Closure of palatal fistula with a local mucoperiosteal flap lined with buccal mucosal graft.

OBJECTIVE: Oro-nasal fistula is a common complication of palatoplasty. Current methods for fistula repair utilize mucoperiosteal flaps or pedicled flaps. These procedures are often cumbersome and leave a raw nasal surface, which may increase the incidence of postoperative risks and problems. In addition, the recurrence rate of the fistula is as high as 34%. We propose a simple two-layer method of fistula repair to avoid recurrences. DESIGN: A standard mucoperiosteal flap is raised on the oral side. A buccal mucosal graft is harvested from the cheeks and sutured to the nasal side of the flap that is then inset into the fistula. SETTING: Patients were either referred to the senior author's private practice (four patients) or were patients who had previously been operated on by the senior author himself (three patients). SUBJECTS: Study subjects consisted of seven patients, four males and three females, ages 14 months to 8 years. All patients had previously undergone cleft palate repair, complicated by subsequent oro-nasal fistula formation. INTERVENTIONS: All patients underwent oro-nasal fistula repair under general anesthesia with a local mucoperiosteal flap lined with buccal mucosal grafts placed on the nasal side of the flap. RESULTS: In all cases, the fistula was completely closed at first attempt without complications. Patients were followed for a minimum of 2 years, without evidence of recurrence. CONCLUSIONS: Our proposed surgical procedure for fistula closure using a standard mucoperiosteal flap lined with a buccal mucosal graft is a suitable alternative for the repair of postpalatoplasty oro-nasal fistulas. Further study and long-term follow-up is needed to establish this method as a new standard form of repair.

Number of nodes examined and staging accuracy in colorectal carcinoma.

PURPOSE: The objective of this study was to determine the number of nodes that need to be examined to accurately reflect the histology of the regional lymphatics in colorectal carcinoma. PATIENTS AND METHODS: Patients undergoing curative resection for T2 and T3 colorectal cancer between 1992 and 1996 were reviewed. Pathologic data from these patients were entered into a computerized database for storage, retrieval, and analysis. The major outcome measured was the number of nodes that need to be examined to achieve a node-positive rate consistent with that reported in the National Cancer Data Base (NCDB) report. RESULTS: The number of nodes examined ranged from 0 to 78 (mean, 17 nodes). Node-negative patients had fewer nodes examined (mean, 14 nodes) than node-positive patients (mean, 20 nodes; P =.003). The entire sample had a node-positive rate of 38.8% (95% confidence interval [CI], 32% to 45.5%), not statistically different from that in the NCDB report. When at least 14 nodes were examined, the percent of patients with at least one positive node was 33.3% (95% CI, 24.6% to 42.3%), not statistically different from the NCDB report. CONCLUSION: In a sample of patients statistically similar to the sample in the NCDB report, the examination of at least 14 nodes after resection of T2 or T3 carcinoma of the colon and rectum will accurately stage the lymphatic basin.

Effect of the oxytocin antagonist atosiban (1-deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/oxytocin) on nocturanl myometrial contractions, maternal cardiovascular function, transplacental passage, and fetal oxygenation in the pregnant baboon during the last third of gestation.

The oxytocin antagonist, atosiban (1-deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/oxytocin), was infused i.v. to chronically instrumented pregnant baboons in the last third of pregnancy. Atosiban (6 microg/kg per min) inhibited myometrial electromyographic activity associated with spontaneous myometrial contractions that occurred around the onset of darkness between 134 and 162 days gestation (term 180 days gestation). The effect of atosiban on maternal heart rate was minimal. Maternal blood pressure remained unaltered during atosiban infusion. Fetal carotid arterial PO2 was unchanged during a 2-h infusion of atosiban. Transplacental passage of atosiban from mother to fetus was assessed at cesarean section under halothane anesthesia in four baboons and in two chronically instrumented fetuses in the absence of anesthesia. The maternal:fetal concentration gradient ranged from 9.2 to 22.8. Maternal atosiban clearance rates were 9.2-16.9 ml/kg per min. In conclusion, atosiban was very effective at inhibiting spontaneously occurring nocturnal myometrial contractions during the last third of gestation in the pregnant baboon. Although atosiban crosses the placenta relatively freely, there was no effect on fetal oxygenation.

Cocaine's effect on plasma oxytocin concentrations in the baboon during late pregnancy.

