Effects of Wnt10a and Wnt10b Double Mutations on Tooth Development.

WNT molecules are the regulators of various biological functions, including body axis formation, organ development, and cell proliferation and differentiation. WNTs have been extensively studied as causative genes for an array of diseases. WNT10A and WNT10B, which are considered to be genes of the same origin, have been identified as causative genes for tooth deficiency in humans. However, the disrupted mutant of each gene does not show a decrease in teeth number. A negative feedback loop, interacting with several ligands based on a reaction-diffusion mechanism, was proposed to be important for the spatial patterning of tooth formation, and WNT ligands have been considered to play a pivotal role in controlling tooth patterning from mutant phenotypes of LDL receptor-related proteins (LRPs) and WNT co-receptors. The Wnt10a and Wnt10b double-mutants demonstrated severe root or enamel hypoplasia. In Wnt10a-/- and Wnt10a+/-;Wnt10b-/- mice, changes in the feedback loop may collapse the modulation of fusion or split a sequence of tooth formation. However, in the double-knockout mutant, a decrease in the number of teeth was observed, including the upper incisor or third molar in both jaws. These findings suggest that there may be a functional redundancy between Wnt10a and Wnt10b and that the interaction between the two genes functions in conjunction with other ligands to control the spatial patterning and development of teeth.

Nonsurgical orthodontic treatment for a patient with Sotos syndrome.

Sotos syndrome is a genetic disorder characterized by overgrowth in childhood, specific facial manifestations, advanced bone age, and mental retardation. The purpose of this article is to describe the nonsurgical orthodontic treatment of a 10-year-old boy with a skeletal mandibular protrusion, unilateral posterior crossbite, and Sotos syndrome. After maxillary lateral expansion, the skeletal Class III relationship with an anterior crossbite improved because of mandibular clockwise rotation, whereas the facemask had a marginal effect. After growth at 16 years, he had a skeletal Class I relationship, and thus, conventional orthodontic treatment with preadjusted edgewise appliances was initiated. After 41 months of multibracket treatment, acceptable occlusion with a functional Class I relationship was obtained. One year postretention, few changes in occlusion and facial features were observed. Our results demonstrate that considering the maxillofacial vertical growth during the peripubertal period associated with Sotos syndrome, more attention should be paid to the early orthopedic treatment with the facemask and/or chincap.

Immediate Effect of Masticatory Muscle Activity with Transcutaneous Electrical Nerve Stimulation in Muscle Pain of Temporomandibular Disorders Patients.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment modality for acute and chronic pain. However, little information for muscle activity is available on the immediate effects of TENS in masticatory muscle pain related to temporomandibular disorders (TMDs). The present study aimed to evaluate the immediate effects of TENS treatment on TMD-related muscle pain. Thirty-six patients with TMD-related muscle pain and 39 healthy subjects served as TMD and control groups, respectively. For objective evaluations, maximum mouth opening, and maximum bite force were measured before and after TENS. The pain intensity was assessed according to a 100-mm visual analog scale (VAS). TENS was applied to painful muscles for 20 min with frequencies of 100-200 Hz. The treatment outcome was evaluated using Global Rating of Change (GRC) scales. In the TMD group, VAS values significantly decreased after TENS. Although there was significant increase in the maximum mouth opening after TENS for only TMD group, the maximum bite force of both groups was significantly greater after TENS. According to GRC scales, one patient with TMD-related muscle pain expressed negative feelings after TENS. Conclusively, TENS treatment might quickly relieve pain in masticatory muscles and improve masticatory functions in patients with TMD-related muscle pain.

Prognostic significance of the brachial-ankle pulse wave velocity in patients with essential hypertension: final results of the J-TOPP study.

Brachial-ankle pulse wave velocity (baPWV) is a new tool for measuring arterial stiffness. The prognostic significance of this measure, however, is not fully established. We initiated a multicenter cohort study to examine the prognostic significance of baPWV in patients with essential hypertension in 2002. After baseline measurements were obtained, 662 previously untreated patients (mean age 60±12 years, mean blood pressure 156±19/94±12 mm Hg, 45% men) underwent long-term follow-up according to the current hypertension treatment guidelines. During the follow-up period (mean: 3 years, range: 3 months-8 years), 24 cardiovascular events were observed. The subjects were divided into high and low baPWV groups according to the median value (1750, cm s(-1)). Patients in the high baPWV group were older and had a lower body mass index, higher blood pressure, faster heart rate and higher fasting glucose and plasma creatinine concentrations compared with those in the low baPWV group. Cardiovascular morbidities per 1000 person-years for the high and low baPWV groups were 17.48 and 6.38, respectively (P<0.05), and the 8-year cardiovascular event-free survival rates were 78.2% and 93.5%, respectively (log-rank test, P=0.01). A multivariate Cox proportional hazard analysis showed that high baPWV compared with low baPWV was associated with a significantly poorer outcome (hazard ratio (HR) 2.97; 95% CI: 1.006-9.380). In conclusion, baPWV is an independent risk factor for future cardiovascular events in patients with essential hypertension.

