Observational study of effects of pharyngeal stimulation by carbonated solution on repetitive voluntary swallowing in humans.

In this study, we conducted observational study to examine the effects of pharyngeal stimulation by a bolus of carbonated solution on repetitive voluntary swallowing in humans. Twelve healthy participants had a fine silicone tube inserted into their pharyngeal region, through which various solutions were slowly infused (0.2 mL/minute) to stimulate the pharyngeal mucosa without activating mechanoreceptors. The solutions included 0.3M NaCl (NaCl), carbonated 0.3M NaCl (NaCl + CA), 0.3M NaCl with acetic acid, distilled water, and carbonated distilled water. We used NaCl to inhibit water-sensitive neurons in the pharyngeal mucosa and enable the evaluation of the effects of carbonic acid stimulation on swallowing. Participants were instructed to repeat swallows as rapidly as possible during the infusion, and the swallowing interval (SI) was measured via submental surface electromyographic activity. SI was significantly shorter during the infusion of NaCl + CA, distilled water, and carbonated distilled water than during the infusion of NaCl. There was a significant positive correlation between SI with NaCl stimulation and the facilitative effects of the other solutions. Longer SIs with NaCl stimulation indicated potent facilitative effects. Thus, stimulation with NaCl + CA facilitated swallowing by reducing SI. Furthermore, the facilitative effects of SI were more pronounced in participants who had difficulty with repetitive voluntary swallowing. The sensation induced by carbonated solution may enhance the ability for repetitive voluntary swallowing, making it a potentially useful approach for rehabilitating patients with dysphagia.

A Japanese prospective multicenter study of urinary oxysterols in biliary atresia.

Diagnosis of biliary atresia (BA) can involve uncertainties. In the present prospective multicenter study, we considered whether urinary oxysterols represent a useful marker for diagnosis of BA in Japanese children. Subjects under 6 months old at 7 pediatric centers in Japan were prospectively enrolled, including patients with cholestasis and healthy controls (HC) without liver disease. Patients with cholestasis constituted 2 groups representing BA patients and others with cholestasis from other causes (non-BA). We quantitatively analyzed 7 oxysterols including 4ß-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol by liquid chromatography/electrospray ionization-tandem mass spectrometry. Enrolled subjects included 14 with BA (median age 68 days; range 26-170) and 10 non-BA cholestatic controls (59; 14-162), as well as 10 HC (57; 25-120). Total urinary oxysterols were significantly greater in BA (median, 153.0 µmol/mol creatinine; range 24.1-486.7; P < 0.001) and non-BA (36.2; 5.8-411.3; P < 0.05) than in HC (2.7; 0.8-7.6). In patients with BA, urinary 27-hydroxycholesterol (3.61; 0.42-11.09; P < 0.01) was significantly greater than in non-BA (0.71; 0-5.62). In receiver operating characteristic (ROC) curve analysis for distinguishing BA from non-BA, the area under the ROC curve for urinary 27-hydroxycholesterol was 0.83. In conclusion, this first report of urinary oxysterol analysis in patients with BA indicated that 27-hydroxycholesterol may be a useful marker for distinguishing BA from other causes of neonatal cholestasis.

Association between histological features of epicardial adipose tissue and coronary plaque characteristics on computed tomography angiography.

The means by which epicardial adipose tissue (EAT) could influence coronary plaque progression biologically remain unclear. We investigated the association between the histological findings of EAT and coronary plaque characteristics assessed by coronary computed tomography angiography (CCTA). We enrolled 34 patients in whom one or more coronary plaques containing non-calcified components were detected on CCTA before cardiac surgery [coronary artery bypass graft (CABG) or non-CABG]. We evaluated visceral adipose tissue (VAT) area, EAT volume, and coronary plaque characteristics including minimum computed tomography density (CTD) and vascular Remodeling Index (RI). Lower CTD and higher RI were considered as high-risk characteristics, and coronary plaque with both CTD < 39 Hounsfield units and RI > 1.05 was defined as two-characteristic plaque (2-CP). The numbers of CD68+ macrophages and CD31+ microvessels were assessed in six random high-power fields (400×) of EAT samples obtained during cardiac surgery. The entire cohort showed a wide range of EAT volume, which were similar between patients with 2-CP and those without. Patients with 2-CP had more amounts of EAT macrophages (85 ± 38 versus 45 ± 22, p = 0.0005) and vascularity (62 ± 33 versus 37 ± 19, p = 0.013) than those without. On multivariate analyses adjusted for age, sex, coronary risk factors, statin use, type of surgery, VAT area, EAT volume, and coronary calcium score, the presence of 2-CP showed significant correlation with increased EAT macrophages (ß = 0.65, p = 0.014) and vascularity (ß = 0.74, p = 0.0053). Our findings support the hypothesis that EAT biologic activities are associated with coronary plaque vulnerability.

