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Uncertain value of electronic fetal monitoring in predicting cerebral palsy.

BACKGROUND: Electronic monitoring of the fetal heart rate is commonly performed, in part to detect hypoxia during delivery that may result in brain injury. It is not know whether specific abnormalities on electronic fetal monitoring are related to the risk of cerebral palsy. METHODS: Among 155,636 children born from 1983 through 1985 in four California counties, we identified singleton infants with birth weights of at least 2500 g who survived to three years of age and had moderate or severe cerebral palsy. The children with cerebral palsy were compared with randomly selected control children with respect to characteristics noted in the birth records. RESULTS: Seventy-eight of 95 children with cerebral palsy and 300 of 378 controls underwent intrapartum fetal monitoring. Characteristics found to be associated with an increased risk of cerebral palsy were multiple late decelerations in the heart rate, commonly defined as slowing of the heart rate well after the onset of uterine contractions (odds ratio, 3.9; 95 percent confidence interval, 1.7 to 9.3), and decreased beat-to-beat variability of the heart rate (odds ratio, 2.7; 95 percent confidence interval, 1.1 to 5.8); there was no association between the highest or lowest fetal heart rate recorded for each child and the risk of cerebral palsy. Even after adjustment for other risk factors, the association of abnormalities on fetal monitoring with an increased risk of cerebral palsy persisted (adjusted odds ratio, 2.7; 95 percent confidence interval, 1.4 to 5.4). The 21 children with cerebral palsy who had multiple late decelerations or decreased variability in heart rate on fetal monitoring represented only 0.19 percent of singleton infants with birth weights of 2500 g or more who had these fetal-monitoring findings, for a false positive rate of 99.8 percent. CONCLUSIONS: Specific abnormal findings on electronic monitoring of the fetal heart rate were associated with an increased risk of cerebral palsy. However, the false positive rate was extremely high. Since cesarean section is often performed when such abnormalities are noted and is associated with risk to the mother, our findings arouse concern that, if these indications were widely used, many cesarean sections would be performed without benefit and with the potential for harm.

Adult↗

Improvement of exercise capacity and left ventricular diastolic function with metoprolol XL after acute myocardial infarction.

BACKGROUND: Left ventricular (LV) diastolic function predicts and correlates with exercise capacity. Beta-blockers improve exercise capacity and LV diastolic function in patients with severe LV systolic dysfunction in dilated cardiomyopathy. However, information on the effect of metoprolol XL on exercise capacity in relation to LV diastolic function in patients with mild to moderate LV systolic dysfunction after acute myocardial infarction is limited. METHODS: In a randomized, double-blind, placebo-controlled study of 77 patients, a subgroup of 59 patients with mild to moderate LV systolic dysfunction after acute myocardial infarction were given metoprolol XL (n = 29) or placebo (n = 30). The effects of metoprolol XL on exercise capacity in relation to effects on LV diastolic filling were studied. Two-dimensional Doppler echocardiography and maximal symptom limited bicycle test were performed on days 5 through 7 and after 3 months. RESULTS: Maximal exercise capacity increased in the metoprolol XL group (124 +/- 30 W vs 135 +/- 29 W) compared with placebo (125 +/- 31 W vs 126 +/- 34 W) (P <.01). E/A ratio decreased, A peak velocity increased, reverse pulmonary flow decreased, and deceleration time was significantly prolonged in the metoprolol XL group. A significant correlation was found between the changes of deceleration time (metoprolol XL: rho = 0.69, P <.0001; placebo: rho = 0.31, P = not significant) and A peak velocity (metoprolol XL: rho = 0.71, P <.0001; placebo: rho = -0.15, not significant) in relation to changes of exercise capacity. CONCLUSION: Metoprolol XL increases exercise capacity after 3 months, and this change seems related to improvement of LV diastolic filling after acute myocardial infarction.

Adrenergic beta-Antagonists↗

An angiotensin-converting enzyme inhibitor improves left ventricular systolic and diastolic function in transfusion-dependent patients with beta-thalassemia major.