Higher brachial-ankle pulse wave velocity as an independent risk factor for future microalbuminuria in patients with essential hypertension: the J-TOPP study.

OBJECTIVE: Brachial-ankle pulse wave velocity (baPWV) is a new measure of arterial stiffness. We have shown that a higher baPWV is associated with more severe albuminuria in patients with essential hypertension. However, it is still unclear as to whether baPWV predicts the future albuminuria status in patients under standard care. METHODS: A total of 321 nondiabetic patients with essential hypertension who had normoalbuminuria or microalbuminuria and were receiving treatment under the current hypertension guidelines were followed up for 2 years. Resting BP, fasting blood glucose, urinary albumin excretion and baPWV were measured before treatment, and periodically thereafter for 2 years. RESULTS: A 2-year treatment regimen lowered BP from 156/93 to 135/81 mmHg (P < 0.0001) and reduced the incidence of microalbuminuria from 25.8 to 14.0%. To determine the predictors for future microalbuminuria status, we compared the baseline data between patients with normoalbuminuria (n = 276) and those with microalbuminuria (n = 45) 2 years after the treatment. The microalbuminuric patients had a significantly higher baPWV and urinary albumin excretion and a significantly lower high-density lipoprotein concentration than the normoalbuminuric patients. Furthermore, the frequency of the use of renin-angiotensin system inhibitors was significantly lower in the microalbuminuric patients than in the normoalbuminuric patients. A multiple logistic regression analysis showed that higher baPWV was an independent risk factor for microalbuminuria 2 years after treatment of hypertension. When we restricted our analysis to a cohort of patients without microalbuminuria at the baseline, we found that higher baPWV was an independent predictor of the development of microalbuminuria after 2 years. CONCLUSION: Higher baPWV could be an independent risk factor for future microalbuminuria in patients with essential hypertension.

A randomized trial of the effect of an angiotensin II receptor blocker SR47436 (irbesartan) on 24-hour blood pressure in patients with essential hypertension.

The aim of this placebo-controlled, double-blind randomized study was to evaluate the duration of the effect of once-daily administration of irbesartan in patients with essential hypertension. After a placebo run-in baseline period (of 2-4 weeks), 79 patients were randomized to either irbesartan (one 100 mg tablet per day) or placebo, for 6 weeks. The primary outcome was the reduction in the mean 24-h blood pressure (BP) as assessed by ambulatory BP monitoring under standardized conditions. Seventy-six patients completed the study protocol. In the irbesartan group, the average reductions in 24-h systolic and diastolic BPs were 5.8 and 3.4 mmHg, respectively (95% confidence interval: 3.2-8.4/1.6-5.1 mmHg), and in the placebo group, they were -1.7 and -0.5 mmHg, respectively (95% confidence interval: -4.3 to 1.0/-1.8 to 0.7 mmHg). There were statistically significant differences in the average reductions of 24-h BP (7.5/3.9 mmHg, p<0.001), daytime BP (8.6/4.0 mmHg, p<0.001) and nighttime BP (6.1/3.4 mmHg, p<0.05) as well as casual BP (9.0/5.0 mmHg, p<0.001). The trough/peak (T/P) ratios for the systolic and diastolic BPs were 0.84 and 0.78, respectively, in the irbesartan group. The incidence of adverse events was similar in both groups. The results showed that irbesartan administered 100 mg once daily was well tolerated in the treatment of essential hypertension and was effective in producing sustained 24-h BP control.

Brachial-ankle pulse wave velocity is an independent risk factor for microalbuminuria in patients with essential hypertension--a Japanese trial on the prognostic implication of pulse wave velocity (J-TOPP).

