Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.

Pulmonary arterial hypertension (PAH) is a rare but serious disease with a grave prognosis. Bone morphogenetic protein type 2 receptor (BMPR2) gene is a strong pathogenic factor for PAH. As a collaborative team from Kyorin University and Keio University in Japan, we have analyzed the BMPR2 gene in 356 probands and more than 50 family members, including secondary patients. Importantly, the study population is a racially, ethnically, and socially homogeneous population. In PAH patients, there is a high incidence of unique mutations in BMPR2, and several mutations are frequently observed in the Japanese population, suggesting that these common and recurring mutations may be highly pathogenic or have high penetrance, explaining why they are found frequently throughout the world. We have also mapped each breakpoint of exonic deletions/duplications and found that most break and rejoining points are in the Alu elements. Reviewing the distribution of the reported mutations on each exon of BMPR2 revealed that the number and frequency of mutations are imbalanced among exons. The penetrance of BMPR2 gene mutations was 3-fold higher in females than males. Full elucidation of BMPR2-mediated pathogenic mechanisms in PAH requires persistent efforts to achieve precision or individualized medicine as a therapeutic strategy for PAH.

Effects of Acupuncture on Anxiety Levels and Prefrontal Cortex Activity Measured by Near-Infrared Spectroscopy: A Pilot Study.

There is increasing evidence that acupuncture is useful in treating somatic and psychological disorders caused by stress; however, the physiological basis of the effect remains unclear. In the present study, we evaluated the effect of acupuncture on psychological conditions (i.e., anxiety) and prefrontal cortex (PFC) activity. We studied 10 patients with anxiety disorders and measured anxiety levels by means of the State-Trait Anxiety Inventory (STAI), including state anxiety (STAI-1) and trait anxiety (STAI-2). Employing a two-channel NIRS device, we measured oxy-Hb concentration in the bilateral PFC at rest, and evaluated asymmetry of the PFC activity by calculating the Laterality Index at Rest (LIR). The patients were treated by acupuncture at Yui Clinic in Osaka. The treatment significantly decreased the STAI-1 score (p<0.001), but not the STAI-2 score (p>0.05). The NIRS measurements indicated the presence of spontaneous oscillations of oxy-Hb in the bilateral PFC at rest before and after the treatment. Notably LIR decreased significantly in 7 out of the 10 subjects (p<0.01), while 3 subjects showed an increasing tendency. The present pilot study indicates that acupuncture is effective in decreasing anxiety levels in patients with anxiety disorders. Our NIRS data suggest that acupuncture may alter the balance of PFC activity at rest, resulting in relaxation effects. Our NIRS data suggest that acupuncture changes the balance of PFC activity toward left-dominant, resulting in relaxation effects on the patients.

Pressure-induced valence crossover and novel metamagnetic behavior near the antiferromagnetic quantum phase transition of YbNi_{3}Ga_{9}.

We report electrical resistivity, ac magnetic susceptibility, and x-ray absorption spectroscopy measurements of intermediate valence YbNi_{3}Ga_{9} under pressure and magnetic field. We have revealed a characteristic pressure-induced Yb valence crossover within the temperature-pressure phase diagram, and a first-order metamagnetic transition is found below P_{c}∼9 GPa where the system undergoes a pressure-induced antiferromagnetic transition. As a possible origin of the metamagnetic behavior, a critical valence fluctuation emerging near the critical point of the first-order valence transition is discussed on the basis of the temperature-field-pressure phase diagram.

Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway.

