Fatty Acid Accumulation and Resulting PPARα Activation in Fibroblasts due to Trifunctional Protein Deficiency

To examine fatty acid accumulation and its toxic effects in cells, we analyzed skin fibroblasts from six patients with mitochondrial trifunctional protein deficiency, who had abnormalities in the second through fourth reactions in fatty acid β-oxidation system. We found free fatty acid accumulation, enhanced three acyl-CoA dehydrogenases, catalyzing the first reaction in the β-oxidation system and being assumed to have normal activities in these patients, and PPARα activation that was confirmed in the experiments using MK886, a PPARα specific antagonist and fenofibrate, a PPARα specific agonist. These novel findings suggest that the fatty acid accumulation and the resulting PPARα activation are major causes of the increase in the β-oxidation ability as probable compensation for fatty acid metabolism in the patients' fibroblasts, and that enhanced cell proliferation and increased oxidative stress due to the PPARα activation relate to the development of specific clinical features such as hypertrophic cardiomyopathy, slight hepatomegaly, and skeletal myopathy. Additionally, significant suppression of the PPARα activation by means of MK886 treatment is assumed to provide a new method of treating this deficiency

Effects of mechanical insufflation-exsufflation on compartmental chest wall volume in patients with chronic cervical spinal cord injuries

　The purpose of this study was to evaluate the effects of mechanical insufflationexsufflation (MI-E) on volume change of the chest wall and each compartment of the chest wall in patients with cervical spinal cord injury using optoelectronic plethysmography (OEP).　Fourteen male patients with chronic cervical spinal cord injuries were included with the following characteristics: age, 56.2 ± 13.6 years; height, 168.4 ± 5.5 cm; body weight, 62.3 ± 12.7 kg; median number of days after injury, 387 days (range, 200-3575 days). The change of chest wall volume was significantly greater during MI-E of ≥ ±30 cmH2O than when taking a deep breath. The volume change in the upper and lower thorax compartment was significantly greater during MI-E of ≥ ±30 cmH2O than when taking a deep breath. However, MI-E made no significant difference to the volume of the upper and lower thorax compartment between pressures of ±30 cmH2O and ±50 cmH2O. The volume change in the abdomen compartment was slightly greater during MI-E than when taking a deep breath, but this was not statistically significant.　The findings of this study indicate the possibility of maintenance or improvement of the compliance of the chest wall, especially the rib cage in patients with spinal cord injuries, using MI-E. In turn, these findings could lead to the prevention of pulmonary complications

Ultrasonographic evaluation of geniohyoid muscle mass in perioperative patients

Surgical invasion and postoperative disuse are known to promote systemic skeletal muscle atrophy; however, similar effects on the mass of the muscles of deglutition have yet to be confirmed. Our method of using ultrasonography to measure the area of the geniohyoid muscle (GM), to evaluate the mass of the muscles of deglutition, has been shown to have high reliability. In the present study, we measured the GM area before and after surgery in patients to investigate changes in their muscle mass. Parameters including GM area, quadriceps femoris muscle (QF) thickness, hand grip strength (HGS), and arm muscle circumference were measured preoperatively and at 7 and 14 days postoperatively in patients who underwent thoracotomy and laparotomy. Patient height, weight, and serum albumin (Alb) level were also obtained from medical charts. Comparison of each evaluation parameter between measurement time points demonstrated significant decreases in GM area, QF thickness, HGS, and Alb between preoperatively and both postoperative day (POD) 7 and POD 14. The patients were divided into good (n = 19) and poor (n = 12) postoperative oral intake groups for comparison of GM area. The percentage decrease in GM area was significantly greater in patients with poor oral intake. To our knowledge, this is the first study to demonstrate that muscle atrophy due to surgical invasion or disuse may occur in the muscles of deglutition, as in the limb muscles. The findings showed that muscle atrophy occurs in the early postoperative period and persists even at 2 weeks postoperatively. Furthermore, insufficient oral intake may promote disuse muscle atrophy

Peroxisome proliferator-activated receptor alpha mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