Brachial-ankle pulse wave velocity is a new measure of arterial stiffness. The clinical significance of brachial-ankle pulse wave velocity as a measure of early vascular damage remains unclear. We examined the hypothesis that higher brachial-ankle pulse wave velocity is associated with a much greater risk of albuminuria by employing a cohort of 718 never-treated hypertensive patients registered in a prospective study. The 718 patients consisted of 500 patients with normoalbuminuria (69.6%), 191 patients with microalbuminuria (26.6%) and 27 patients with macroalbuminuria (3.8%). The prevalence of microalbuminuria increased with a graded increase in brachial-ankle pulse wave velocity (17.6, 22.8, 28.2 and 39.6%, p < 0.0001). The prevalence of macroalbuminuria remained constant until the third grade group of the brachial-ankle pulse wave velocity but increased significantly in the highest grade group compared with the lower grade groups (2.3, 3.2, 2.3, 9.9%, p < 0.0001). Age, systolic and diastolic blood pressure, pulse pressure, heart rate, and fasting glucose concentration were also significantly increased with an increase in brachial-ankle pulse wave velocity (p < 0.0001 for all). Multiple logistic regression analysis has shown that systolic blood-pressure, fasting blood glucose, and brachial-ankle pulse wave velocity are significant risk factors for microalbuminuria. After adjusting for other risk factors, the odds ratio for an increase of 200 cm/s in brachial-ankle pulse wave velocity was 1.192 (95% confidence interval: 1.022-1.365; p < 0.05). These data suggest that brachial-ankle pulse wave velocity is an independent risk factor for microalbuminuria and could be used as a marker for early vascular damage in never-treated hypertensive patients.

Higher plasma homocysteine concentration is associated with more advanced systemic arterial stiffness and greater blood pressure response to stress in hypertensive patients.

Hyperhomocysteinemia has been reported to be associated with both vascular structure alteration and increased cardiovascular risk. This study examined whether hyperhomocysteinemia causes increased systemic arterial stiffness, thereby enhancing blood pressure response to stress in hypertensive patients. In 50 treated hypertensive patients, we studied brachial-ankle pulse wave velocity (PWV), a new measure for arterial stiffness, blood pressure response to stress, and blood pressure recovery after stress. Autonomic nervous activities were examined by spectral analysis of blood pressure and RR interval variabilities. Total plasma homocysteine and neurohumoral parameters were determined from fasting blood. Brachial-ankle PWV correlated with age (r=0.64, p<0.001), plasma homocysteine concentration (r=0.35, p<0.05), and systolic blood pressure (SBP) (r=0.62, p<0.001). Higher plasma homocysteine concentration was independently associated with greater brachial-ankle PWV (beta=0.388, p=0.01). We classified the subjects into high homocysteine (7.3 nmol/ml or over) and low homocysteine (7.2 nmol/ml or below) groups. Baseline SBP, plasma renin activity, aldosterone, and norepinephrine concentrations were similar between the two groups. However, the SBP values during stress and the recovery periods were higher in the high homocysteine group than the low homocysteine group even after adjusting for sex and age. The behavior of sympathetic vasomotor activity did not differ between the two groups. These data suggest that higher plasma homocysteine concentration is associated with increased systemic arterial stiffness, which may enhance blood pressure reactivity to stress in hypertensive patients.

Higher brachial-ankle pulse wave velocity is associated with more advanced carotid atherosclerosis in end-stage renal disease.

Brachial-ankle pulse wave velocity is a new measure of arterial stiffness. We examined whether higher brachial-ankle pulse wave velocity is associated with more advanced carotid atherosclerosis and left ventricular hypertrophy in patients with end-stage renal disease, and whether this effect would be mediated by the influence of wave reflection on central arterial pressure. In 68 patients with end stage renal disease, we examined blood pressures, brachial-ankle pulse wave velocity and the augmentation index of the left common carotid artery, a measure of the impact of wave reflection on the systolic peak in central arteries. The degree of carotid atherosclerosis was quantified by a plaque score and maximum intimal-medial thickness. Echocardiography was used to determine the left ventricular mass index. In simple regression analysis, brachial-ankle pulse wave velocity was correlated with both plaque score and maximum intimal-medial thickness (r = 0.420, p < 0.001 and r = 0.452, p < 0.0005, respectively) but not with left ventricular mass index. Multiple regression analysis was performed with the plaque score or maximum intimal-medial thickness as the dependent variable and brachial-ankle pulse wave velocity and known clinical risk factors as the independent variables. The brachial-ankle pulse wave velocity was an independent risk factor for both plaque score (beta = 0.006, p = 0.004) and maximum intimal-medial thickness (beta = 0.008, p = 0.04). Independent risk factors for left ventricular mass index were left ventricular diastolic dimension (beta = 3.509, p = 0.000007) and augmentation index (beta = 0.580, p = 0.04). The brachial-ankle pulse wave velocity was unrelated to augmentation index in patients with end stage renal disease. In conclusion, higher brachial-ankle pulse wave velocity was found to be a risk factor for carotid atherosclerosis in patients with end-stage renal disease; this effect was independent of the influence of wave reflection on central arterial pressure. The brachial-ankle pulse wave velocity was unrelated to left ventricular structure.