Helicobacter pylori (H. pylori) produces vacuolating cytotoxin (VacA), a potent protein toxin, which is associated with gastric inflammation and ulceration. Recent studies demonstrated that connexins (Cxs), which are responsible for intracellular communication at gap junctions (GJs) as well as cell homeostasis, participate in VacA-induced cell death. We now demonstrate in AZ-521 cells that VacA increased cytoplasmic Cx43, accompanied by LC3-II generation in a time- and dose-dependent manner without induction of Cx43 mRNA expression. Inhibition of VacA-induced Rac1 activity prevented ERK phosphorylation and the increase in Cx43. Suppression of ERK activity and addition of N-acetyl-cysteine inhibited VacA-dependent increase in Cx43 and LC3-II. DIDS, an anion-selective inhibitor, suppressed VacA-dependent increase in Cx43, suggesting that VacA channel activity was involved in this pathway. By confocal microscopy, Cx43 increased by VacA was predominately localized in cholesterol-rich, detergent-resistant membranes including GJs, and a fraction of Cx43 was incorporated in endocytotic vesicles and autophagolysosomes. Accumulation of Cx43 was also observed in gastric mucosa from H. pylori-infected patients compared with healthy controls, suggesting that the pathogen caused a similar effect in vivo. Our findings show that VacA-mediated effects on autophagy inhibits turnover of Cx43, resulting in increased levels in the cytoplasm, leading eventually to apoptotic cell death.

Treatment referral system for tuberculosis patients in Dhaka, Bangladesh.

OBJECTIVE: To evaluate the referral system in an urban DOTS-based programme in Dhaka, Bangladesh, including the peri-urban area, and to identify opportunities to strengthen the system. DESIGN: This was a retrospective cohort study in which diagnosed tuberculosis (TB) patients and health providers from DOTS centres were interviewed. Research tools included pre-tested structured questionnaires and the TB patients' referral records. RESULTS: Of 4974 TB patients who were referred to the different treatment centres, only 1756 (35%) of the counterfoils of the referral slips were returned. Of 250 patients randomly selected for interview, 165 reported to a DOTS centre, 69 did not and 16 could not be traced. Variations in educational qualification, residence and the identification of DOTS centres after counselling were statistically significant (P < 0.05). Lower monthly income (RR = 7.84, RR = 5.03), distance from the centre (RR = 36.21) and those receiving treatment from pharmacies (RR = 3) or non-governmental organisations (RR = 28.48) have more risk of irregular treatment. CONCLUSION: A high proportion of referred patients were registered and initiated treatment, but many did not report to the referral treatment centre. Proper counselling and taking into account the patients' preferences during referral are essential to address access barriers to treatment adherence and improved treatment outcome.

Objectif : Evaluer le système de référence dans les programmes de DOTS urbains dans la ville de Dhaka, Bangladesh, et sa banlieue et à identifier les opportunités de renforcer ce système.Schéma : Une étude rétrospective de cohorte a interviewé les patients ayant eu un diagnostic de TB et les prestataires de soins des centres de diagnostic et de traitement (DOTS). Les outils de recherche ont inclus des questionnaires structurés pré testés et de registres de référence de patients TB.Résultats : Un total de 4974 patients TB a été référé aux différents centres de traitement. Seulement 1756 (35%) des fiches de référence des homologues ont été retournées. Parmi eux, 250 patients ont été sélectionnés au hasard pour un entretien. Parmi eux, 165 patients sont allés dans les centres DOTS, 69 n'y sont pas allés et 16 n'ont pas pu être retrouvés. On a découvert des variations statistiquement significatives en matière de niveau d'instruction, de lieu de résidence et d'identification du centre DOTS après conseil (P < 0,05). Les personnes ayant un revenu mensuel plus faible (RR = 7,84 ; RR = 5,03), la distance par rapport au centre (RR = 36,21) et prenant leur traitement dans une pharmacie et divers autres lieux ont eu un risque plus élevé (RR = 3 ; RR = 28,48) de prendre un traitement irrégulier.Conclusion : Un bon nombre de patients référés ont été enregistrés et ont mis en route le traitement mais ne sont pas retournés au centre de traitement indiqué. Un conseil adapté et le fait de tenir compte des préférences du patient pendant la référence sont essentiels pour répondre aux contraintes d'accès, pour l'adhésion au traitement et pour un meilleur résultat du traitement.