OBJECTIVE: The hypothesis for this investigation was that intravenous cocaine would result in an elevation of maternal plasma oxytocin levels in the baboon during late pregnancy. STUDY DESIGN: Five gravid chronically instrumented baboons had timed arterial blood samples obtained before and after an intravenous bolus cocaine infusion at least 5 days after surgery. Plasma oxytocin concentrations were measured by specific radioimmunoassays, and baseline samples were compared with postcocaine samples. RESULTS: The plasma oxytocin concentrations were significantly elevated at all sampling times after the 1.0 mg/kg cocaine dose (p<0.05). CONCLUSION: The increased oxytocin concentration after cocaine use may be responsible for the increased incidence of preterm labor.

Regulation of the switch from myometrial contractures to contractions in late pregnancy: studies in the pregnant sheep and monkey.

Myometrial contractility occurs throughout pregnancy and characteristic patterns of myometrial activity exist according to the endocrine status and the relationship to parturition. These characteristic patterns differ between species, yet certain common features can be observed. Throughout pregnancy, myometrial activity is of the contractures type, long-lasting, low-amplitude epochs of activity switching to contraction-type activity at term. This switch from contractures to contractions tends to occur at night and is related to alteration in maternal plasma oestrogen concentrations, and maternal oxytocin function. Studies in several animal species support the hypothesis that maternal oestrogen prepares the myometrium for a periodic signal that causes the switch from contractures to contractions. Several lines of evidence implicate oxytocin in the switch. These studies show that the detailed preparation for parturition takes longer than previously considered and is brought about by a carefully regulated sequence of events in which oestrogen production by the placenta plays a central role.

Primate parturition and the role of the maternal circadian system.

Several 24-h rhythms have been observed in the mother and in the fetus during primate gestation. In the mother, 24-h rhythms occur in biophysical variables, pregnancy-associated plasma hormones and preparturient myometrial activity. In addition, both pregnant non-human primates and pregnant women deliver preferentially during the night and early morning hours. A crucial question pertaining circadian rhythms is whether 24-h rhythms that may be observed during pregnancy are endogenous in nature and entrained by the light-dark cycle or whether the daily photoperiod is a causal stimulus. Our work has addressed the role of the maternal and fetal circadian system for 24-h rhythms in pregnancy-associated maternal plasma hormones, preparturient myometrial activity and parturition in human and non-human primate pregnancy. In the present review, the results of some of our studies are being discussed in combination with data available from the literature. It is apparent that 24-h rhythms that may be observed during primate pregnancy are determined by the maternal circadian system, suggesting that the developing fetus receives information about the ambient time of the day via the mother. Fetal entrainment by the mother may ensure fetal cooperation so that parturition occurs at the most favorable time of the day. We conclude that the functioning of the maternal circadian system is integral to the pregnant state. Thus, proper care and management of pregnant women and the ultimate outcome of obstetrics may benefit from more timely methodologies. A chronopharmacological attitude towards the prevention of premature labor and the induction and augmentation of labor at term may yield new therapeutic strategies. Such an approach will enable delivery to take place under optimal conditions for mother and child.

Circadian timekeeping during pregnancy: endogenous phase relationships between maternal plasma hormones and the maternal body temperature rhythm in pregnant rhesus monkeys.

Nine pregnant rhesus monkeys maintained in constant low level lighting (5 Lux) from 56-80 days gestation (dGA) onward were studied to assess the presence or absence of circadian maternal body temperature and maternal plasma hormone variations. Maternal arterial blood samples were taken every 4 h in six monkeys (105-120 dGA) for 48-56 h and every 2 h in three monkeys (108-115 dGA) for 60 h. Maternal intraabdominal temperature was recorded continuously. Cosinor analysis was used to determine circadian rhythmicity. Individual endogenous timekeeping was demonstrated by 1) free-running circadian variations in maternal body temperature in all nine animals, 2) consistent internal acrophase relationships between the maternal body temperature and maternal plasma cortisol rhythm, and 3) idiosyncrasy of the temporal relationship of detectable rhythms to the external environment in individual animals. Only one animal had a significant maternal plasma ACTH rhythm, whereas the presence of 24-h variations in the other hormones varied in individual animals. The mean +/- SD acrophase profiles in hours from the temperature acrophase in those animals who showed significant rhythms were 19.7 +/- 0.6 (n = 8) for cortisol, 19.4 +/- 2.4 (n = 6) for dehydroepiandrosterone sulfate, 8.3 +/- 1.1 (n = 6) for progesterone, and 18.9 +/- 1.6 (n = 3) for estradiol. We conclude that 24-h variations in maternal plasma hormones are truly endogenously generated and not passively dependent on the light-dark cycle. The maternal circadian system regulates the 24 h temporal organization of endogenous plasma hormone variations. We hypothesize that rhythms in cortisol, dehydroepiandrosterone sulfate, progesterone, and estradiol during pregnancy are directly or indirectly governed by the maternal hypothalamus via the circadian oscillatory output of the maternal adrenal.