Effects of valsartan and nifedipine coat-core on systemic arterial stiffness in hypertensive patients.

BACKGROUND: The aim of this study was to compare the effects of long-term antihypertensive treatment on brachial-ankle pulse wave velocity (PWV), a marker of systemic arterial stiffness, between angiotensin II receptor blocker valsartan and long-acting calcium channel blocker nifedipine coat-core. METHODS: Forty-one patients (54 +/- 3 years of age, 20 men and 21 women) with essential hypertension (155 +/- 3/95 +/- 3 mm Hg) were randomly allocated to the treatment with valsartan (80 mg once daily) or nifedipine coat-core (20 mg once daily). Brachial-ankle PWV and 24-h ambulatory blood pressures (BP) were measured before and 3 months after treatment. RESULTS: Baseline data did not differ between the valsartan and nifedipine groups. The PWV also was similar between the groups (1669 +/- 65 v 1622 +/- 64 cm/sec). Three months of treatment similarly reduced resting systolic and diastolic BP (nifedipine, -18.4 +/- 4.2/-11.9 +/- 2.7 mm Hg; valsartan, - 17.4 +/- 3.3/-9.8 +/- 2.1 mm Hg, all P < .001). The PWV was significantly reduced compared with baseline values in the valsartan group (-195 +/- 42 cm/sec, P < 0.001) but not in the nifedipine group (-69 +/- 40 cm/sec, NS). The 24-h mean heart rate increased in the nifedipine group but remained unchanged in the valsartan group, although BP were similarly lowered for 24 h. A tachycardic response was associated with an increase or lesser reduction in PWV in a group treated with nifedipine (r = 0.584, P < .01). CONCLUSIONS: These data suggest that long-term treatment with valsartan could reduce arterial stiffness better than nifedipine-coat core. The favorable vascular effect of valsartan was due in part to its nonhypotensive effect. The expected decrease in arterial stiffness may be offset by reflex sympathetic activation in some patients treated with nifedipine.

Utility of automated brachial ankle pulse wave velocity measurements in hypertensive patients.

BACKGROUND: We examined whether pulse wave velocity (PWV), determined by brachial ankle arterial pressure wave measurements, using a newly developed, fully automated device could be a surrogate measure for carotid femoral PWV. METHODS & RESULTS: This device (AT-form PWV/ABI, Nippon Colin, Komaki, Japan) can simultaneously monitor bilateral brachial and ankle pressure wave forms using the volume plethysmographic method, with two optional tonometry sensors for carotid and femoral arterial wave measurements. We examined the right brachial-right ankle PWV and left carotid-left femoral PWV in 89 normotensive and untreated hypertensive patients. The brachial ankle PWV correlated well with carotid femoral PWV (r = 0.755, P <.00001). The Bland-Altman plots of the two variables, however, showed a significant difference exists between the two techniques over the range of measurement. The within-observer and between-observer coefficients of variation of the brachial ankle PWV were 6.5% +/- 4.1% and 3.6% +/- 3.9%, respectively. To determine the factors affecting brachial ankle PWV, we studied treated and untreated hypertensive patients with World Health Organization stage I (n = 146), stage II (n = 74), or stage III (n = 54). In multiple regression analysis, age, brachial ankle PWV, and the presence of diabetes were significant predictors of the severity of hypertensive organ damage. Age, systolic blood pressure, and the stage of hypertensive organ damage were major determinants of brachial ankle PWV. CONCLUSIONS: Although the brachial ankle PWV does not agree with the carotid femoral PWV, this parameter may yet become a new, useful measure for arterial stiffness. Further longitudinal studies are necessary to confirm the clinical significance of the brachial ankle PWV.