Tumor Necrosis Factor-α Gene Expression in Epicardial Adipose Tissue is Related to Coronary Atherosclerosis Assessed by Computed Tomography.

AIMS: Tumor necrosis factor (TNF)-α reportedly has key pro-inflammatory properties in both atherosclerosis and adipocytes. To further investigate the biologic impact of epicardial adipose tissue (EAT) on coronary atherosclerosis, we evaluated the relationship between TNF-α gene expression in EAT and clinically-assessed coronary atherosclerosis on computed tomography (CT). METHODS: We studied 47 patients before cardiac surgery (coronary artery bypass grafting [CABG], n=26; non-CABG, n=21), assessing visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaque (NCP) on CT angiography. EAT and subcutaneous adipose tissue (SAT) samples were obtained during cardiac surgery. TNF-α mRNA in EAT was measured using quantitative real-time PCR, and normalized to that of SAT as control adipose tissue. RESULTS: There was no difference in the TNF-α expression level between patients scheduled for CABG and non-CABG surgery (p=0.23), or among the subgroups based on CCS (p=0.68), while patients with NCP had the higher TNF-α expression level than those without NCP (median [interquartile range], 2.50 [1.01-5.53] versus. 1.03 [0.64-2.16], p=0.022). On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CABG versus non-CABG, VAT area, and EAT volume, the presence of NCP had close correlation with the elevated TNF-α expression level (ß=0.79, p=0.003). CONCLUSIONS: TNF-α expressed regionally in EAT may exert potent effects on the progression of coronary atherosclerosis, suggesting a contribution of EAT to coronary artery disease through behavior of molecule.

Data on analysis of coronary atherosclerosis on computed tomography and 18F-sodium fluoride positron emission tomography.

This article contains the data showing illustrative examples of plaque classification on coronary computed tomography angiography (CCTA) and measurement of 18F-sodium fluoride (18F-NaF) uptake in coronary atherosclerotic lesions on positron emission tomography (PET). We divided the lesions into one of three plaque types on CCTA (calcified plaque, non-calcified plaque, partially calcified plaque). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio. This article also provides a representative case with a non-calcified coronary plaque detected on CCTA and identified on 18F-NaF PET/non-contrast computed tomography based on a location of a vessel branch as a landmark. These complement the data reported by Kitagawa et al. (2017) [1].

18F-sodium fluoride positron emission tomography for molecular imaging of coronary atherosclerosis based on computed tomography analysis.

BACKGROUND AND AIMS: We aimed at evaluating the relation of 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) to coronary atherosclerosis detected and assessed by computed tomography (CT). METHODS: Thirty-two patients with one or more coronary atherosclerotic lesions detected on cardiac CT underwent 18F-NaF PET/CT. Each coronary atherosclerotic lesion was evaluated on CT angiography for plaque types (calcified plaque [CP], non-calcified plaque [NCP], partially calcified plaque [PCP]), and the presence of CT-based high-risk features (minimum CT density <30 Hounsfield units and vascular remodeling index >1.1). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio (TBRmax). RESULTS: A total of 111 lesions were studied. In a patient-based analysis, logarithmically transformed coronary calcium score correlated positively with maximum TBRmax per patient, and 15 patients with myocardial infarction or unstable angina history showed a higher maximum TBRmax per patient than those without (1.36 ± 0.15 versus 1.15 ± 0.15, p = 0.0006). In a lesion-based analysis, PCP showed a higher TBRmax than CP and NCP (1.17 ± 0.19 versus 1.00 ± 0.24 and 0.92 ± 0.18, respectively, p < 0.0001), and the lesions with high-risk features had a higher TBRmax than those without (1.20 ± 0.21 versus 1.02 ± 0.20, p = 0.0011). CONCLUSIONS: Coronary arterial 18F-NaF uptake is related to total plaque burden, coronary event history, and specific features of coronary atherosclerosis based on CT analysis. 18F-NaF PET/CT, in combination with cardiac CT, may provide a new molecular imaging approach to identify high-risk patients and coronary atherosclerotic lesions.

