = 0.002), whereas in male patients, there was no significant difference in the mean QTc interval among the four SGA groups. Post hoc analyses showed that sex differences in QTc interval were observed only in OLZ treatment group (p = 0.007). Conclusion To our knowledge, this is the first study to demonstrate sex differences in the effect of four SGAs on the QTc interval. Copyright © 2013 John Wiley & Sons, Ltd.

Although second-generation antipsychotics (SGAs) are characterized by fewer prolactin (PRL)-related side effects compared with first-generation antipsychotics, the detailed effects of SGAs on the plasma PRL levels still remain unclear. We examined the differences in plasma PRL levels among 268 patients treated for schizophrenia with olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), quetiapine (QTP), or perospirone (PER). The participants had received antipsychotic monotherapy with stable doses of OLZ, RIS, ARP, QTP, or PER for ≥ 3 weeks, and fasting blood samples were drawn to examine plasma PRL levels. The differences in median plasma PRL levels in all (P

To establish a covalent chromatography system for purification of naturally occurring chymotrypsin-like serine proteases, a diphenyl 1-amino-2-phenylethylphosphonate derivative bearing Gly-Gly-Gly as a spacer was immobilized on the Sepharose 4FF gel. In this system, bovine chymotrypsin was selectively bound to the phosphonate immobilized on the gel and then released by the action of 2-pyridinealdoxime methiodide as the reactivated enzyme. Based on the study results for selective binding and reactivation conditions, chymotrypsin-like proteases from pancreatin (hog pancreas) were rapidly and highly purified within three hours. Keywords

The underlying mechanism for second-generation antipsychotic (SGA)-related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects.The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor α, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups.Second-generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor α, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, and the CONT subjects were detected to be a factor associated with lower leptin levels.The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus.

Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR). Mean ± SD nighttime QTcFs were 411.6 ± 29.0, 395.9 ± 21.2, and 387.8 ± 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 ± 23.4, 392.4 ± 18.9, and 382.6 ± 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

Objective The sum of the serum levels of risperidone (RIS) and 9-hydroxyrisperidone (9-OH-RIS), which is the active moiety serum level, could be important for estimating the clinical effects of RIS. However, there have been no consistent results reported about the relationship between cytochrome P450 (CYP) 2D6*10 allele and plasma 9-OH-RIS or active moiety levels. We investigated the effect of the number of CYP2D6*10 alleles on steady-state plasma RIS, 9-OH-RIS, and active moiety levels in Japanese patients. Methods Steady-state plasma RIS, 9-OH-RIS, and active moiety levels were measured in 64 patients treated with an average dosage of 4.6 mg/day. Results The number of CYP2D6*10 alleles significantly affected dose-corrected plasma RIS levels (p = 0.001), and the median concentrations in ng/ml/mg were 0.94 (0 allele) vs. 1.73 (1 allele) vs. 3.05 (2 alleles). The number of CYP2D6*10 alleles did not affect plasma 9-OH-RIS or active moiety levels. Conclusion The present study shows that the number of CYP2D6*10 alleles affected plasma RIS levels but not plasma 9-OH-RIS and plasma active moiety levels. Because the plasma active moiety levels can influence antipsychotic effects or side effects, the genetic screening of the CYP2D6*10 allele for RIS in Asian populations may not be clinically important. Copyright © 2012 John Wiley & Sons, Ltd.

Objective A dose-dependent increase in risk of sudden cardiac death for the antipsychotic drug risperidone was reported. However, few reports have so far addressed QT prolongation associated with the use of risperidone or its major active metabolite, which is also used as a separate antipsychotic drug, paliperidone. Methods The present study evaluated associations between risperidone metabolism and QT interval in 61 psychiatric patients who had been receiving risperidone for ≥4 weeks at an average dosage of 4.7 mg/day. Plasma risperidone and paliperidone levels were measured and electrocardiographic measurements were also obtained. Results There was no correlation between risperidone dosage and QTc or plasma risperidone levels and QTc. However, there was a significant positive correlation between plasma paliperidone levels and QTc (r = 0.361; p = 0.004). There was no correlation between age and dose-corrected plasma risperidone levels or between age and QTc. There was a significant positive correlation between age and dose-corrected plasma paliperidone levels (r = 0.290; p = 0.023). Conclusion Clinically, paliperidone is considered to play a more important role in QT prolongation than risperidone. Copyright © 2011 John Wiley & Sons, Ltd.