The influence of one-year treatment by angiotensin converting enzyme inhibitor on baroreflex sensitivity and flow-mediated vasodilation of the brachial artery in essential hypertension--comparison with calcium channel blockers.

BACKGROUND: Both baroreflex sensitivity and flow-mediated vasodilator function have been recognized to have prognostic significance in cardiovascular diseases. Long-term antihypertensive treatment effects on these parameters, however, remain unclear. SUBJECTS AND METHODS: We examined the effects of long-term treatment by angiotensin converting enzyme inhibitors (ACEI) orcalcium channel blockers (CCB) on baroreflex and flow-mediated vasodilator function in patients with essential hypertension (EH). We recruited 36 patients aged 56 +/- 11 years, with systolic blood pressure > or = 160 mmHg and/or diastolic blood pressure > or = 95 mmHg. Patients were assigned either to treatment by long-acting ACEI (n = 12) or CCB (n = 24). All patients were followed for 12 months. Optimal BP was achieved by two optional increases in treatment: dose-doubling of the primary drug during the first three months and the addition of diuretics or beta-blockers thereafter. Target blood pressure was 140/90 mmHg or a fall > or = 20/10 mmHg. Baroreflex sensitivity was examined by spectral analysis of blood pressure and RR interval variabilities before treatment and after 3 and 12 months of treatment. The flow-mediated vasodilator function was determined before and 12 months after treatment by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. RESULTS: Baseline blood pressures were similar between the ACEI and CCB groups (172 +/- 5/103 +/- 2 vs. 172 +/- 4/101 +/- 3 mmHg). Blood pressures after 3 and 12 months of treatment also did not differ between the ACEI and CCB groups (149 +/- 4/91 +/- 2 vs. 145 +/- 2/85 +/- 2 mmHg, and 133 +/- 5/84 +/- 2 vs. 133 +/- 2/81 +/- 2 mmHg, respectively). Baseline baroreflex sensitivity was similar between the groups (6.7 +/- 0.8 vs. 5.9 +/- 0.6 msec/mmHg). This parameter remained unchanged at three months but increased after 12 months of treatment in both the ACEI (9.5 +/- 1.6 msec/mmHg, p = 0.05) and CCB (9.1 +/- 1.2 msec/mmHg, p = 0.006) groups. Percent increases in brachial arterial diameter and flow during reactive hyperemia increased in the group treated with ACEI (12.4 +/- 3.5 vs. 25.8 +/- 6.3% and 618 +/- 72 vs. 953 +/- 166, p < 0.05 for both) but both parameters remained unchanged in the group treated with CCB. CONCLUSION: These data suggest that long-term blood pressure control with modem antihypertensive drugs improves baroreflex function. Treatment with ACEI may be more favorable for flow-mediated vasodilator function than treatment with CCB.

Clinical significance of blood pressure response triggered by a doctor's visit in patients with essential hypertension.

The clinical significance of the pressor response triggered by blood pressure measurement, the so-called "white-coat effect," was studied in relation to left ventricular structure and function in patients with essential hypertension. We studied 75 consecutive, never-before treated patients with essential hypertension (54 +/- 2 (SE) years; 31 men). Beat-to-beat blood pressure (Finapres) was monitored at rest, during conventional blood pressure measurement by a doctor, and during a mental stress test. The left ventricular mass index and diastolic function (EIA ratio) were determined by echocardiography. The systolic blood pressure response triggered by the doctor's visit (deltaSBP) correlated positively with the left ventricular mass index (r= 0.326, p<0.03) and negatively with the EIA ratio (r=-0.325, p<0.02). A positive relationship between the deltaSBP and left ventricular mass index was observed in men (r=0.556, p<0.01) but not in women. The greater ASBP also was associated with lower EIA ratio in women (r=-0.434, p<0.02). The deltaSBP correlated with the mental stress-induced increase in systolic blood pressure in men (r=0.586, p<0.005) but not in women (r=0.148, n.s.). Blood pressures outside the clinic were higher in men than in women (p<0.05 for systolic and p<0.005 for diastolic) despite the similar level of clinic blood pressures between the sexes. Stepwise multiple linear regression analysis showed that the deltaSBP was an independent predictor of the left ventricular mass index in men (beta=0.783, p=0.0009) and of the EIA ratio in women (beta=-0.003, p=0.05). These data suggest that the pressor response triggered by a doctor's visit has clinical significance in never-before treated hypertensive patients, possibly because it mirrors real-life stress reactivity in men.