Intravascular ultrasound for morphological assessment of napkin-ring sign detected on multidetector computed tomography.

BACKGROUND: Although napkin-ring sign (NRS) plaques assessed by multidetector computed tomography (MDCT) is identified as a high-risk feature, the detailed morphological features are still unknown. The purpose of this study was to elucidate the morphological features of the MDCT-assessed NRS using intravascular ultrasound (IVUS). METHODS: We evaluated 204 plaques in 193 patients with non-ST-elevation acute coronary syndrome who were diagnosed using 128-slice MDCT and were assessed using IVUS prior to coronary intervention. Morphology was compared between plaques with and without MDCT-assessed NRS. Severe IVUS-assessed attenuation was defined as an attenuation angle >180°. RESULTS: NRS was detected in 49 lesions. MDCT-assessed plaque attenuation was lower (p<0.0001), and cross-sectional plaque areas at lesion sites, remodeling index, and the prevalence of positive remodeling were greater, in lesions with NRS (p<0.005, p<0.0001, and p<0.0001, respectively). Furthermore, the IVUS-assessed remodeling index and prevalence of severe attenuation and speckled echo appearance were significantly greater in lesions with NRS (p<0.01, p<0.0001, and p<0.0001, respectively). Using multivariate analysis, IVUS-assessed speckled echo appearance was identified as an independent predictor of MDCT-assessed NRS (odds ratio, 3.59; 95% confidence interval, 1.49-8.66; p<0.005). CONCLUSION: MDCT assessment of NRS may be associated with larger heterogeneous necrotic cores and greater positive remodeling.

Visit-to-visit blood pressure variability and classes of antihypertensive agents; associations with artery remodeling and the risk of stroke.

Recent studies have shown that visit-to-visit blood pressure (BP) variability was emerging as an independent risk factor for stroke. Although the mechanism is not fully understood, artery remodeling would be closely associated with the relationship between visit-to-visit BP variability and stroke. In addition, the class of antihypertensive agents is suggested to be an important determinant of visit-to-visit BP variability. This review article summarizes the recent literature on these topics. In the elderly hypertensives, strict BP control using calcium channel blockade would play a crucial role to prevent stroke via reducing the visit-to-visit BP variability.

[Analysis of dopamine transporter knockout mice as an animal model of AD/HD].

Attention deficit/hyperactivity disorder (AD/HD) is characterized by significant difficulties of inattention and/or hyperactivity and impulsiveness. Dopamine transporter (DAT) knockout (KO) mice have been suggested to constitute an animal model of AD/HD. DAT KO mice exhibit persistently and profoundly elevated extracellular dopamine levels in the striatum and nucleus accumbens. These mice display numerous behavioral alterations that model aspects of AD/HD that include hyperactivity in novel environments and impulsivity. Both hyperactivity and impulsivity can be ameliorated by treatment with methylphenidate and nisoxetine. These drugs increase extracellular dopamine and norepinephrine levels in the prefrontal cortex. It is likely that methylphenidate and nisoxetine activate the prefrontal catecholamine systems by blocking the norepinephrine transporter (NET) function, thereby helping to improve AD/HD-like behavior in DAT KO mice.

Animal models of attention-deficit/hyperactivity disorder.

Attention-deficit hyperactivity disorder (AD/HD) is a clinically heterogenous disorder including hyperactivity, impulsivity, and inattention. Both psychostimulant and non-psychostimulant drugs such as methylphenidate and atomoxetine, respectively, to modulate catecholeamine neurotransmission are used as current pharmacotherapies for AD/HD. Multiple lines of evidence suggest that genetic factors play major roles in the etiology of AD/HD. meta-Analyses and pooled data analyses have suggested associations between AD/HD and polymorphisms in genes encoding monoamine neurotransmission molecules. There has been considerable research on this disorder using genetic, pharmacological, and neuroimaging approaches, and several animal models of AD/HD such as spontaneously hypertensive rat (SHR), dopamine transporter (DAT) knockout mice, coloboma mutant mouse, and Grin1 mutant mouse have been reported. These animal models are valuable tools for investigating molecular, cellular, and behavioral mechanisms as well as the neural development and circuit mechanisms of AD/HD. Here, we review the recent literature on animal models of AD/HD and discuss their advantages and limitations.

[Neuronal development of the hyperdopaminergic animal model].

Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD.