Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension

Since the discovery of nitric oxide (NO) as a physiological substance produced in the endothelium, the impairment of endothelial NO production and reactivity of the pulmonary vasculature to NO have been described in animal models and patients with pulmonary hypertension (PH). The NO synthase-NO-cyclic guanosine monophosphate (cGMP) pathway is impaired in pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease (PVOD), pulmonary capillary hemangiomatosis (PCH), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Pioneering clinicians conceived that NO can be administered to the lung by inhalation and used this strategy to treat PH in humans and acute hypoxic PH in animal models. Inhaled NO (iNO) selectively decreases pulmonary arterial pressure with no changes in systemic arterial pressure. When iNO diffuses into the blood, it is converted to NO3−, thereby losing its vasodilatory effects. NO might then be recycled in hypoxic remote organs, where NO3− and NO2− are reduced to NO. In the present chapter, the metabolic fate of iNO, based on previous air pollution research in Japan, is discussed. Then, we describe recent clinical applications of iNO in pediatric patients with various diseases, including bronchopulmonary dysplasia (BPD), persistent PH of neonates, and congenital diaphragmatic hernia (CDH). We also summarize the role of iNO in the catheterization lab, including acute vasoreactivity testing to assess prognosis, indications for specific PH therapy, and operability of congenital heart disease

Aharonov-Bohm Exciton Absorption Splitting in Chiral Specific Single-Walled Carbon Nanotubes in Magnetic Fields of up to 78 T

The Ajiki-Ando (A-A) splitting of single-walled carbon nanotubes(SWNT) originating from the Aharanov-Bohm effect was observed in chiral specific SWNTs by the magneto-absorption measurements conducted at magnetic fields of up to 78 T. The absorption spectra from each chirality showed clear A-A splitting of the $E_{11}$ optical excitonic transitions. The parameters of both the dark-bright exciton energy splitting and the rate of A-A splitting in a magnetic field were determined for the first time from the well-resolved absorption spectra.Comment: 5 pages, 3 figure

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient

BACKGROUND: Spinocerebellar ataxias (SCAs) are heterogeneous diseases characterized by progressive cerebellar ataxia associated with dysarthria, oculomotor abnormalities, and mental impairment. To identify the causative gene, we performed exome sequencing on a Japanese patient clinically diagnosed with recessive SCA. METHOD: The patient is a 37-year-old Japanese woman with consanguineous parents. The head magnetic resonance imaging (MRI) showed cerebellar atrophy and T1 low/T2 high intensity at the bilateral inferior olives. Single-nucleotide polymorphism (SNP) genotyping and next-generation sequencing were performed, and the variants obtained were filtered and prioritized. RESULTS: After these manipulations, we identified a homozygous nonsense mutation of the TTC19 gene (p.Q277*). TTC19 has been reported to be a causative gene of a neurodegenerative disease in Italian and Portuguese families and to be involved in the pathogenesis of mitochondrial respiratory chain complex III (cIII) deficiency. This report is the first description of a TTC19 mutation in an Asian population. Clinical symptoms and neuroimaging are consistent with previous reports. The head MRI already showed abnormal features four years before her blood lactate and pyruvate levels were elevated. CONCLUSIONS: We should consider the genetic analysis of TTC19 when we observe such characteristic MRI abnormalities. Genes associated with mitochondrial function cause many types of SCAs; the mutation we identified should help to elucidate the pathology of these disorders

Analysis on the Susceptibility Genes in Two Chinese Pedigrees with Familial Parkinson's Disease

Objective. To screen the susceptibility genes in Chinese pedigrees with early-onset familial Parkinson's disease (FPD). Methods. Fifty-one genomic DNA samples extracted from two Chinese pedigrees with FPD, the alpha-synuclein genes (SNCA), the leucine-rich repeat kinase 2(LRRK2), PINK1(PTEN-induced putative kinase 1), PARK7(Protein DJ1), PARK2(Parkinson juvenile disease protein 2), the glucocerebrosidase (GBA), and ATP(Ezrin-binding protein PACE-1), were sequenced by the use of polymerase chain reaction (PCR) technique. The gene dose of SNCA was checked. Results. There were only two missense mutations observed, respectively, at exon 5 of LRRK2 and exon 10 of PARK2, and both were enrolled in SNPs. Conclusion. No meaningful mutations could be detected, and other susceptibility genes should be detected in FDP patients in China

The Effect of a Portable Electrical Muscle Stimulation Device at Home on Muscle Strength and Activation Patterns in Locomotive Syndrome Patients: A Randomized Control Trial

