Systemic infection in the newborn (neonatal sepsis) is the most common cause of neonatal mortality. Neonatal sepsis is complicated by pulmonary hypertension. In this study, we analyzed the effect of edaravone, a free radical scavenger that is known to reduce the production of inflammatory mediators, such as tumor necrosis factor α (TNFα), on pulmonary hypertension. Experimental and sham groups were drawn from 19 three-day-old piglets; 5 underwent a modified procedure of cecal ligation and perforation (CLP) (CLP group), 8 underwent CLP followed 30 min later by edaravone intravenous administration (edaravone group), and 6 did not undergo CLP and did not receive edaravone (sham group). To evaluate the pulmonary blood pressure despite the sepsis-induced low cardiac output, mean arterial blood pressure (mABP), mean pulmonary arterial pressure (mPAP), and comparative pulmonary hypertension ratio (mPAP/mABP) were determined. Serum TNFα levels were measured before the procedure and at 1, 3, and 6 h after. The mPAP levels were higher in the CLP group at 9 h compared to the edaravone group. The mPAP/mABP ratio was lower in the edaravone and sham groups compared to the CLP group at 6 and 9 h. TNFα in the edaravone and sham groups were lower at 1 and 3 h compared to that in the CLP group. In all animals, mPAP/mABP at 6 h correlated with serum levels of TNFα at 1, 3, and 6 h. These findings suggest that edaravone ameliorates the severity of pulmonary hypertension in a neonatal sepsis model by reducing serum TNFα levels.
Vasculogenic mimicry (VM) is an alternative type of blood supplement and is responsible for aggressive tumor biology and increased tumor-related mortality. Tumor cells obtain oxygen and nutriment through VM channels in the early, rapid-growth stage when blood vessels are insufficient. VM channels are characterized by tubular structures with tumor cells. Autophagy is a catabolic process, by which the cell digests damaged components or organelles of its own cytoplasm in response to nutrient deprivation, hypoxia, and the presence of non-functional protein aggregates. In fact, autophagy plays an important role in normal cell growth, development, and homeostasis. However, it is still controversial whether autophagy is also involved in cell death or cell survival in malignancy. In the present study, we therefore investigated the expression levels of two autophagy-related proteins, microtubule-associated protein-1 light chain 3 (LC3) and beclin-1, with respect to melanoma metastasis and vasculogenic mimicry. Melanoma is characterized by rapid growth, high-metastasis rate, and unpredictable behavior. A total of 70 human melanoma tissues were analyzed, showing that VM was present in 31 melanoma specimens (44.3%). Melanoma cells displayed high levels of autophagy when VM was present. Real-time quantitative PCR and immunohistochemical analyses showed that the expression levels of beclin-1 and LC3 mRNAs and proteins were both higher in the VM-positive melanoma than those in the VM-negative melanoma (p < 0.05). Moreover, the expression of LC3, rather than beclin-1, was strongly associated with metastasis and poor clinical prognosis of human melanoma. Therefore, the enhanced autophagic activity may be related to VM and metastasis of melanoma.
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries, and its pathogenesis is underlined by genetic and environmental factors. Oxidative stress is a major environmental risk factor of AMD; namely, AMD is associated with the increased level of reactive oxygen species, which may be produced in reactions catalyzed by iron present in the retina. Therefore, variability of the genes of iron metabolism may be important in the AMD risk. In the present study, we analyzed the association between AMD and the -576G>A polymorphism of the transferrin gene or the 1892C>T polymorphism of the transferrin receptor 2 (TFR2) gene in 278 patients with AMD and 105 controls. The former polymorphism is located in the promoter region of the transferrin gene and may affect the level of its transcription, while the latter is a synonymous mutation in the exon 16, which may affect the efficiency of translation of TFR2 mRNA. Transferrin and TFR2 are important in iron homeostasis. The A allele of the -576A>G polymorphism was significantly associated with the increased risk of AMD in tobacco smokers, whereas the 1892C>T polymorphism did not influence the risk of AMD related to smoking. Moreover, each polymorphism does not influence the risk of AMD associated with age, sex or the family history of the disease. In conclusion, the A allele of the -576A>G polymorphism of the transferrin gene may increase the risk of AMD in smokers.
High-sensitivity C-reactive protein (hsCRP) has been demonstrated to play a causal role in atherosclerosis and to predict cardiovascular events in the general population. On the other hand, left ventricular (LV) hypertrophy and diastolic dysfunction assessed by echocardiography can also predict cardiovascular events in patients with cardiovascular risk factors. However, there are few data regarding the relationships among hsCRP, LV hypertrophy, and diastolic function. We examined the relationships among hsCRP, LV hypertrophy, and diastolic function in 185 patients (65 ± 11 years), who had no overt heart disease, but had cardiovascular risk factors, including hypertension, diabetes, and dyslipidemia. Echocardiography was performed to measure the left ventricular mass index (LVMI) as a parameter of LV hypertrophy. LV diastolic function was assessed by the ratio (E/A) of early (E) and late (A) diastolic transmitral flows, early diastolic mitral annular velocity (E'), and the ratio (E/E') of E to E' using Doppler echocardiography. The hsCRP was correlated with LVMI (r = 0.228, p = 0.002), E' (r = −0.276, p < 0.001), and E/E' (r = 0.419, p < 0.001). The E/E' as a parameter of LV diastolic function showed the closest correlation to hsCRP. These results indicate that elevated hsCRP reflects LV diastolic dysfunction rather than LV hypertrophy. We therefore suggest that hsCRP may be a marker of subclinical LV diastolic dysfunction in patients with cardiovascular risk factors.
A focus exclusively on waist circumference, the main component used in the diagnosis of metabolic syndrome (MetS), may lead to ignoring non-obese individuals with other MetS components, including high levels of blood pressure, fasting blood glucose, and triglycerides and low levels of high-density lipoprotein. This study investigated lifestyles and eating behaviors among non-obese individuals with components of MetS. Of the 918 Japanese male workers, 151 subjects (16.4%) had a waist circumference < 85 cm with more than one MetS component. This non-obese high-risk group for MetS gained weight in adulthood, consume alcohol, and engage in less leisure-time physical activity compared to 317 subjects (34.5%) with a waist circumference < 85 cm and without MetS components (p < 0.05). The remaining 450 subjects (49%) were obese with a waist circumference ≥ 85, including 93 men with MetS. A lack of leisure-time physical activity was associated with the non-obese high-risk group for MetS [odds ratio 1.59, 95% confidence interval 1.02 - 2.49] compared to the 317 non-obese men without MetS (reference group). Such a difference in physical activity was not found between the 450 obese subjects and the reference group. Instead, eating behaviors, such as eating rapidly, preference for fatty foods, and eating out for dinner, were significantly associated with MetS. Thus, men with smaller waist circumferences and any MetS component should be carefully monitored for physical activity to prevent further development of MetS, while men with larger waist circumferences including MetS need to be monitored for unfavorable eating behaviors.
There is no reliable way to identify the high-risk patients with intermediate coronary artery lesions (diameter stenosis 20%-70%) in early stage. Soluble CXC chemokine ligand 16 (CXCL16) is a newly discovered chemokine that can mediate inflammatory responses. It is released by proteolytic cleavage of its membrane-bound form, named scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) that can promote the uptake of oxidized low-density lipoprotein cholesterol by macrophages. We have hypothesized that CXCL16 is an indicator of the prognosis of intermediate coronary artery lesions, and thus assessed the association between plasma CXCL16 concentrations and the 2-year prognosis in 616 patients with intermediate coronary artery lesions. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, revascularization and angina pectoris requiring re-hospitalization. During the median follow-up time of 24 months, 69 events occurred. The plasma concentrations of CXCL16 (median 7712.88 pg/ml vs. 6792.43 pg/ml, P = 0.014) and high-sensitivity C-reactive protein (hs-CRP) (median 2.82 mg/L vs. 1.68 mg/L, P < 0.001) were higher in patients with events than patients without events. Cox hazard proportion analysis showed patients in upper CXCL16 quartile were more likely to suffer from adverse outcome than patients in lower quartile (RR = 1.271, P = 0.029, 95% CI: 1.025-1.577) after adjusting for sex, age, smoking, hypertension, diabetes, fat, dyslipidemia, hs-CRP, and medication use. In conclusion, plasma level of CXCL16 is an independent predictor of the prognosis of the patients with intermediate coronary lesions. Elevated plasma CXCL16 is associated with higher risk for these patients.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent sleep disorder characterized by recurrent episodes of oxygen desaturation during sleep, decreased sleep quality, and excessive daytime sleepiness. A basic method of evaluating sleep quality is polysomnography (PSG) where sleep stages are identified from the electroencephalogram (EEG), electrooculogram and chin electromyogram. The implementation of PSG is limited to sleep laboratories because this test is rather complicated to perform and quite time-consuming to analysis, requiring skilled technicians. Development of simple alternative methods to PSG could enable sleep tests to be performed at home. Our study aimed to identify simple measures for evaluating the sleep quality. We focused on a simple index, entropy, which is derived from power spectrum of EEG signals throughout the night, and reflects the dynamics of EEG signals, and examined whether the entropy of EEG reflects the sleep quality of OSAHS. The EEG signals for the analysis of EEG entropy were recorded from the temple area. The EEG entropy was compared with the sleep quality by traditional approaches of EEG from PSG in 58 OSAHS patients and 8 healthy volunteers. The EEG entropy in each subject showed the negative values and fluctuated during sleep. There was a significant correlation between the EEG entropy and the sleep quality (r = 0.626, p < 0.001); namely, the amplitude of the fluctuation was increased with the increase in the sleep quality. We therefore propose that the EEG entropy could be useful for evaluating the sleep quality of OSAHS.