Background. Hyponatremia (HN) is relatively common in adults with congenital heart disease and is a powerful predictor of mortality. However, the precise relationship of HN to the Fontan pathophysiology remains unknown. Purpose. Our study aimed to clarify the association of HN to the Fontan pathophysiology. Methods and Results. We measured the plasma sodium (Na) level in 169 consecutive Fontan patients (78 children) and HN (≤137 mEq/L) was observed in 50 patients (30% of the total patients, 31% of the children). The HN patients showed a lower peak oxygen uptake (VO2) with a greater New York Heart Association class (P < .0001). The plasma level of norepinephrine (NE), rennin activity (PRA), arginine vasopressin, central venous pressure (CVP) and medications were associated with the Na levels and the NE, PRA, and diuretic use were the independent determinants (P < .01−.0001). The plasma B-type natriuretic peptide was not correlated with the Na levels. In the children, diuretic use and the PRA independently determined the Na levels without any association to the CVP or peak VO2. During a median follow-up of 2.1 years, the HN in addition to the CVP and peak VO2 independently predicted the unscheduled hospitalizations in all patients, while the HN was the only independent predictor of the hospitalizations in the adult patients (hazard ratio: 3.1, 95% confidence interval 1.2–8.0, P= .021). Conclusions. Child and adult Fontan patients exhibited a high prevalence for HN that closely reflected some neurohumoral activation and predicted adverse clinical events, especially in adult Fontan patients.

We investigated the association between remission of depressive symptoms in fluvoxamine treatment and catechol- O -methyltransferase (COMT) gene. Sixteen SNPs in the COMT gene were investigated in 123 outpatients with major depression. Three single nucleotide polymorphisms located in the 5′ region were associated with remission in fluvoxamine-treated outpatients with moderate to severe depression.

The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype–phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e.g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups ( p 2) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only ( p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.

Performing magnetic resonance imaging (MRI) in patients with a metallic implant raises concern over the potential complications, including susceptibility artifacts, implant migration, and heat injury. The purpose of this study was to investigate these complications in dogs with implanted microchips by evaluating MR images and the histopathological changes after 1.5 Tesla (T) MRI. Five dogs underwent microchip implantation in the cervicothoracic area. One month later, the area was imaged using 1.5T MRI in three dogs. The microchips were removed surgically together with the surrounding tissue in all dogs. There was significant signal loss and image distortion over a wide range around the area where the microchip was implanted. This change was consistent with susceptibility artifacts, which rendered the affected area including the spinal cord undiagnostic. The artifact was more extensive in T2*-weighted images (gradient-echo) and less extensive in proton density-weighted images (fast spin-echo with short echo time). Histopathologically, all microchips were well-encapsulated with granulation tissue, and there were no evidence of migration of microchips. Cell debris and a moderate number of degenerated cells with fibrin were seen in the inner layer of the granulation tissue in each dog that underwent MRI. These changes were very subtle and did not seem to be clinically significant. The results of this study suggest that, in 1.5T MRI, susceptibility artifacts produced by implanted microchips can be marked, although the dogs with implants appeared to be scanned safely.

Several studies have reported that the cytochrome P450 (CYP) 2D6 plays an important role in the fluvoxamine metabolism. However, some other studies have reported that the CYP2D6 genotype has no major impact on the fluvoxamine concentration. This study investigated the dose-dependent effect of CYP2D6-variant alleles on the steady-state fluvoxamine concentration. There were 23 patients whose plasma concentrations of fluvoxamine were measured at 4 doses (50, 100, 150, and 200 mg/d). The differences in the plasma fluvoxamine concentration were analyzed between 2 genotype groups divided by the number of CYP2D6-variant alleles (with 0 and 1 or 2 variant alleles). The results demonstrated the nonlinear kinetics of fluvoxamine metabolism, and the degree of nonlinear kinetics decreased as the dose was increased. Significant differences in fluvoxamine concentration were observed between the subjects with 0 variant alleles and the subjects with 1 or 2 variant alleles (P = 0.044) when they were treated by 50 mg of fluvoxamine. There were no significant differences in the plasma concentration of fluvoxamine at 100, 150, and 200 mg/d. The present study suggests that the effect of the CYP2D6 genotype on fluvoxamine metabolism is greater at lower doses of fluvoxamine.

Diphenyl (α-aminoalkyl)phosphonates act as mechanism-based inhibitors against serine proteases by forming a covalent bond with the hydroxy group of the active center Ser residue. Because the covalent bond was found to be broken and replaced by 2-pyridinaldoxime methiodide (2PAM), we employed a peptidyl derivative bearing diphenyl 1-amino-2-phenylethylphosphonate moiety (Phe(p) (OPh)2 ) to target the active site of chymotrypsin and to selectively anchor to Lys175 in the vicinity of the active site. Previously, it was reported that the configuration of the α-carbon of phosphorus in diphenyl (α-aminoalkyl)phosphonates affects the inactivation reaction of serine proteases, i.e., the (R)-enantiomeric diphenyl phosphonate is comparable to l-amino acids and it effectively reacts with serine proteases, whereas the (S)-enantiomeric form does not. In this study, we evaluated the stereochemical effect of the phosphonate moiety on the selective chemical modification. Epimeric dipeptidyl derivatives, Ala-(R or S)-Phe(p) (OPh)2 , were prepared by separation with RP-HPLC. A tripeptidyl (R)-epimer (Ala-Ala-(R)-Phe(p) (OPh)2 ) exhibited a more potent inactivation ability against chymotrypsin than the (S)-epimer. The enzyme inactivated by the (R)-epimer was more effectively reactivated with 2PAM than the enzyme inactivated by the (S)-epimer. Finally, N-succinimidyl (NHS) active ester derivatives, NHS-Suc-Ala-Ala- (R or S)-Phe(p) (OPh)2 , were prepared, and we evaluated their action when modifying Lys175 in chymotrypsin. We demonstrated that the epimeric NHS derivative that possessed the diphenyl phosphonate moiety with the (R)-configuration effectively modified Lys175 in chymotrypsin, whereas that with the (S)-configuration did not. These results demonstrate the utility of peptidyl derivatives that bear an optically active diphenyl phosphonate moiety as affinity labeling probes in protein bioconjugation. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 521-530, 2016.