BACKGROUND: Cardiac complications are the major cause of death in patients with beta-thalassemia major. The purpose of this study was to assess the impact of long-term treatment with the angiotensin-converting enzyme inhibitor enalapril on left ventricular (LV) performance, with an emphasis on diastolic LV function because diastolic dysfunction has been found to be an early event in an asymptomatic thalassemic population with only mild impairment of LV systolic function. METHODS: We used echocardiography to study the impact of treatment with oral enalapril on the evolution of standard M-mode and Doppler indices, along with a recently introduced Doppler index of combined systolic and diastolic LV performance. RESULTS: Patients were found to have significantly increased LV end-diastolic dimensions (LVEDD), LV end-systolic dimensions (LVESD), and left atrial dimensions and decreased LV fractional shortening (LVFS) compared with controls. After treatment with enalapril, LVESD decreased from 3.58 +/- 0.3 cm to 3.23 +/- 0.4 cm (P <.01) and LVFS increased from 32.6% +/- 4.0% to 38.0% +/- 3.1% (P <.001). Patients at baseline were found to have a significantly higher E-wave velocity, E/A ratio, and Doppler index compared with controls. The E-wave deceleration time was significantly shorter compared with that of controls. After treatment with enalapril, the E/A ratio decreased from 2.10 +/- 0.42 to 1.50 +/- 0.30 (P <.05), E-wave deceleration time increased from 0.12 +/- 0.02 seconds to 0.15 +/- 0.03 seconds (P <.01), and the Doppler index decreased from 0.46 +/- 0.10 to 0.37 +/- 0.14 (P <.05). CONCLUSIONS: Enalapril was well tolerated in asymptomatic or minimally symptomatic patients with LV dysfunction resulting from beta-thalassemia major. Echocardiographically we demonstrated significant improvement in LV systolic and diastolic function. Whether this translates to improved long-term prognosis and survival remains to be further evaluated.

Adult↗

Usefulness of peak mitral inflow velocity to predict severe mitral regurgitation in patients with normal or impaired left ventricular systolic function.

BACKGROUND: The aim of this study was to evaluate the reliability of peak mitral inflow (E-wave) velocity, which was thought to be easier and more practical than qualitative and quantitative methods used to grade mitral regurgitation (MR) in patients both with normal and low left ventricular (LV) ejection fraction (EF). It is known that peak E-wave velocity increases in MR. But correlation of this increase with regurgitant fraction (RF), its usefulness in grading MR, and the effect of EF on peak E-wave velocity have not been studied in detail. METHODS: We prospectively examined 135 consecutive patients with varying grades of MR with echocardiography. MR was evaluated both qualitatively and quantitatively, and concordance of these 2 methods was determined. Peak E-wave velocity, A-wave velocity, and E-wave deceleration time were measured and the E/A ratio was calculated. LV isovolumetric relaxation and contraction times were measured. Different MR groups classified by RF were compared with each other. RESULTS: Concordance of quantitative and qualitative evaluation was low in patients with low EF (kappa 0.37 vs 0.65). Peak E-wave velocity and E/A ratio showed significant differences between MR groups. Peak E-wave velocity correlated with the RF and EF (r = 0.47, r = 0.33, respectively, P <.001). Sensitivity, specificity, and negative predictive value of peak E-wave velocity >1.2 m/s suggesting severe MR were found to be different in patients with normal and low EF (96% vs 66%, 78% vs 83%, 97% vs 78%, respectively). E-wave deceleration, LV isovolumetric relaxation, and contraction time did not show a correlation with RF. CONCLUSION: Peak E-wave velocity is a screening method that could be used in common for determining severity of MR semiquantitatively, especially in patients with normal EF.

Adult↗

Losartan treatment and left ventricular filling during volume loading in patients with dilated cardiomyopathy.