Objetivo: Evaluar el sistema de remisiones en el marco de la estrategia DOTS y reconocer las oportunidades que existen de fortalecer el sistema y se llevó a cabo en la ciudad de Dhaka, Bangladesh, incluida su zona periurbana.Método: Fue este un estudio retrospectivo de cohortes, en el cual se administraron entrevistas a los pacientes con diagnóstico de tuberculosis (TB) y a los trabajadores de salud de los centros DOTS de diagnóstico y tratamiento. Los instrumentos de la investigación consistieron en cuestionarios estructurados y registros de las remisiones de los pacientes con TB.Resultados: Se remitieron 4974 pacientes con diagnóstico de TB a los diferentes centros de tratamiento. Solo se recibieron 1756 notificaciones de contrarreferencia en los centros de origen (35%). De estos pacientes se escogieron de manera aleatoria 250 para las entrevistas. De los pacientes escogidos, 165 se habían registrado en el centro DOTS, 69 no se presentaron y fue imposible localizar a 16 de los pacientes. Los factores significativos que determinaron estas diferencias fueron el grado de instrucción, el lugar de residencia y la capacidad de seguir las instrucciones para localizar el centro DOTS (P < 0,05). Se observó que el riesgo de irregularidad en cumplimiento terapéutico se asoció con un ingreso mensual más bajo (hasta 10 000 takas, riesgo relativo [RR] = 7,84; de 10 000 takas a 20 000 takas, RR = 5,03), el hecho de vivir a una distancia mayor del centro DOTS (RR = 36,21) y de haber recibido el tratamiento en una farmacia (RR = 3) o en centros diferentes a los designados (RR = 28,48).Conclusión: Un buen número de pacientes remitidos se registró e inició el tratamiento antituberculoso, pero muchos no acudieron al centro específico DOTS. Es primordial ofrecer una orientación adecuada y tener en cuenta las preferencias del paciente durante la remisión, a fin de superar los obstáculos que existen al cumplimiento del tratamiento y obtener mejores resultados terapéuticos.

Three-dimensional characterization of BaHfO3 precipitates in GdBa2Cu3O7-y flim using STEM tomography.

IntroductionSince the discovery of REBa2Cu3O7-y (RE: Rare Earth element, REBCO) superconductors, they have been expected as the best candidates for the power cable application due to its high critical temperature (Tc) and critical current density (Jc). Among those REBCO superconductors, GdBa2Cu3O7-y (GdBCO) have been receiving great interest because they have higher Tc and Jc than YBa2Cu3O7-y [1].GdBCO with various types of precipitates as artificial pinning centers (APCs) have been proposed to minimize the anisotropy of Jc characteristics under the magnetic field. Among those precipitates, BaHfO3 (BHO) was found most effective precipitates as APCs in GdBCO film prepared by pulsed laser deposition (PLD) method [2]. It is therefore necessary to investigate not only the morphologies but also the dispersion of BHO precipitates within the GdBCO, to understand the role of BHO for the superconducting characteristics. In this study, morphologies and dispersions of BHO precipitates were characterized three-dimensional by scanning transmission electron tomography ExperimentalBHO dispersed GdBCO films were fabricated on Hastelloy C-276TM substrates with buffer layers of CeO2/LaMnO3/MgO/ Gd2ZrO7 by PLD method.To observe microstructure of GdBCO film with BHO precipitates, cross-section TEM specimens were prepared by FIB method using Quanta 3D-200 (FEI, USA) with acceleration voltage from 2 to 30 kV. Three-dimensional information such as morphology and dispersion, of BHO precipitates were characterized by electron tomography using STEM-HAADF. Result and discussionFigure 1 shows three-dimensional reconstructed volume of BHO precipitates in GdBCO, which revealed that fine BHO precipitates have rod- and plate-like morphologies with homogeneous dispersion in GdBCO. In addition, growth directions of these precipitates were found with wide angular distributions from growth direction of GdBCO. Anisotropy of Jc in the magnetic fields was probably enhanced by various growth directions and homogeneous dispersion of nanosized BHO within GdBCO.jmicro;63/suppl_1/i26/DFU080F1F1DFU080F1Fig. 1.Three-dimensional reconstructed volume of BHO.