This study aimed to clarify whether there is an association between ventricular sympathetic nervous activity (SNA) and clinically relevant ventricular arrhythmia (a run of ≥ 3 consecutive ventricular beats, RVA) in postoperative patients with tetralogy of Fallot (TOF). We performed a retrospective study in a national referral center of pediatric cardiology in Japan. Twenty-four postoperative TOF patients (13 males, median age 17 years) undergoing myocardial (123)I metaiodobenzylguanidine (MIBG) scintigraphy were included. We measured the heart-to-mediastinum ratio (HMR) and washout ratio (WR) from planar MIBG myocardial scintigraphy. Tomographic images and polar maps were generated with 20 segments. The standard deviation of percentage uptake of 20 segments (SD-uptake) as an index of heterogeneous MIBG uptake to the ventricular myocardium was calculated. We compared these MIBG-derived variables with the patients' clinical profiles, including ECG findings and hemodynamics. Eight of 24 patients had RVA (RVA group), and the other 16 did not have RVA (non-RVA group). There were no significant differences in the HMR (1.9 ± 0.5 vs. 2.2 ± 0.4) and WR (50 ± 5 vs. 42 ± 10) between the two groups. SD-uptake was significantly higher in the RVA group than in the non-RVA group (15 ± 3 vs. 12 ± 3, p = 0.03). QT dispersion (ms) was also higher in the RVA group than in the non-RVA group (53 ± 23 vs. 44 ± 18, p = 0.04). Multivariate logistic regression showed that SD-uptake and QT dispersion were independent predictors in the RVA group (p = 0.02, p = 0.03). In addition to greater QT dispersion, heterogeneous SNA is associated with RVA in TOF patients postoperatively.

For site-selective chemical modification in the vicinity of the active site of chymotrypsin (Csin), a peptide derivative 1 bearing a diphenyl 1-amino-2-phenylethylphosphonate moiety for targeting t...

Serine proteases are typically synthesized as proteolytically inactive zymogens that often become activated in a limited and highly localized manner. Consequently, determination of the spatial and temporal activation pattern of these molecules is of great importance to understanding the biological processes that they mediate. Until only recently, the tools to conveniently address the question of where and when serine proteases are active within complex tissues have been lacking. In order to detect spatially restricted serine protease activities in Drosophila embryos and ovaries we introduce a technique using fluorescent synthetic and protein-based inhibitors. With this approach we have detected a novel serine protease activity with a relative mobility of 37 kDa, localized to the surface of pole cells, the germ-line precursors, in embryos between nuclear cycles 11 and 14 in development. A second novel cell-specific protease activity was localized to the tissues of early gastrulating embryos. Microinjection of inhibitors into the perivitelline space of stage 2 embryos perturbed normal embryonic development. Fluorescein-conjugated chymotrypsin inhibitor and Bowman-Birk inhibitor labeled protease activity localized to the oocyte-somatic follicle cell interface of the developing egg chamber. Our results suggest that this technique holds promise to identify new spatially restricted activities in adult Drosophila tissues and developing embryos.

To assess the polyhydroxyalkanoate (PHA)-biodegrading capacity of soil, numbers of aerobic poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/V)-degrading microorganisms (degraders) were estimated by the film-MPN method. The numbers of PHB/V degraders were estimated to be 4.3 × 105 per gram of dry garden soil, 5.06 × 105 per gram of dry paddy-field soil, and 3.87 × 105 per gram of dry river-bank soil. The degradations of PHB/V in suspensions of the three kinds of soil were investigated. It was found that the PHB/V-biodegrading capacity of the soil increased as the number of PHB/V degraders in the soil increased. The relationship between weight loss of PHB/V and proliferation rate of PHB/V degraders in garden soil suspension was investigated. The effect of glucose on the biodegradation of PHB/V in garden soil was also studied. The weight loss after one week in garden soil suspension supplemented with 20 mM of glucose (GSS-20G) was 2.60%, which was lower than that in garden soil suspension (GSS) (7.14%). After five weeks, the weight loss had increased to 24.97% in GSS-20G but only to 18.26% in GSS. The results showed that glucose played important roles in inhibition and acceleration of different biodegrading phases and finally accelerated the PHB/V biodegradation in soil suspension. Copyright © 2003 John Wiley & Sons, Ltd.