In the rhesus monkey placental retention after fetectomy at 121 to 130 days' gestation outlasts the normal duration of pregnancy.

OBJECTIVE: Our aim was to reassess the role of the fetus in the initiation of parturition in nonhuman primates. We tested the effect of the removal of the fetus at 121 to 130 days' gestation on the duration of gestation in pregnant rhesus monkeys. STUDY DESIGN: Nine monkeys underwent fetectomy with the placenta in situ. Five monkeys underwent surgery without removal of the fetus. RESULTS: In five control monkeys spontaneous vaginal delivery of live fetuses occurred at 163.8 +/- 4.6 days' gestation (mean +/- SD). In four of nine monkeys that underwent fetectomy the placenta delivered spontaneously at 185, 193, 201, and 207 days' gestation. The five remaining monkeys underwent cesarean section at 162, 189, 201, 202, and 219 days' gestation. Duration of placental retention in monkeys that underwent fetectomy (195 +/- 16.1 days' gestation) exceeded that in controls (p less than 0.05). Plasma progesterone and estradiol concentrations were normal for gestational age at fetectomy, indicating continued placental function. CONCLUSION: We conclude that the presence of a live fetus plays a significant role in the determination of the duration of normal pregnancy in the rhesus monkey.

Temporal structuring of delivery in the absence of a photoperiod: preparturient myometrial activity of the rhesus monkey is related to maternal body temperature and depends on the maternal circadian system.

No convincing evidence exists that the shift from myometrial contractures to contractions, which determines the synchronized 24-h rhythm in the dynamics of the primate uterus, may be attributed to an endogenous circadian rhythm. We therefore wished to ascertain whether a 24-h periodic shift would also occur in the myometrial activity of animals kept under constant conditions. We studied five pregnant rhesus monkeys, kept in continuous darkness from 56-77 days gestational age until delivery at 117-167 days gestational age. During the last week before delivery we determined the individual phase, level, and amplitude of circadian changes in maternal body temperature and 24-h myometrial activity patterns in the form of contractions. In all five monkeys, a rhythm with a period of 24-h characterized the temporal incidence of preparturient contraction activity. A consistent phase lag of 6-7 h from the temperature crest was observed in four out of the five animals. The circadian phase of all individual rhythms was idiosyncratic among animals. We conclude that endogenous rhythms in body temperature and preparturient myometrial activity are truly circadian. In addition, these rhythms are either interdependent or subject to the same maternal timekeeping mechanism, supporting the hypothesis that the exact time of the day at which birth occurs in the rhesus monkey depends on the maternal circadian system.

Alteration of 24-hour rhythms in myometrial activity in the chronically catheterized pregnant rhesus monkey after a 6-hour shift in the light-dark cycle.

We determined the effect of a 6-hour phase shift in the light-dark cycle on the 24-hour rhythm of myometrial activity with 15 chronically catheterized pregnant rhesus monkeys during the last third of gestation. Monkeys were housed indoors in constant temperature on a 14-hour-light/10-hour-dark photoperiod in two groups based on the time the lights were turned on (group A lights on at 6 AM and group B lights on at midnight). The power spectra were calculated for periods of 512 readings (1.138 hours) starting at the time the lights were turned on for continuous periods of 25.03 hours of data showing well-developed contraction-type activity at any time during that period. The power spectra data for contractures and contractions were analyzed separately from myometrial electromyographic data. During the 14 hours of light, myometrial activity was primarily composed of contractures. In all experimental animals the switch from contractures to contractions occurred around the time the lights were turned off. The proportion of contraction-type activity in each 1.138-hour analysis interval expressed as a percentage of the total contraction power for the whole 25.03-hour analysis period for all monkeys increased around the time the lights were turned off in both groups. The increase in contractions was observed 12 to 15 hours after the lights were turned on. No systematic change in the proportion of contracture activity was observed. Peak contraction activity was 22.6 +/- 0.60 hours (16.6 hours after lights on), and was at 18.3 +/- 1.4 hours (18.31 hours after lights on) in groups A and B, respectively. This difference was statistically significant (22.6 +/- 0.6 vs 18.3 +/- 1.4 hours, p less than 0.05). Seven of eight monkeys in group A and six of seven in group B had switched from contractures to contractions before lights were turned off. We have confirmed a 24-hour rhythm in myometrial activity in the pregnant rhesus monkey and provided new evidence to support the endogenous nature of this rhythm and its direct relationship to the light-dark cycle.

