Molecular Diagnostics and In Utero Therapeutics for Orofacial Clefts.

Orofacial clefts and their management impose a substantial burden on patients, on their families, and on the health system. Under the current standard of care, affected patients are subjected to a lifelong journey of corrective surgeries and multidisciplinary management to replace bone and soft tissues, as well as restore esthetics and physiologic functions while restoring self-esteem and psychological health. Hence, a better understanding of the dynamic interplay of molecular signaling pathways at critical phases of palate development is necessary to pioneer novel prenatal interventions. Such pathways include transforming growth factor-ß (Tgfß), sonic hedgehog (Shh), wingless-integrated site (Wnt)/ß-catenin, bone morphogenetic protein (Bmp), and fibroblast growth factor (Fgf) and its associated receptors, among others. Here, we summarize commonly used surgical methods used to correct cleft defects postnatally. We also review the advances made in prenatal diagnostics of clefts through imaging and genomics and the various in utero surgical corrections that have been attempted thus far. An overview of how key mediators of signaling that drive palatogenesis are emphasized in the context of the framework and rationale for the development and testing of therapeutics in animal model systems and in humans is provided. The pros and cons of in utero therapies that can potentially restore molecular homeostasis needed for the proper growth and fusion of palatal shelves are presented. The theme advanced throughout this review is the need to develop preclinical molecular therapies that could ultimately be translated into human trials that can correct orofacial clefts at earlier stages of development.

Sympathetic ophthalmia associated with pars plana vitrectomy without antecedent penetrating trauma.

PURPOSE: To evaluate, describe, and categorize the clinical presentation, clinical course, histopathology, and response to therapy in patients without a history of penetrating ocular trauma who developed sympathetic ophthalmia following pars plana vitrectomy. METHODS: The records of patients without a history of trauma who underwent pars plana vitrectomy and developed sympathetic ophthalmia were retrospectively reviewed. Cases were analyzed with respect to clinical presentation, fluorescein angiographic findings, anatomic and visual outcomes, histopathology, and response to therapy. RESULTS: Eight eyes were identified. The median age at presentation was 55 years, with a range of 14 to 62 years. The time from vitrectomy to diagnosis of sympathetic ophthalmia ranged from 2 months to greater than 2 years, with a median of 7 months. Six of eight patients (75%) presented with anterior chamber reaction. All eight patients presented with a vitreous inflammatory response. The optic nerve was inflamed clinically or angiographically in four of eight cases (50%). Small yellow-white sub-retinal pigment epithelial deposits were present in four of eight cases (50%). Two eyes had lesions characterized as multifocal choroiditis. One eye had larger yellow placoid-like lesions. One eye presented with vitritis but no retinal lesions. Subretinal choroidal neovascularization was noted in the inciting eye of one patient. Vision improved in the sympathizing eye with immunosuppressive therapy in five of eight cases (62.5%). CONCLUSIONS: Sympathetic ophthalmia can be seen following pars plana vitrectomy in patients without penetrating injuries or a history of trauma. Indeed, it may be seen after successful vitrectomy for retinal detachment. Diverse clinical presentations are possible, and persistent or atypical uveitis following vitrectomy should alert the surgeon to the development of sympathetic ophthalmia.

Parenting stress in mothers of very-low-birth-weight (VLBW) and full-term infants: a function of infant behavioral characteristics and child-rearing attitudes.

OBJECTIVE: To examine the moderating effects of child-rearing attitudes on the relation between parenting stress and infant behavioral characteristics for mothers of very-low-birth-weight (VLBW) and full-term infants. METHODS: Fifty-six 9-month-old infants (23 VLBW and 33 full-term) and their mothers were the participants. Mothers completed measures of parenting stress, child-rearing attitudes, infant temperament, and infant behavioral problems. RESULTS: The VLBW infants had a higher frequency of behavioral problems, and their mothers reported more child health concerns than the mothers of the full-term infants. Regression analyses showed that the relation between parenting stress and infant distress was moderated at medium and high levels of parental strictness for only the VLBW infants. CONCLUSIONS: The amount of stress the mothers of the VLBW infants experienced was a result of the congruence between their infant's behavioral characteristics and their own child-rearing attitudes.

