Prostanoids Regulate Angiogenesis and Lymphangiogenesis in Pathological Conditions.

Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis.

Influence of hooks and a lag screw on internal fixation plates for lateral malleolar fracture: a biomechanical and ergonomic study.

BACKGROUND: For internal fixation of AO classification Type B lateral malleolar fracture, insertion of lag screws into the fracture plane and fixation with a one-third tubular plate as a neutralization plate are the standard treatment procedures. The one-third tubular plate is processed to a hook shape and hung on the distal end of the fibula. In this study, to compare the function of the hook and lag screws of a one-third tubular plate and LCP for osteosynthesis of lateral malleolar fracture, mechanical indices of internal fixation were compared among the one-third tubular plates with lag screws with and without the hook and a locking compression plate. METHODS: As mechanical tests, a compression test was performed in which compression in the bone axis direction produced by supporting the body weight was simulated, and a torsion test was performed in which external rotation of the bone axis caused by plantar flexion of the ankle joint was simulated. Muscle strength during walking and the force and torque acting on the ankle and knee joints were determined using inverse dynamic analysis. Finite element analysis was performed to analyze the function of hooks and lag screws. The joint reaction force determined by inverse dynamic analysis was adopted as the loading condition of finite element analysis. RESULTS: A stiffness equivalent to that of healthy bone could be achieved by all three internal fixations. It was clarified that the presence of the hook does not make a difference in stiffness. Displacement of the one-third tubular plate was small regardless of the presence or absence of the hook compared with those of locking compression plates. CONCLUSIONS: The presence of the hook did not make any difference in stiffness, suggesting that active preparation of the hook is unnecessary. We also clarified that lag screws inhibit displacement.

Blood pressure and sympathetic nerve tone relation during hemodialysis may reflect cardiovascular dysfunction.

BACKGROUND: The blood pressure response to the rapid removal of fluid during hemodialysis is complex and the pathophysiological mechanisms underlying intradialytic hypotension are not clear and sometimes these mechanisms render dialysis difficult to continue. PURPOSE: We analyzed the changes in blood pressure and sympathetic nerve tone and attempted to clarify whether the dynamic pattern of this relationship reflects cardiovascular dysfunction. METHODS: The dynamic pattern of sympathetic nerve activity throughout dialysis was analyzed by frequency analysis of RR intervals recorded by 24 hours Holter electrocardiography in 64 patients and 3 minutes ECG every 15 minutes during dialysis in 121 stable end-stage renal failure patients who underwent maintenance hemodialysis. Blood pressure and fluid volume removed was measured every 15-30 minutes during dialysis and the average value of the ratio of low to high frequency components (LF/HF) was calculated as an index of sympathetic nerve tone. The relationship between removed fluid volume, systolic blood pressure (Bp) and LF/HF was analyzed. RESULTS: The patients were classified into 3 groups based on the correlation between the LF/HF and Bp as follows: positive (52 cases), inverse (54 cases), and not significant (NS; 61 cases). Eighteen patients who showed multiple arrhythmias, atrial fibrillation and other artifacts or noises were eliminated as they were inadequate for frequency analysis of RR intervals. The positive group was characterized by a hypotension-resistant response with a low LF/HF, whereas the inverse group was characterized by a hypotension-prone response with high LF/HF. These results suggest that cardiovascular dysfunction is responsible for the inverse correlation. CONCLUSION: Analysis of the relationship between sympathetic nerve tone and Bp is effective in predicting the existing of cardiovascular dysfunction.

Effects of daily physical activity level on the degree of sympathetic tone.

BACKGROUND: Exercise is recommended for the treatment and prevention of cardiac disorders. Relaxation of the sympathetic nervous system has been considered to be one of the therapeutic mechanisms. However, the means by which the level of daily physical activity affects sympathetic activity remains unclear. OBJECTIVE: To evaluate the effects of daily physical activity on autonomic nervous tone. METHODS: Daily physical activity was measured for 5 or more days in 26 patients with various cardiac disorders of NYHA class 1 or 2 and in 6 healthy individuals using an intelligent calorie counter. Recumbent resting ECG was recorded for 3 minutes immediately before waking up and after going to bed using a digital ECG. Low- (Lf, 0.03-0.15 Hz) and high- (Hf, 0.15-0.45 Hz) frequency components were calculated by frequency analysis of the R-R interval, and Lf/Hf ratio was calculated as an index of sympathetic tone. RESULTS: The average values of energy expenditure and time were 145+/-93.6 kcal/day and 47.8+/-24.3 min/day, respectively. The morning Lf/Hf ratio decreased following an increased physical activity level the day before, but increased with subsequent increase in the activity level in 65.6% of subjects. A negative correlation was observed in 34.4% of subjects, which suggested that an appropriate level of physical activity led to relaxation of sympathetic tone. CONCLUSION: The daily level of physical activity affects sympathetic tone, and an appropriate level results in sympathetic relaxation. The results of this study provide a useful index to enable patients with cardiac disorder to perform exercise without overloading.