Development of vasopressin neurons in the human suprachiasmatic nucleus in relation to birth.

The number of neurons expressing vasopressin (AVP) was determined in the suprachiasmatic nucleus (SCN) of the hypothalamus of 41 human subjects ranging in age from 27 weeks of gestation up to 30 years of age. At term, i.e. at 38-42 weeks of gestation, the fetal SCN is still immature, since it then contains only about 13% of the adult number of AVP-expressing neurons. The period of rapid increase in the number of AVP-staining neurons in the SCN during the first few months postnatally coincides with the appearance of overt diurnal rhythms in the child.

Biphasic effect of a prostacyclin methyl ester analog on uterine contractility in the chronically catheterized pregnant rhesus monkey in late gestation.

We determined the in vivo effects of a prostacyclin methyl ester analog (PGI2) administration on myometrial activity in twelve chronically- catheterized pregnant rhesus monkeys during the last third of pregnancy under three different states of myometrial contractility: postsurgical contractions, spontaneous contractures and oxytocin induced contractions. Prostacyclin (200 micrograms) was administered to four monkeys 2-3 h after surgery, to eight monkeys having only contractures, and to four monkeys having oxytocin induced contractions. Vehicle administration was performed in six animals having contractures and to four having oxytocin induced contractions. In all three experimental paradigms PGI2 administration elicited a biphasic response in uterine contractility. An initial increase in the 5 min average intrauterine pressure (IUP) value from 2.3 +/- 1.29 to 5.8 +/- 2.29; 3.6 +/- 2.38 to 7.6 +/- 3.59; and 2.3 +/- 0.65 to 8.6 +/- 0.72 (SD); was observed in the post-surgical, spontaneous contracture and oxytocin induced contraction groups respectively (mmHg, P less than 0.05). This increase was followed by a fall in the 5 min average IUP from 2.3 +/- 1.29 to 0.6 +/- 0.49; 3.6 +/- 2.38 to 1.3 +/- 0.86; and 2.3 +/- 0.65 to 0.1 +/- 0.11 in the post-surgical, spontaneous contracture and oxytocin induced contraction groups respectively (mmHg, P less than 0.05). A fall in mean arterial blood pressure from 89 +/- 9.0 to 55 +/- 10.9 (mmHg, P less than 0.05) and a compensatory tachycardia from 108 +/- 18.2 to 164 +/- 56.2 (beats.min-1, P less than 0.05) was observed by 10 min after PGI2 administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the role of oxytocin in late pregnancy in the pregnant rhesus monkey: plasma concentrations of oxytocin in the maternal circulation throughout the 24-h day and the effect of the synthetic oxytocin antagonist [1-beta-Mpa(beta-(CH2)5)1,(Me(Tyr2, Orn8] oxytocin on spontaneous nocturnal myometrial contractions.

Previous observations have demonstrated that under several different circumstances the pregnant rhesus monkey myometrium shows a spontaneous shift in activity from contractures to contractions around the beginning of the hours of darkness. Preliminary studies were conducted to demonstrate that the competitive oxytocin antagonist ([1-beta-Mpa(beta-(CH2)5)1,) Me)Tyr2, Orn8] oxytocin was effective in vivo in inhibiting oxytocin induced contraction type myometrial activity in the pregnant rhesus monkey in the last third of gestation. Four pregnant and one fetectomized rhesus monkey (98-141 days gestation) received one intra-arterial dose of oxytocin antagonist to study its ability to inhibit myometrial contractions occurring spontaneously around the onset of prevailing nighttime. In three pregnant monkeys (105-121 days gestation) maternal arterial plasma oxytocin levels were measured at 4-h intervals for a period of 48 h. Maternal plasma oxytocin concentration was maximal during the early hours of darkness and demonstrated a significant 24-h rhythm. From the combined results of both experiments it may be concluded that circulating oxytocin and/or a change in one of the many potential regulatory sites for oxytocin function plays a role in the switch from contractures to contractions that occurs around the beginning of the hours of darkness.