The aim of the present study was to quantify the effect of electrical muscle stimulation (EMS) intervention using a portable device on muscle strength and activation patterns in locomotive syndrome. Nineteen women were randomly assigned to the intervention group (n = 10; age = 71–82 years) and control group (n = 9; age = 70–84 years). Participants in the intervention group used a portable EMS device to stimulate the bilateral quadriceps muscles for 8 weeks (23 min/5 days/week). To understand the effects of EMS, the following measurements were made at baseline, 8 weeks, and 12 weeks: locomotive syndrome assessment score, knee extensor strength, vastus lateralis muscle activation patterns during a maximal isometric knee extension contraction using multi-channel surface electromyography, and muscle thickness. The locomotive syndrome assessment, muscle strength, muscle thickness, and muscle activity patterns in the intervention group were significantly different to control after 8 weeks (p \u3c 0.05). However, these results were not sustained at 12 weeks. EMS increased locomotor assessment scores, which were accompanied by enhanced muscle strength, increased muscle thickness, and changes in muscle activation patterns in locomotive syndrome patients. These results suggest that EMS is potentially useful for improving muscle neural activation and force output in locomotive syndrome

Laterality of the Activation of the Vastus Lateralis Muscle in Females with Parkinson\u27s Disease during the Medication State Compared with Healthy Controls

This study quantified the laterality of motor unit activation properties in females with Parkinson’s disease during force production (low to high-intensity contraction) using high-density surface electromyography. Sixteen females with Parkinson’s disease (age = ± 7.6 years, disease duration = 4.9 ± 5.1 years) and 14 healthy female subjects (age = 68.6 ± 3.6 years) performed submaximal ramp-up contractions during isometric knee extension. High-density surface electromyography signals were recorded from both vastus lateralis muscles. The level of heterogeneity was calculated in the spatial distribution patterns of the high-density surface electromyography signals to determine the modified entropy, coefficient of variation of the root mean square and correlation coefficient to evaluate motor unit activation properties. Pearson’s correlation coefficients were calculated to examine the relationships between disease severity and the root mean square and electromyography variables. The root mean square value and heterogeneity were significantly higher and lower on the more-affected side in females with Parkinson’s disease than on the contralateral side in females with Parkinson’s disease or either side in control subjects (p \u3c 0.05). Females with Parkinson’s disease that exhibited temporal changes of spatial motor unit activation properties showed significant laterality when compared to healthy control subjects in both the low and high-intensity contractions. Moderate-to-strong correlations were observed between disease severity and root mean square and electromyography variables in females with Parkinson’s disease (r\u3e 0.6, p \u3c 0.001). The laterality of motor unit activation properties was compared between the subjects with Parkinson’s disease and the control subjects. The findings suggest that females with Parkinson’s disease have asymmetrical motor unit activation properties, independent of the magnitude of force production

Abeta Is Internalized via Macropinocytosis

Intracellular amyloid β peptide (Aβ) accumulation has drawn attention in relation to the pathophysiology of Alzheimer’s disease in addition to its extracellular deposition as senile plaque. Cellular uptake of extracellular Aβ is one of the possible mechanisms by which intracellular Aβ deposits form. Given the relevance of Aβ inside cells, it is important to understand the mechanism by which it is taken up by them. In this study, we elucidated that Neuro2A and SH-SY5Y cells internalize specifically oligomerized Aβ in a time- and dose-dependent manner. The depletion of plasma membrane cholesterol with methyl-β-cyclodextrin or treatment with trypsin diminished the internalization of oAβ, suggesting that the oAβ uptake might be both a lipid raft-dependent and heparan sulfate proteoglycan-mediated process. Treatment with a macropinocytosis inhibitor (ethylisopropyl amiloride and wortmannin) also drastically reduced the uptake of oligomer-Aβ (oAβ). oAβ-treated cells exhibited an increase in Rac1 activity, indicating that macropinocytosis induced by oAβ is regulated by these small GTPases. These findings suggest that macropinocytosis is a major endocytic route through which oAβ42 enters cells

Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population

Mutations in the optineurin (OPTN) gene cause amyotrophic lateral sclerosis (ALS). We previously reported 3 types of OPTN mutation in Japanese ALS subjects. Here, to identify the OPTN mutations in individuals of different ethnicity, we screened 563 sporadic ALS (SALS) subjects and 124 familial ALS (FALS) subjects who were mainly Caucasian. We found a c. 964T>C synonymous variation in exon 8. However, we could not find the meaningful OPTN mutations. The results indicate that OPTN mutations causing ALS are rare, especially in mainly Caucasian ALS subjects