BACKGROUND: Patients with mild heart failure show a reduction in preload reserve mechanism during volume expansion. At this time, the effects of volume expansion on left ventricular (LV) diastolic filling in this subset of patients have not been well characterized. METHODS: We evaluated the effects of acute volume loading on Doppler parameters of LV filling in 10 healthy control subjects and in 12 patients with idiopathic dilated cardiomyopathy (DCM). In patients with DCM, the effects of losartan on diastolic adaptation to volume load were also investigated. RESULTS: During volume loading, the healthy control subjects showed a decrease in isovolumic relaxation time (F = 5.3, P <.05) but an increase in the LV peak filling rate (F = 52.9, P <.001) and velocity time integral of both systolic (F = 72.8, P <.001) and diastolic (F = 4.6, P <.05) pulmonary venous flow. In patients with DCM, isovolumic relaxation time decreased more than in control subjects (F = 8.1, P <.01), and the deceleration time of the early mitral wave was reduced (F = 26.3, P <.001). Furthermore, the duration of pulmonary venous flow reversal exceeded that of mitral flow at atrial contraction (F = 28.5, P <.001). After treatment with losartan, the deceleration time of early mitral wave remained unchanged, and the duration of pulmonary venous flow reversal at atrial contraction did not exceed that of mitral flow; thus, a significant treatment effect was detectable (F = 5.6, P <.05; and F = 6.6, P <.05, respectively). CONCLUSIONS: Control subjects respond to volume load with enhancement in early LV filling, whereas patients with DCM show an increase of LV filling pressure. Diastolic adaptation to volume load improves in patients with DCM after treatment with losartan.

Adult↗

Determinants of tissue Doppler measures of regional diastolic function during dobutamine stress echocardiography.

BACKGROUND: Diastolic dysfunction induced by ischemia may alter transmitral blood flow, but this reflects global ventricular function, and pseudonormalization may occur with increased preload. Tissue Doppler may assess regional diastolic function and is relatively load-independent, but limited data exist regarding its application to stress testing. We sought to examine the stress response of regional diastolic parameters to dobutamine echocardiography (DbE). METHODS: Sixty-three patients underwent study with DbE: 20 with low probability of coronary artery disease (CAD) and 43 with CAD who underwent angiography. A standard DbE protocol was used, and segments were categorized as ischemic, scar, or normal. Color tissue Doppler was acquired at baseline and peak stress, and waveforms in the basal and mid segments were used to measure early filling (Em), late filling (Am), and E deceleration time. Significant CAD was defined by stenoses >50% vessel diameter. RESULTS: Diastolic parameters had limited feasibility because of merging of Em and Am waves at high heart rates and limited reproducibility. Nonetheless, compared with normal segments, segments subtended with significant stenoses showed a lower Em velocity at rest (6.2 +/- 2.6 cm/s vs 4.8 +/- 2.2 cm/s, P <.0001) and peak (7.5 +/- 4.2 cm/s vs 5.1 +/- 3.6 cm/s, P <.0001). Abnormal segments also showed a shorter E deceleration time (51 +/- 27 ms vs 41 +/- 27 ms, P =.0001) at base and peak. No changes were documented in Am. The same pattern was seen with segments identified as ischemic with wall motion score. However, in the absence of ischemia, segments of patients with left ventricular hypertrophy showed a lower Em velocity, with blunted Em responses to stress. CONCLUSION: Regional diastolic function is sensitive to ischemia. However, a number of practical limitations limit the applicability of diastolic parameters for the quantification of stress echocardiography.

Blood Flow Velocity↗

Prognostic importance of systolic and diastolic function after acute myocardial infarction.