Variation in myometrial response to intravenous oxytocin administration at different times of the day in the pregnant rhesus monkey.

To assess a potential underlying rhythm in the sensitivity of the pregnant primate myometrium to oxytocin we infused five pregnant rhesus monkeys (gestational age, 121-142 days) with oxytocin at three different periods of the 24-h day, in the order night, afternoon, and morning, via the maternal inferior vena cava. Oxytocin was administered for 1 min every 5 min over 30 min at four doses 400, 800, 2000, and 4000 pg/min.kg. The response of the myometrium, evaluated as the number of contractions per pulse of oxytocin, was greatest in the early hours of darkness. Studies in three additional monkeys in which the order of the oxytocin challenge tests was changed, again showed that the response to oxytocin was greatest in the hours of darkness. We conclude that an underlying, as yet undefined, rhythm exists in the sensitivity of the pregnant primate myometrium to oxytocin at different times of the 24-h day. This change in myometrial sensitivity may be due to variation in one or more of the many potential regulatory sites of oxytocin's action at the cellular level. We hypothesize that this difference in myometrial sensitivity to oxytocin plays a role in the switch from myometrial contractures to contractions that occurs around the hours of darkness, e.g. postsurgery, during food withdrawal, and before delivery.

Power spectrum analysis of myometrial electromyogram and intrauterine pressure changes in the pregnant rhesus monkey in late gestation.

Various methods have been used to quantify myometrial activity in the pregnant rhesus monkey during the last third of gestation. A precise definition of activity must retain the characteristics of epoch duration, amplitude, and the repetitive frequencies of active epochs. We used Fast Fourier Transform and power spectrum analysis to determine whether the patterns of myometrial contractility consist predominantly of contractions or contractures. This analysis allows quantification of activity represented by each of these patterns of activity. We applied these methods to myometrial electromyogram and intrauterine pressure recordings in pregnant rhesus monkeys to characterize the changes in myometrial activity that occur after surgery, after intravenous indomethacin administration, and when food is withdrawn for 48 hours. We conclude that changes in the frequency pattern of myometrial activity provide important information in relation to labor and delivery contractions.

Effect of a 48-hour intravenous delta 4-androstenedione infusion on the pregnant rhesus monkey in the last third of gestation: changes in maternal plasma estradiol concentrations and myometrial contractility.

Increased myometrial activity in the pregnant rhesus monkey occurs in situations in which plasma estrogen concentrations are elevated. Examples of such situations are after laparotomy, with or without hysterotomy, and before delivery. The increased activity occurs primarily in the hours of darkness. To investigate the possibility of a causal relationship between the rise in estrogens and myometrial activity, we infused androstenedione intravenously for 48 hours to the rhesus monkey in the last third of gestation. Myometrial activity was quantified either as an increase in the number of individual contraction events or as a change in the power spectrum at high frequencies characteristic of contractions. Androstenedione infusion was followed by increased myometrial activity. Maternal plasma 17 beta-estradiol concentration was significantly elevated at 10 AM on the second day of androstenedione infusion. We conclude that, in the rhesus monkey late in gestation, estradiol may play a role in the regulation of the contraction activity observed during the hours of darkness in several different situations.

Endocrine changes during 48 hours of food withdrawal in the pregnant rhesus monkey in the last third of gestation.

We studied the hormonal responses in four pregnant rhesus monkeys between 112 and 149 days gestation. After 2 days, during which the monkeys were fed ad libitum, their food was withdrawn at 1500 h for 48 h while allowing free access to water. The food then was returned, and the animals were studied for a further 2 days. The mean maternal whole blood glucose concentration significantly decreased, and plasma cortisol and dehydroepiandrosterone sulfate (DHEAS) concentrations significantly increased within 30 h of food withdrawal (P less than 0.05). The maternal plasma estradiol concentration increased significantly at 1000 h on the second day of food withdrawal (P less than 0.05), whereas the plasma progesterone concentration did not change. The maternal blood glucose and plasma cortisol, DHEAS and estradiol concentrations returned to baseline by the second day of food replacement. We conclude that the stress of hypoglycemia and/or the attendant inability to eat, together or separately, stimulate maternal adrenal glucocorticoid and androgen secretion during the period of food withdrawal. The increased maternal DHEAS and perhaps other adrenal androgen concentrations result in increased maternal estrogen production.