Recovery characteristics of propofol anaesthesia, with and without nitrous oxide: a comparison with halothane/nitrous oxide anaesthesia in children.

Few studies have examined whether nitrous oxide influences the recovery characteristics of propofol anaesthesia. The present study examined the effect of nitrous oxide on the recovery characteristics of propofol anaesthesia, and compared these data with those for halothane/nitrous oxide anaesthesia. Sixty children aged 3-12 years were assigned at random to receive one of three maintenance regimens: propofol with or without nitrous oxide (70%) or halothane/nitrous oxide (70%). During propofol/N2O anaesthesia, the infusion rate of propofol (180 +/- 39 micrograms.kg-1.min-1) required to maintain the mean arterial pressure and heart rate within 20% of the baseline values was significantly less than that during propofol/O2 (220 +/- 37 micrograms.kg-1.min-1; P < 0.005). The time from discontinuation of anaesthesia to eye-opening (11 +/- 6 min), to response to commands (12 +/- 6 min), and to return of full wakefulness (21 +/- 10 min) after propofol/N2O were similar to those after propofol/O2, but significantly less (by approximately 30%) than those after halothane (P < 0.05). The overall incidence of emesis after propofol/N2O (53%) was greater than that after propofol/O2 (17%, P < 0.05) and comparable to that after halothane/N2O (58%). These data suggest that N2O has little effect on the rate of recovery after propofol, but significantly increases the incidence of postoperative emesis, thereby attenuating one of the main attributes of propofol anaesthesia.

Temporomandibular disorders: clinical and laboratory analyses for risk assessment of criteria for surgical therapy, a pilot study.

Temporomandibular disorder (TMD) is a broad category involving dysfunction of the skeletomuscular structures of the head and neck, and the temporomandibular joint (TMJ). A total of 66 patients, 54 with TMD, participated in this study. Group 1 (G1) had 31 patients suffering from early to intermediate stage disease, and no prior surgeries. G1 patients had arthrotomy/meniscectomy performed on the diseased joint(s). Group 2 (G2) consisted of 23 patients with late stage disease. All G2 patients had previously had unsuccessful TMJ surgery and were treated with either a partial or total joint prosthesis. Group 3 (G3) consisted of 12 patients who were clinically and radiographically asymptomatic. Medical histories including inflammatory bowel disease, headaches, vertigo, tinnitus and anemia, as well as surgical tonsillectomies, appendectomies and cholecystectomies, were significantly greater in G1 and G2 when compared to G3. Serological testing included HLA subtype, positive (ANA) antinuclear antibody, erythrocyte sedimentation rate (ESR), anemia profile, hormonal levels of prolactin and estradiol, and rheumatoid factor (RF). HLA frequencies, as well as some serological analyses, were significantly different among the three groups. These findings suggest that surgical failure may be secondary to autoimmune dysfunction with a predisposition to multisystem disease. The utilization of genetic markers, serological testing, and thorough medical and surgical histories should allow the clinician to determine which patients are potentially better surgical risk candidates for treatment of TMD.

Behavioral intervention and post-natal growth in full-term intrauterine growth retarded (IUGR) infants.

The purpose of this study was twofold: (1) to describe the patterns of post-natal growth in full-term infants as a function of IUGR and (2) to assess the impact of an individualized behavioral feeding intervention with the mothers on these patterns of infant growth. Eighty-eight (88) full-term infants, including 54 with IUGR, half of whom received behavioral intervention were included. Weight, length, skinfold thickness, head circumference and Ponderal Index were measured at birth and at 1, 4, 8, 12, and 18 months. Results show positive intervention effects between birth and 1 month in weight, length, skinfold thickness, and Ponderal Index. However, there were no intervention effects at subsequent ages. No evidence was found for catch-up growth in full-term IUGR infants in weight, length, and head circumference. We conclude that an individualized behavioral feeding intervention can accelerate early growth in IUGR infants, but the positive effects on growth are only seen while the intervention lasts (between birth and 1 month). On most parameters of physical growth, there is no lasting catch-up growth over the first 18 months in IUGR full-term infants.

The most proximal and accurate site for sampling end-tidal CO2 in infants.