BACKGROUND: Although risk stratification after acute myocardial infarction (AMI) often is focused on systolic left ventricular (LV) function, it appears that a more complete study of ventricular function including assessment of LV filling would be useful. Doppler echocardiography allows assessment of LV filling, and with the use of the Tei index (sum of isovolumic relaxation and contraction times divided by ejection time), a global estimate of ventricular function may be obtained. Therefore, the aim of this study was to determine the prognostic importance of LV systolic, diastolic, and overall LV function in a large consecutive population with AMI. METHODS: Echocardiography was performed within 6 days of AMI. LV systolic, diastolic, and global function was assessed by means of wall motion index (WMI), mitral flow pattern, and Tei index. The primary end point was all-cause death. RESULTS: Of 799 enrolled patients, 197 died during a median follow-up of 34 months. In a multivariate model including WMI and clinical parameters, WMI had important prognostic information. When mitral filling pattern and quartiles of Tei index were added to the model, restrictive filling (mitral deceleration time <140 ms) was associated with a risk ratio of 1.9 (95% CI 1.3-2.7, P <.0001, Tei index values of >0.68/0.56-0.68/0.46-0.55/<0.46 were associated with risks of 4.0 [2.1-6.9]/2.3 [1.5-3.9]/2.1 [1.2-3.6]/1.0, P <.001). In this model, WMI had no prognostic value (P =.18). CONCLUSIONS: Mitral deceleration time and the Tei index have independent and important prognostic value after AMI.

Adult↗

Usefulness of early diastolic flow propagation velocity measured by color M-mode Doppler technique for the assessment of left ventricular diastolic function in patients with hypertrophic cardiomyopathy.

Flow propagation velocity (FPV) of left ventricular (LV) filling flow has been shown to be a useful index for the evaluation of LV diastolic function, which is relatively independent of preload in myocardial infarction and dilated cardiomyopathy, but the usefulness of FPV for hypertrophic cardiomyopathy (HCM) has not yet been determined. In 23 HCM patients and 26 control subjects, peak transmitral flow velocities in early diastole (E) and during atrial contraction (A), E/A ratio, deceleration time of E velocity, and isovolumic relaxation time were measured with the conventional Doppler technique, and FPV was measured from color M-mode Doppler images of LV filling flow. The time constant of LV isovolumic pressure decay (tau) was measured by a micro-manometer-tipped catheter in all HCM patients and 13 control subjects. Flow propagation velocity was significantly lower and deceleration time was significantly greater in HCM patients than in the control subjects, though no significant differences were observed in the other noninvasive indexes. Tau was significantly prolonged in HCM patients compared with that of control subjects (54+/-12 cm/s and 32 +/-7 cm/s, respectively; P<.0001). While the conventional indexes did not correlate with tau among the 36 patients in whom invasive studies were performed, FPV correlated well with tau (r = -0.76, P<.0001). Flow propagation velocity is a useful noninvasive index for the assessment of LV diastolic function in patients with HCM.

Adolescent↗

The impact of maternal ketonuria on fetal test results in the setting of postterm pregnancy.

OBJECTIVE: The aim of this study was to determine whether ketonuria, a commonly assessed urinary marker of maternal starvation and dehydration, is associated with abnormal fetal test results in the setting of postterm pregnancy. STUDY DESIGN: During a 4-year period (January 1993-December 1996), a total of 3655 visits for antepartum maternal-fetal testing of postterm pregnancies (> or =41 weeks' gestation) occurred at our institution. Maternal assessment included vital signs and urinalysis. The presence and degree of maternal ketonuria was correlated against abnormal results of fetal heart rate tests, nonstress tests, amniotic fluid index measurements, and biophysical profile scores performed on the same day. RESULTS: There were 3601 encounters suitable for inclusion in the study. Clinically detectable ketonuria occurred in 10.9% of the patients studied. Patients with clinically detectable ketonuria were at increased risk relative to patients without ketonuria for abnormal outcomes during postterm testing, including the presence of oligohydramnios (24% vs. 9.3%; P<.0001 ), nonreactive nonstress tests (6.2% vs. 2.15%; P<.0001), and fetal heart rate decelerations (14% vs 9.2%; P =.0039 ). CONCLUSION: Maternal ketonuria among patients with postterm pregnancy was associated with a >2-fold increase in the occurrence of oligohydramnios, a 3-fold increase in nonreactive nonstress tests, and a significant increase in fetal heart rate decelerations. Further studies are required to evaluate the potential benefits of treating ketonuria before fetal testing.

Adult↗

Left ventricular diastolic filling response to stationary bicycle exercise during pregnancy and the postpartum period.