Sulfatides, 3-O-sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue. Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPAR alpha. To confirm this hypothesis, we treated wild-type and Ppara-null mice with the specific PPAR alpha agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPAR alpha-dependent manner. However, these effects of fenofibrate were absent in the brain or colon. Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPAR alpha has demonstrated that fenofibrate treatment activated PPAR alpha in the kidney, heart, liver, and small intestine but did not affect the brain or colon. These findings suggest that PPAR alpha activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPAR alpha is a possible transcriptional regulator for the mouse CST gene.ArticleGLYCOCONJUGATE JOURNAL. 30(6):553-560 (2013)journal articl

Assessment of chest movements in tetraplegic patients using a three-dimensional motion analysis system

We used optoelectronic plethysmography (OEP) to evaluate the effects of posture on chest and abdominal movements during respiration in patients with chronic-stage complete spinal cord injuries. The subjects were five cervical injury patients (male, C4-C8 injury, American Spinal Injury Association Impairment Scale grade A) and five healthy people matched to each of the cervical injury patients for age, height, and weight. The chest wall movement each of the subjects was recorded using OEP during six quiet breathing and three deep breathing periods in each of the following positions: supine, with the trunk elevated to 30°, and with the trunk elevated to 60°. Data on the chest wall volume and compartment volumes (upper thorax, lower thorax, abdomen) were then compared among the postures. During quiet breathing in the tetraplegic patients, the change in upper thorax volume was smaller at the end of inhalation than at the end of exhalation, presenting as a paradoxical breathing pattern. During deep breathing in the tetraplegic patients, abdominal volume accounted for a large portion of the change in total chest wall volume. Posture affected the recorded abdominal volume; volume was greatest in the supine position and decreased as the posture became more upright

The potential role of Arhgef33 RhoGEF in foveal development in the zebra finch retina

The fovea is a pit formed in the center of the retina that enables high-acuity vision in certain vertebrate species. While formation of the fovea fascinates many researchers, the molecular mechanisms underlying foveal development are poorly understood. In the current study, we histologically investigated foveal development in zebra finch (Taeniopygia guttata) and found that foveal pit formation begins just before post-hatch day 14 (P14). We next performed RNA-seq analysis to compare gene expression profiles between the central (foveal and parafoveal) and peripheral retina in zebra finch at P14. We found that the Arhgef33 expression is enriched in the middle layer of the inner nuclear layer at the parafovea, suggesting that Arhgef33 is dominantly expressed in Müller glial cells in the developing parafovea. We then performed a pull-down assay using Rhotekin-RBD and observed GEF activity of Arhgef33 against RhoA. We found that overexpression of Arhgef33 in HEK293 cells induces cell contraction and that Arhgef33 expression inhibits neurite extension in Neuro 2A cells, which is partially recovered by a Rho-kinase (ROCK) inhibitor. Taken together, we used zebra finch as a model animal to investigate foveal development and identified Arhgef33 as a candidate protein possibly involved in foveal development through modulating RhoA activity

Investigation into the safety of driving by individuals with higher brain dysfunction

Dangerous driving by drivers with diseases or disabilities such as dementia, epilepsy, or higher brain dysfunction is viewed as a problem In Worldwide. Given that the majority of such cases of dangerous driving are caused by impairments to cognitive function resulting from these conditions, there is an urgent need to create systems to detect drivers with cognitive functional disability and develop criteria for safe resumption of driving. Because driving would understandably be extremely dangerous for people with higher brain dysfunction, particularly in cases of attention dysfunction, we first examined the correlation between the Clinical Assessment of Attention (CAT), a theoretical task offering an index of attention function, and the cathode ray tube (CRT) driving aptitude test. We then examined correlations between CRT total score and CRT sub-scores. Only the time required for the position Stroop test had a moderate correlation (r=-0.43, p<0.01) with CRT total score. Correlations between CRT total score and sub-scores relating to reaction speed showed a strong correlation. Other than reaction speed, items with significant moderate to strong correlations were also seen in the maintenance of moderate mental tension, attention distribution and situation processing skill. The present results show a correlation between CAT score and CRT total score, indicating that CRT total score places relative weights on speed of information processing and suppression of stereotypes, representing a very meaningful result

Ultrasonographic evaluation of geniohyoid muscle mass in perioperative patients

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