The most proximal site to sample end-tidal CO2 with reasonable accuracy in infants during pulmonary ventilation using a Mapleson D circuit remains controversial. The utilisation of high fresh gas flow near the site of gas sampling dilutes the expired gas and causes an underestimation of end-tidal CO2. In this study a laboratory model was used to identify, qualitatively and quantitatively, the most proximal site in the Mapleson D circuit where the measurement of end-tidal CO2 is not influenced by mixing with fresh gas. A fresh gas flow rate of between 2 and 15 L.min-1 with a respiratory rate of 20-30.min-1 and a tidal volume of 30-100 ml.min-1 was evaluated. This experiment was divided into two parts. Firstly, an infant lung model was used to visualize the site of mixing between fresh gas and smoke-labelled exhaled gas. Secondly, fresh gas flow and expired gas flow were controlled and the end-tidal CO2 concentration was measured along the length of the anaesthetic circuit to identify the site of mixing of fresh gas and expired gas during steady-state conditions. Three expired gas flows were studied at six fresh gas flows. In all our studies, the rate of fresh gas flow and expired gas flow influenced the site of mixing and degree of dilution but no mixing was observed distal to the point at which the endotracheal tube connector narrows to the diameter of the endotracheal tube (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Perioperative complications of superior pharyngeal flap surgery in children.

A 7-year retrospective review of perioperative complications associated with surgical correction of velopharyngeal insufficiency was carried out. A total of 219 children who underwent surgery for velopharyngeal insufficiency between the years 1985 and 1992 were reviewed. Gender distribution was 58 percent male and 42 percent female. The mean age was 9.6 years, with a range of 4 to 22 years, at the time of surgery. Fourteen cases (6.4 percent) were considered a difficult intubation. There were 36 patients with early complications (16.4 percent incidence). Of these, 18 had postoperative bleeding and 20 developed airway obstruction. Most of these episodes occurred in the first 24 hours. Three patients required reintubation. Nine children developed sleep apnea after discharge. Four patients required take-down of the pharyngoplasty, while 7 others had revision of the flap. There was 1 death in the 219 patients. In summary, most complications following surgical correction of velopharyngeal insufficiency in our institution occur in the early postoperative period and are the result of bleeding and/or airway obstruction.

The effects of SCH 23390 and raclopride on cocaine-induced analepsis and EEG arousal in rabbits.

The effects of the dopamine D1 and D2 receptor antagonists on cocaine-induced, cholinergically-mediated analeptic and hippocampal theta activity in anesthetized rabbits were investigated. Cocaine (2 mg/kg, i.v.) reduced by 35% the duration of loss of righting reflex produced by a 25 mg/kg dose of pentobarbital. This shortening of narcosis time was blocked by pretreating the animals with the D1 antagonist, SCH 23390 (0.1 mg/kg) but not with the D2 antagonist raclopride (1-2 mg/kg). Cocaine (5 mg/kg, i.v.) also produced a short burst of increased hippocampal theta activity in urethane-anesthetized rabbits, which was also blocked by SCH 23390 but not by raclopride. An unexpected finding was that raclopride itself, at 2 mg/kg (i.v.), produced a marked activation of theta activity that lasted for 15-20 min. When cocaine was administered after this time it produced a potentiated theta response, both in duration and in magnitude. These results suggest that in the rabbit, cocaine exerts a cholinergically-mediated behavioral and EEG arousal through a D1 dopamine mechanism. The role of the D2 system is less clear but appears to be antagonistic to the D1-mediated response.

Ultra-rapid cycling bipolar affective disorder following a closed-head injury.

A young adult with no prior history of affective disease suffered the onset of a rapid cycling bipolar illness, marginally responsive to psychotropic medications, following a mild closed-head injury, and persisting after the cognitive effects of the injury had resolved. A concurrence of findings on the neurological examination, neurobehavioural examination, SPECT scan, EEG and neuropsychological test battery suggested the presence of a diffuse cerebral injury with a predominance of left frontotemporal findings. This case demonstrates that a severe and disabling mood disorder may follow a mild head injury, and that its course may be independent of cognitive impairment and recovery.

Sleeping through the night: a developmental perspective.