Integrated-fin gasket for palm cubic-anvil high pressure apparatus.

We described an integrated-fin gasket technique for the palm cubic-anvil apparatus specialized for the high-pressure and low-temperature measurements. By using such a gasket made from the semi-sintered MgO ceramics and the tungsten-carbide anvils of 2.5 mm square top, we successfully generate pressures over 16 GPa at both room and cryogenic temperatures down to 0.5 K. We observed a pressure self-increment for this specific configuration and further characterized the thermally induced pressure variation by monitoring the antiferromagnetic transition temperature of chromium up to 12 GPa. In addition to enlarge the pressure capacity, such a modified gasket also improves greatly the surviving rate of electrical leads hanging the sample inside a Teflon capsule filled with the liquid pressure-transmitting medium. These improvements should be attributed to the reduced extrusion of gasket materials during the initial compression.

Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model.

Iron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous iron [Fe(II)], but not to labile ferric iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an iron chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10-35 mg iron/kg Fe-NTA, which was dose-dependent, according to semiquantitative analysis. The RhoNox-1 signal colocalized with the generation of hydroxyl radicals, as detected by hydroxyphenyl fluorescein (HPF). The results demonstrate the transformation of Fe(III)-NTA to Fe(II) in vivo in the Fe-NTA-induced renal carcinogenesis model. Therefore, this probe would be useful for localizing catalytic Fe(II) in studies using tissues.

The effect of phosphatidylserine administration on memory and symptoms of attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of childhood, affecting 3-5% of school-age children. The present study investigated whether the supplementation of soy-derived phosphatidylserine (PS), a naturally occurring phospholipid, improves ADHD symptoms in children. METHODS: Thirty six children, aged 4-14 years, who had not previously received any drug treatment related to ADHD, received placebo (n = 17) or 200 mg day(-1) PS (n = 19) for 2 months in a randomised, double-blind manner. Main outcome measures included: (i) ADHD symptoms based on DSM-IV-TR; (ii) short-term auditory memory and working memory using the Digit Span Test of the Wechsler Intelligence Scale for Children; and (iii) mental performance to visual stimuli (GO/NO GO task). RESULTS: PS supplementation resulted in significant improvements in: (i) ADHD (P < 0.01), AD (P < 0.01) and HD (P < 0.01); (ii) short-term auditory memory (P < 0.05); and (iii) inattention (differentiation and reverse differentiation, P < 0.05) and inattention and impulsivity (P < 0.05). No significant differences were observed in other measurements and in the placebo group. PS was well-tolerated and showed no adverse effects. CONCLUSIONS: PS significantly improved ADHD symptoms and short-term auditory memory in children. PS supplementation might be a safe and natural nutritional strategy for improving mental performance in young children suffering from ADHD.

Microstructural characterization of TFA-MOD processed Y(1-x)Gd(x)Ba2Cu3O(7-y) with BaZrO3.