OBJECTIVE: The purpose of this study was to determine the effects of pregnancy and of maximal exercise on left ventricular diastolic filling response. STUDY DESIGN: Transmitral pulsed Doppler echocardiography was obtained in 10 healthy women during each trimester of pregnancy and at 12 weeks after delivery. Doppler studies were performed at rest and at each exercise workload. The P-R interval, the early and atrial peak flow velocities, the mitral early deceleration time, and the isovolumetric relaxation time were analyzed. Data are expressed as the mean and standard deviation of the mean. Values obtained during the last trimester of pregnancy were used as the pregnant value; values at the 12 weeks after delivery were used as the nonpregnant value. Paired t -test, analysis of variance, and mixed models were used to determine significance with a probability value of <.05. RESULTS: Pregnancy significantly increased the early and atrial peak flow velocities. Pregnancy decreased the P-R interval, the early deceleration time, and the isovolumetric relaxation time. Exercise significantly decreased these diastolic functions; but pregnancy, in any of the 3 trimesters, did not significantly affect this response. CONCLUSION: Pregnancy increased left ventricular diastolic camber stiffness at rest and shifted left ventricular diastolic filling during exercise from predominantly early to atrial filling. This finding suggests that there is an increase in left ventricular chamber stiffness during maximal upright bicycle exercise in pregnancy.

Adult↗

Predictability of intrapartum and neonatal outcomes with the amniotic fluid volume distribution: a reassessment using the amniotic fluid index, single deepest pocket, and a dye-determined amniotic fluid volume.

OBJECTIVE: The purpose of this study was to establish whether ultrasound-estimated or dye-determined amniotic fluid distribution (upper compared with lower quadrant) is predictive of perinatal outcome. STUDY DESIGN: Amniotic fluid distribution as measured by the amniotic fluid index, single deepest pocket, and dye-determined volumes was ascertained and correlated with intrapartum and neonatal outcomes. RESULTS: Between January 1997 and January 2001, 135 women (70 upper-greater and 65 lower-greater) participated in this prospective observational study. The sum of the amniotic fluid index (P =.309), single deepest pocket (P =.168), and dye-determined amniotic fluid volume (P =.368) for the upper-greater compared with the lower-greater groups were similar. Decelerations in labor (P =.597), late decelerations (P =.999), cesarean deliveries for fetal distress (P =.413), and umbilical cord pH < 7.2 were similar (P =.647) CONCLUSION: Ultrasound-estimated and dye-determined amniotic fluid volumes are similar between upper-greater and lower-greater groups, and intrapartum/neonatal outcomes are not affected by the amniotic fluid distribution.

Adult↗

Mandibular growth as related to cervical vertebral maturation and body height.

The purpose of this study was to analyze the validity of 6 stages of cervical vertebral maturation (Cvs1 through Cvs6) as a biologic indicator for skeletal maturity in 24 subjects (15 females, 9 males). The method was able to detect the greatest increment in mandibular and craniofacial growth during the interval from vertebral stage 3 to vertebral stage 4 (Cvs3 to Cvs4), when the peak in statural height also occurred. The prevalence rate of examined subjects who presented with the peak in body height at this interval was 100% for boys and 87% for girls. Statural height and total mandibular length (Co-Gn) showed significant increments during the growth interval Cvs3 to Cvs4 when compared with the growth interval Cvs2 to Cvs3, and significant growth deceleration occurred during the interval Cvs4 to Cvs5 when compared with Cvs3 to Cvs4. Ramus height (Co-Goi) and S-Gn also showed significant deceleration of growth during the interval Cvs4 to Cvs5 when compared with Cvs3 to Cvs4. Cervical vertebral maturation appears to be an appropriate method for the appraisal of mandibular skeletal maturity in individual patients on the basis of a single cephalometric observation and without additional x-ray exposure. The accuracy of the cervical vertebral method in the detection of the onset of the pubertal spurt in mandibular growth provides helpful indications concerning treatment timing of mandibular deficiencies.

Adolescent↗

Eating behavior in Prader-Willi syndrome, normal weight, and obese control groups.