This study examines falling asleep and night waking in human infants during the first 8 months of life. All-night time-lapse video recordings were obtained at 3 weeks and 3 months of age; a Sleep Habits Interview was completed at these ages and repeated at 8 months of age by telephone interview. At the 3-week and 3-month ages, self-report measures of maternal psychologic distress, depression, and self-esteem were also obtained. The data are examined from both cross-sectional (age group) and longitudinal (individual) perspectives. Parent-infant interactions at bedtime and during the middle of the night changed significantly with increasing age. At 3 weeks of age, most infants were put into their cribs for the night already asleep. When they awakened in the middle of the night, they were removed from their cribs. By the time they returned to their cribs, they were again asleep. By 3 months of age, infants who were put into the crib awake at bedtime and allowed to fall asleep on their own were more likely to return to sleep on their own after awakenings later in the night. In contrast, infants who were put into the crib already asleep at the beginning of the night were significantly more likely to be removed from the crib following a subsequent nighttime awakening. Thus, the pattern of bedtime sleep onset was related to sleep onset following an awakening in the middle of the night. This association was present at 8 months as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous gastric pH monitoring in children: the effect of gastric emptying on the measurement of gastric acid secretion.

Continuous gastric pH monitoring offers the opportunity to evaluate gastric acid secretion in humans without the need for collection of gastric aspirates. However, gastric emptying may be an important variable for the accurate measurement of gastric acid secretion using continuous gastric pH monitoring. We conducted an in vitro study (phase I) to evaluate the effect of gastric emptying on gastric pH. The in vitro study used a laboratory model in which continuous pH monitoring of a standard formula (Nutramigen, 100 mL) in a reservoir was performed while varying both the reservoir emptying rate (10% to 80%) over 1 hour and the amount of added acid (2 to 15 mEq/h: in vivo equivalent of 6 to 45 mEq/m2 BSA/h). An in vivo study (phase II) was then performed in 28 infants less than 6 months of age who had gastroesophageal reflux (GER) documented by 18- to 24-hour esophageal pH monitoring. At the end of esophageal pH monitoring, the pH electrode was advanced into the stomach for measurement of gastric pH continuously for 2 hours after a feeding of Nutramigen formula (300 mL/m2 BSA). Each patient also had a radionuclide gastric emptying study performed with the same volume of Nutramigen formula. In the in vitro model, the reservoir pH (% time pH less than 4) was proportional to the reservoir emptying rate only when acid was added at less than 15 mEq/h (less than 45 mEq/m2 BSA/h). Reservoir pH was independent of reservoir emptying rate when acid was added at 15 mEq/h (45 mEq/m2 BSA/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Rhythmic motor behavior of preambulatory motor impaired, Down syndrome and nondisabled children: a comparative analysis.

The developmental course of rhythmic motor behavior was followed longitudinally for three groups of preambulatory children--normally developing, Down syndrome, and those with profound motor impairment. The groups differed in chronological age but were comparable with respect to motor age. The motor impaired subjects displayed significantly less rhythmic motor behavior than the nondisabled and Down syndrome groups. In comparing particular subtypes of rhythmic motor behavior, differences were found in both the average number of bouts and duration of subtypes among the groups. Longitudinal analyses of the data over the entire observation period revealed that the rhythmic motor behavior of the children with Down syndrome was more similar to that exhibited by the nondisabled children than was the rhythmic motor behavior of the children with motor impairment. However, there was considerable variability among the groups in several particular subtypes.

The mean duration of gastroesophageal reflux during sleep as an indicator of respiratory symptoms from gastroesophageal reflux in children.

The coexistence of gastroesophageal reflux (GER) and respiratory symptoms has been reported in children, but identifying a reliable indicator of reflux-induced respiratory symptoms has been difficult. The mean duration of reflux episodes during sleep (ZMD), extracted from a 18- to 24-hour esophageal pH recording, has been presented previously as a reliable correlate of respiratory symptoms caused by GER in infants. To reexamine the accuracy of the ZMD we report 519 consecutive children with respiratory symptoms (aged 1 week to 15 years) who were referred for documentation of GER by 18- to 24-hour esophageal pH monitoring. Follow-up information was obtained on 388 patients 1 to 115 months later (mean, 23 months). From the follow-up information, 259 children could be reliably classified; 128 as having reflux-related and 131 as having reflux-unrelated respiratory symptoms. None of the 131 children with reflux-unrelated respiratory symptoms had a prolonged ZMD (greater than 3.8 minutes). In comparison, 119 of the 128 children (93%) with reflux-related respiratory symptoms had a prolonged ZMD (P less than .001). The nine children who had a normal ZMD and improvement in their respiratory symptoms with the successful control of GER had advanced esophagitis (n = 4), central apnea (n = 3), or associated disorders in which respiratory symptoms improved with the avoidance of oral feedings (n = 2). In conclusion, the ZMD was confirmed to correlate directly with both the presence and absence of respiratory symptoms caused by GER in children.