Y(1-x)Gd(x)Ba2Cu3O(7-y) with BaZrO3 film was fabricated on CeO2 buffered LaMnO3/ion beam assisted deposition-MgO/Gd2Zr2O7/Hastelloy C276TM substrates by the metal organic deposition process using trifluoroacetates. Both microstructural and analytical characterizations were performed by transmission electron microscopy with selected area electron diffraction method and energy dispersive X-ray spectroscopy. The thickness of Y(1-x)Gd(x)Ba2Cu3O(7-y) with BaZrO3 film was found approximately 700 nm and the film was composed of c-axis oriented Y(1-x)Gd(x)Ba2Cu3O(7-y) grains. Several types of particles, (Y,Gd)2Cu2O5, CuO and BaZrO3, were formed within the Y(1-x)Gd(x)Ba2Cu3O(7-y) film, whose sizes were about 100-200 nm for (Y,Gd)2Cu2O5 and CuO particles, and about 10-20 nm for BaZrO3 particles, respectively. In the Y(1-x)Gd(x)Ba2Cu3O(7-y) film, (Y,Gd)2Cu2O5 and CuO particles were dispersed heterogeneously, whereas BaZrO3 nanoparticles were found dispersed homogeneously with random orientation. In addition, electron tomographic observation was carried out to attain the three-dimensional information of polyhedral BaZrO3 nanoparticles.

Paraumbilical peritoneal incision using the little finger in shunt operations for hydrocephalus: technical note.

INTRODUCTION: The shunt operation remains the standard procedure for the treatment of hydrocephalus. We describe a simple minilaparotomy method that involves perforation of the peritoneum with the surgeon's little finger. TECHNIQUE: After placing a small paraumbilical incision at the skin and fascia, the little finger is introduced through the incision to perforate the pre-peritoneal fat and peritoneum. The finger should be inserted at a 30-45° angle to the horizontal plane to avoid injuring the underlying viscera and major blood vessels and to put sufficient shear force on the peritoneum. A catheter is inserted into the abdominal cavity after visual confirmation of proper perforation. CONCLUSION: As the paraumbilical wound is not noticeable postoperatively due to the presence of the natural umbilical skin fold, this method yields a cosmetically appealing result.

Characterization of oxide scales thermally formed on single-crystal silicon carbide.

Microstructures of oxide scales thermally formed on single-crystal silicon carbide were investigated using transmission electron microscopy. The oxide scales were formed on the Si-face of 6H-SiC at 1273-1473 K in dry oxygen. Spherical patterns were observed on the surfaces of the oxidized samples by an optical microscope in some regions. In these regions, cross-sectional transmission electron microscopy (TEM) observations show that the oxide scale was divided into two layers; the upper layer (surface side) was composed of crystalline silica, and the lower layer on the silicon carbide substrate was amorphous silica, while the oxide scales in the surroundings of the patterns were composed of only amorphous silica. The oxidation activation energy in the amorphous silica layer of the Si-face of 6H-SiC was found to be 408 kJ/mol by the evolution of thickness directly measured from the cross-sectional scanning electron microscopy and TEM images.

Desorption of cluster ions from solid Ne by low-energy ion impact.

We investigated Ne(+) ions and Ne(n)(+) (n = 2-20) cluster ions desorbed from the surface of solid Ne by 1.0 keV Ar(+) ion impact. Kinetic energy analysis shows a considerably narrower energy distribution for Ne(n)(+) (n ≥ 3) ions than for Ne(n)(+) (n = 1, 2) ions. The dependence of ion yields on Ne film thickness indicates that cluster ions (n ≥ 3) are desorbed only from relatively thick films. We conclude that desorbed ions grow into large cluster ions during the outflow of deep bulk atoms to the vacuum.

Potential sputtering of ionic species from rare gas solids by multiply charged ion impact.

The interaction of low-energy multiply charged Ar(q +) (q ≤ 7) ions with a solid Ne surface is experimentally studied. Desorption of very large cluster ions Nen (+) (n > 100) is observed. The size distribution of smaller (n = 1-3) cluster ions depends strongly on the charge state of the incident ion, whereas that of larger (n > 7) cluster ions exhibits no dependence on the charge state, indicating that desorption of large cluster ions is due to kinetic sputtering. The potential sputtering yield is estimated by analyzing the size distribution of the desorbed cluster ions. The results suggest that the ion desorption mechanism, which is known as desorption induced by electronic transitions, can also be applied to explain the present results.