OBJECTIVE: Hyperphagia in Prader-Willi syndrome (PWS) is hypothesized to be due to hypothalamic dysfunction; thus the study of individuals with PWS might illustrate how hypothalamic dysfunction affects eating behavior. The aim of this study was to document the microstructure of the eating behavior in patients with PWS and to compare it with that of members of obese and normal weight control groups of the same age. STUDY DESIGN: Nine subjects with PWS (age, 10 +/- 4 years), 20 normal weight subjects (age, 12 +/- 3 years), and 20 obese subjects (age, 12 +/- 4 years) were served an excess lunch meal (hash) on a hidden scale built into a table and connected to a computer. The plate of food is placed on top of the scale, and when the food is eaten, the change in food weight is registered continuously. An eating curve is displayed online. After the meal, the eating data are fitted to a polynomial, and the computer calculates the amount of food eaten, time of consumption, eating rate (initial and total), and rate of deceleration. RESULTS: Subjects with PWS were found to have a longer duration of eating (P =.04) and a slower initial eating rate (P =. 01) compared with members of both obese and normal weight groups. In subjects with PWS, 56% of the eating curves were non-decelerating (linear or accelerating) compared with 10% of the normal weight group and 30% of the obese group (P =.02). CONCLUSION: The microstructure of the eating behavior in subjects with PWS differs from that of members of obese and normal weight control groups. Thus the eating behavior found in subjects with PWS might be due to decreased satiation rather than increased hunger.

Adolescent↗

The relationship between amniotic fluid index and successful external cephalic version: a 14-year experience.

OBJECTIVE: This study was undertaken to assess the association between amniotic fluid index (AFI), success of external cephalic version (ECV), and obstetric outcome in patients undergoing ECV. STUDY DESIGN: A prospective observational study was performed that included all patients who had a trial of ECV from 1987 to 2000 in our center. Rates of success, fetal heart decelerations during trial at ECV, and cesarean deliveries were calculated. Groups were divided by an AFI performed immediately before ECV: AFI less than 10 cm, 10 to 15 cm, and more than 15 cm. RESULTS: In our group of 1361 patients undergoing ECV, the rate of success was related to the AFI in both parous women (49.1%, 63.5% and 72.1% [P<.001] for each AFI group, respectively) and nulliparous women (36.5%, 43.6%, and 57.3% [P<.001]). The rate of cesarean section delivery was related to AFI in nulliparous but not multiparous patients (P<.001). The rate of prolonged fetal heart rate decelerations was not significantly related to the AFI. CONCLUSION: The rate of successful ECV and cesarean section deliveries is related to the amniotic fluid volume. This information may be used to consent patient before a trial of ECV.

Amniotic Fluid↗

Serial Doppler assessment of diastolic function before and after the Fontan operation.

Serial Doppler echocardiography was used to evaluate the effects of the Fontan operation (FO) on diastolic ventricular function in 55 patients with univentricular heart. Examinations were performed before operation, before postoperative discharge, and 6 months to 6 years postoperatively. Preoperatively, early diastolic atrioventricular valve (E) flow was reduced and deceleration times prolonged relative to healthy children. All pulmonary vein diastolic flow variables, except diastolic velocity, were increased relative to control subjects. After FO, E/atrial velocity and E/atrial time velocity integral ratios were decreased whereas deceleration and isovolumic relaxation time remained constant. Diastolic pulmonary vein forward flow increased after FO. These data suggest inherently abnormal ventricular relaxation in the univentricular heart and that changes in flow patterns observed postoperatively were subtle and likely a result of reduced ventricular preload after FO. Overall, diastolic function most probably remained stable after FO. This information can be used as a benchmark for further diastolic function assessment in patients with surgically palliated univentricular heart.

Adolescent↗

Interstudy reproducibility of parameters of left ventricular diastolic function: a Doppler echocardiography study.