Circadian variation of the myocardial ischemic threshold in patients with ischemic heart disease.

PURPOSE: Circadian variation of the heart rate (HR) at the myocardial ischemic threshold was compared with that of the HR at the sympathetic tone threshold in 16 cases of effort angina pectoris. METHODS: The high (0.15-0.40 Hz, Hf) and low (0.03-0.15 Hz, Lf) frequency spectral components were extracted every twenty seconds, using frequency domain analysis of the RR interval recorded by a 24-hour Holter ECG with an accelerometer. HR-Hf data collected every five minutes were plotted as the X-Y coordinates, and a two-compartment analysis was performed. The HR at the autonomic tone threshold was then determined at the intersection point of the lines. A loop of the HR-ST segment was drawn during walking to determine the ischemic threshold at which heart rate ischemic ST segment depression began and circadian variation was observed. RESULTS: The circadian rhythm at the sympathetic tone threshold and the HR at the ischemic threshold were high during the day and low at night. The HR at the ischemic threshold was 15-20% higher than that at the sympathetic tone threshold at night but only 9-13% higher during the day. Also, there was a period during which there was no significant difference between the HR at the two thresholds. CONCLUSION: In comparing circadian variation between HR at the sympathetic tone threshold and HR at the ischemic threshold, there was a period during which there was no significant difference between the HRs. This might suggest a period in which a high incidence of cardiac ischemic attack is likely. This information could provide a feasible indicator for appropriate exercise training for patients with ischemic heart disease.

Evaluation of the severity of dementia using expectation control function.

The results of an animal experiment without anesthesia suggested the presence of expectation control in which sympathetic nerve tone increases at rest immediately before behaviors to prepare for the subsequent behavior. We investigated whether such function is present in humans in their daily living and whether patients with dementia could be differentiated from healthy adults based on this finding. Using a Holter electrocardiograph with an acceleration sensor, electrocardiograms (ECG) and behavioral states were recorded. The total recorded ECG was divided by 20 sec, and high (HF, 0. 15-0.4 Hz) and low (LF, 0.03-0.15 Hz) frequency components were extracted by frequency analysis of the RR interval. We used the HF component, L/H ratio, and RR interval as the index grade of parasympathetic/sympathetic nerve tone. The mean value of each parameter was calculated and compared between the time zone during which resting persisted for 1 min or more (3 intervals) and that during which behaviors occurred immediately after a 1-min rest., In 32 patients with dementia, Holter ECG and behaviors were serially recorded, and the time zone during which intentional behaviors occurred was detected. RR interval and HF component decreased and L/H increased. Increasing in sympathetic nerve tone was observed at rest condition immediately before intentional behaviors, suggesting a presence of expectation control function. The expectation control mechanism will present in humans and involved in this function by severity of dementia. This parameter may be useful for objectively evaluating the severity of dementia.

The effects of physical activity and autonomic nerve tone on the daily fluctuation of blood pressure.

The effects of daily activity and autonomic nerve tone on the fluctuation of ambulatory blood pressure were studied in hypertensive patients. The autonomic nerve tone was measured by frequency domain analysis of the RR interval. Physical activity was evaluated by a walk count, converted to a walk rate (WR), recorded using a digital Holter ECG fitted with an accelerometer, with simultaneous monitoring of blood pressure (Bp). Average values of the WR, H and L/H components were calculated for the 15 min. period just prior to Bp monitoring. The relationship between the average WR, H and L/H values and the Bp was determined by a linear regression analysis. Hypertension was classified into three types, autonomic nerve dominant (AN), exercise dominant (EX), and irregular (IR), based on a high correlation coefficient between Bp and either H or L/H (AN type), between Bp and WR (EX type), or no significant correlation between Bp and any of the parameters (IR type). Of the thirty hypertensive patients studied 11 were classified as AN, 12 as EX, and 7 as IR. Patients of the EX type had significantly lower Bp than patients in the other two classes. Furthermore, all of the IR type patients showed non-dipper type hypertension, suggesting that the Bp regulation mechanisms were impaired. The results suggest the significance of simultaneous monitoring of physical activity and autonomic nerve function at the time of Bp monitoring.