Terahertz (THz; 1012 Hz) waves have a frequency from 0.1 to 10 THz between the visible light and microwave domains. THz waves are expected to be useful for analysis of the histological features, without any staining procedure that is an indispensable prerequisite for optical microscopy. It has been demonstrated that THz transmittances at cancer and normal tissues are different. However, spectroscopy that is currently used is applicable for imaging only small areas at fixed-wavelength. In this study, we have developed a spectrometer employing a gallium phosphide (GaP) THz-generator and applied it to examine large areas of tissue specimens using a wide range of wavelengths. We thus examined the whole areas of two paraffin sections (metastatic liver cancer and acute myocardial infarction) in a frequency range of 1 to 6 THz, and compared the THz images of ordinary paraffin sections with the histological features detected by microscopy. THz imaging showed striking contrasts between cancerous and non-cancerous regions at 3.7 THz. Likewise, the precise imaging was achieved in the infarct myocardium at 3.6 THz. Images of THz transmittances in optimal wavelength were well matched with HE histological features both in cancer and myocardial tissues. Cancer regions showed higher transmittance than non-cancerous regions in liver. Old scar regions showed low transmittance, and necrotic regions showed relatively higher transmittance than normal myocardial areas. Thus, THz imaging precisely reflects tissue conditions such as tumor, non-tumor tissues, tissue degeneration and fibrosis. The newly established THz spectroscopy would be useful for pathological diagnosis of routinely processed specimens.
Many previous reports have documented a relationship between metabolic syndrome, in terms of insulin resistance, and colorectal cancer. However, the association of insulin resistance with colorectal adenoma has not been investigated in detail. To elucidate the association of metabolic syndrome components and insulin resistance with adenoma, we investigated homeostasis model assessment insulin resistance (HOMA-IR) in individuals with adenoma. A cross-sectional study was conducted involving individuals who underwent scheduled health examinations using total colonoscopy. Restricting the subjects to males, 261 with adenoma and 702 without adenoma were investigated. HOMA-IR was categorized into three groups: normal (< 1.6), intermediate (≥ 1.6 - < 2.5), and insulin resistance (2.5 ≤). Metabolic syndrome was defined by a combination of any three of the following components: central obesity (waist circumference ≥ 90 cm); elevated blood pressure (systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure 85 mmHg); elevated fasting plasma glucose (≥ 100 mg/dL); reduced high-density lipoprotein-cholesterol (< 40 mg/dL); and elevated triglyceride (≥ 150 mg/dL). Multivariate analysis of HOMA-IR showed that the intermediate and insulin resistance groups had a significantly increased risk for colorectal adenoma, even after adjustment for waist circumference (odds ratio, 1.62 and 2.23; 95% confidence interval, 1.07-2.45 and 1.31-3.79, respectively). Accumulation of any metabolic syndrome components increased the risk of colorectal adenoma (P trend = 0.001). However, none of the components alone demonstrated a significant risk for colorectal adenoma. Our data indicate that an increased level of HOMA-IR is a risk factor for colorectal adenoma in Japanese males.