BACKGROUND AND METHODS: Interstudy reproducibility of echocardiography for the assessment of parameters of left ventricular (LV) diastolic function is disputed. Therefore, we evaluated the reproducibility of echocardiography for assessment of LV diastolic Doppler parameters in 40 consecutive patients (age range: 19-77 years), who underwent 2 echocardiographic examinations by trained sonographers following a standard protocol, in conditions in which intrapatient sources of variability were minimized. RESULTS: Interstudy reproducibility of measurements of the ratio of early (E) to late (A) peak velocities of transmitral flow (E/A) at tips of the mitral valve leaflets was found to be very good and substantially greater than analogous measurement obtained at mitral annulus level. Reproducibility of measurement of atrial filling fraction was good both at tips of mitral leaflets and at annular level. Interstudy reproducibility of isovolumic relaxation time and E-wave deceleration time was moderate. Measurements of E-wave propagation rate and the ratio of early (E') to late (A') peak velocities of diastolic excursion of lateral mitral annulus (E'/A') by Doppler tissue were found highly reproducible. Intrastudy between-reading reproducibility of Doppler parameters of LV diastolic function were overall very good, except for E-wave deceleration time. However, 80% confidence interval of absolute between-study differences of diastolic parameters were relatively large, and ranged from -0.11 to +0.19 for E/A at tips of mitral valve; -5 to +9 cm/s for E-wave propagation rate; and -0.69 to +0.19 for Doppler tissue-derived E'/A'. CONCLUSIONS: Under a standardized echocardiographic protocol and sonographers' training program, echocardiography can be a reproducible method for serial assessment of Doppler parameters of LV diastolic function, especially in cohort studies.

Adult↗

Rates, patterns, and effectiveness of evolution in multi-level situations.

Evolution is a multi-level process. Both actual evidence and theoretical considerations suggest as a first generalization that evolution both at single levels and in series of increasingly complex levels decelerates with time. Additional evidence, the expected difference between rapid nonadaptive speciation in small populations and effective adaptation in large ones, and analysis of explosive evolution suggest further that effective adaptive evolution occurs primarily in large populations, and that segments of such evolution tend to begin slowly; accelerate, sometimes explosively; and then decelerate. The segments are irregular, and do not occur at regular intervals. However, the explosive evolution of a general adaptation pre-adapts to and is often followed by an explosive radiation of derivative lineages. This description seems to fit the origin and initial radiation of mammals, and the evolutionary history of man and man's cultures.

Animals↗

Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide.

Mice in which the genes encoding the parathyroid hormone (PTH)-related peptide (PTHrP) or the PTH/PTHrP receptor have been ablated by homologous recombination show skeletal dysplasia due to accelerated endochondral bone formation, and die at birth or in utero, respectively. Skeletal abnormalities due to decelerated chondrocyte maturation are observed in transgenic mice where PTHrP expression is targeted to the growth plate, and in patients with Jansen metaphyseal chondrodysplasia, a rare genetic disorder caused by constitutively active PTH/PTHrP receptors. These and other findings thus indicate that PTHrP and its receptor are essential for chondrocyte differentiation. To further explore the role of the PTH/PTHrP receptor in this process, we generated transgenic mice in which expression of a constitutively active receptor, HKrk-H223R, was targeted to the growth plate by the rat alpha1 (II) collagen promoter. Two major goals were pursued: (i) to investigate how constitutively active PTH/PTHrP receptors affect the program of chondrocyte maturation; and (ii) to determine whether expression of the mutant receptor would correct the severe growth plate abnormalities of PTHrP-ablated mice (PTHrP-/-). The targeted expression of constitutively active PTH/PTHrP receptors led to delayed mineralization, decelerated conversion of proliferative chondrocytes into hypertrophic cells in skeletal segments that are formed by the endochondral process, and prolonged presence of hypertrophic chondrocytes with delay of vascular invasion. Furthermore, it corrected at birth the growth plate abnormalities of PTHrP-/- mice and allowed their prolonged survival. "Rescued" animals lacked tooth eruption and showed premature epiphyseal closure, indicating that both processes involve PTHrP. These findings suggest that rescued PTHrP-/- mice may gain considerable importance for studying the diverse, possibly tissue-specific role(s) of PTHrP in postnatal development.

Animals↗