Plasma hormone and metabolite concentrations involved in the somatotropic axis of Japanese Black heifers in association with growth hormone gene polymorphism.

Bovine growth hormone (bGH) gene polymorphism of leucine (Leu)-threonine (Thr) (allele A), valine (Val)-Thr (allele B), and Val-methionine (Met) (allele C) at codons 127 and 172 was shown to relate with carcass trait variations in Japanese Black cattle. In this study, 10-mo-old Japanese Black heifers with growth hormone (GH) genotypes AA, AB, BB, AC, BC, and CC (N=141) were compared for basal GH, insulin-like growth factor-1 (IGF-1), insulin, ghrelin, glucose, and nonesterified fatty acid (NEFA) concentrations. Growth hormone release was also measured as response to growth hormone-releasing hormone (GHRH) (0.4 microg/kg body weight [BW]) using 18 heifers with GH genotypes AA, BB, and CC (n=6 for each group). The genotype AA heifers showed the greatest BW among genotypes (P<0.05). Genotype AC, BC, and CC heifers showed greater GH concentrations than genotype AA, AB, or BB heifers, in which genotype CC heifers had the highest concentrations (P<0.05). However, IGF-1 concentrations did not significantly differ. The genotype AA and BB heifers had a greater GH release at 60 min following GHRH injection than did the genotype CC heifers. The area under the curve (AUC; P<0.07) and incremental area (IA; P<0.08) of GH responses to the GHRH challenge tended to be the highest in the genotype AA heifers and the lowest in the genotype CC heifers. In conclusion, GH gene polymorphism altered GH, which may have contributed to differences in BW and carcass traits among genotypes.

[Patent foramen ovale presented hypoxemia with cardiac sarcoidosis].

A 53-year-old woman with a double, double, double (DDD) pacemaker due to complete atrioventricular block was admitted to our hospital with a diagnosis of congestive heart failure. At the time of admission, she was in a hypoxic state with cyanosis and clubbed finger. The ultrasonic cardiogram showed a severe degree of tricuspid valve regurgitation and a thin left ventricular septal wall. Transesophageal echocardiography revealed a patent foramen ovale (PFO) with continuous right to left shunt flow. She was diagnosed with cardiac sarcoidosis with hypoxemia caused by PFO. PFO closure and tricuspid valve annuloplasty (DeVega method) were performed. Following surgery, the patient's hypoxemia improved and the cyanosis disappeared. The patient was discharged 37 days after the operation.

Lipid content and fatty acid composition of the monogenean Neobenedenia girellae and comparison between the parasite and host fish species.

Neobenedenia girellae, a capsalid monogenean, is a destructive fish parasite. We studied the lipid content and fatty acid composition of N. girellae and the skin and cutaneous mucus of a host fish, the amberjack Seriola dumerili (Carangidae). The lipid content of adult N. girellae was less than one-fourth that of both the skin and cutaneous mucus of its host. Adult N. girellae, S. dumerili skin and mucus had a relatively high weight-percentage of C16:0, C18:1(n-9), C18:0 and C22:6(n-3) fatty acids. When S. dumerili were fed a diet supplemented with [13C] fatty acids, [13C] fatty acids were detected in S. dumerili skin and adult N. girellae on S. dumerili, but no [13C] fatty acids were detected in the S. dumerili cutaneous mucus. In addition, the epidermis of S. dumerili, attached with N. girellae, was markedly thin. These results suggest that N. girellae feeds primarily on host epithelial cells. We then infected 2 host fishes, S. dumerili and the spotted halibut Verasper variegatus (Pleuronectidae; a host less susceptible to N. girellae infection), and compared the fatty acid composition of N. girellae with that of the skin and cutaneous mucus of the hosts. The fatty acid profiles from all samples were qualitatively and quantitatively similar. Thus, the fatty acid composition of the host may not contribute to the difference in susceptibility between S. dumerili and V. variegatus. These results may serve to develop new strategies for the control of N. girellae infections.