The risk of sudden infant death from gastroesophageal reflux.

Gastroesophageal reflux (GER) has been a suspected cause of infant deaths and sudden infant death syndrome (SIDS). We examined our 10-year experience with 499 consecutive infants 6 months of age or less who had extended (18 to 24 hours) esophageal pH monitoring performed to evaluate for GER. The data extracted from the esophageal pH records included the pH score, the pattern of GER (type I, II, or III), and the mean duration of reflux during sleep (ZMD). All infants were followed to determine the occurrence and cause of death during the first year of life. Of the 19 deaths found in the series, three were classified as SIDS and two were in-hospital deaths caused by reflux-induced aspiration. All five of these infants who died had a prolonged ZMD (greater than 3.8 minutes) and received either basic medical (n = 4) or no (n = 1) antireflux therapy. Four infants also had the type I pattern of GER. There was a 9.1% (4/44; 95% confidence limits, 2.5% to 21.7%) incidence of reflux-related or SIDS deaths in infants with type I GER and a prolonged ZMD who were treated nonoperatively, compared with none (0/83, P = .03) in the same group of infants treated with antireflux surgery. The incidence of SIDS was higher in infants with type I GER and a prolonged ZMD who were treated nonoperatively (3/44, 6.8%) compared with all other infants treated nonoperatively (0/265, 0%; P = .003).(ABSTRACT TRUNCATED AT 250 WORDS)

The properties of V in newborns across repeated measures.

It has been argued that a recently developed measure, vagal tone (V), is a significant advancement over other existing methods of assessing the periodic variation in heart rate associated with respiration (respiratory sinus arrhythmia). It has been further suggested that, as a noninvasive measure of vagal nerve efferent activity, V may facilitate the early identification of infants at risk for developmental disabilities. This study addressed the relationship between V and other measures of cardiac activity and behavioral state and the stability of V across repeated measures. Twelve samples of cardiac activity were collected from each of 20 full term infants, 6 samples on each of two consecutive days. V values were derived using a spectral analysis program comparable to Porges' patented MXedit process. Measures of behavioral states were collected by continuous observation. Heart period and heart period variability were highly correlated with V. Variation in V between behavioral states was also detected. Repeated assessments revealed that average V values collected in the same state were not significantly correlated across successive days. This short-term variability both between and within individuals does not support the notion that a single assessment of V can, by itself, be used to identify at-risk infants or predict developmental outcome.

Gastroesophageal reflux: a significant association with central nervous system disease in children.

An association between gastroesophageal reflux (GER) and central nervous system (CNS) disease has been suggested, but not defined clearly in children. We report on 613 children (ages 1 week to 16 years; mean, 16 months) studied at three institutions who were referred to the pediatric surgical service for documentation of GER by an abnormal pH score derived from 18- to 24-hour esophageal pH monitoring. Follow-up (range, 1 to 115 months; mean, 25 months) was obtained in 368 patients. One hundred thirty-two children had CNS disease documented prior to the evaluation for GER. In children older than 1 year, there was an increased incidence of GER (31/45, 69%) in those children with CNS disease compared with those without CNS disease (38/81, 47%; P = .014). On follow-up, only 4.6% (14/282) of children who were not diagnosed initially with CNS disease were found later to have overt CNS disease. There was no significant difference in the prevalence of newly diagnosed CNS disease in children with and without GER in long-term follow-up. In conclusion, in the population of children referred to the pediatric surgeon for evaluation of GER, children older than 1 year with CNS disease are at high risk to have associated GER documented by extended esophageal pH monitoring. Despite this association, those children with GER and no obvious CNS disease do not appear to be at increased risk to develop CNS disease.

The influence of rotary vestibular stimulation upon motor development of nonhandicapped and Down syndrome infants.

The vestibular system plays a major role in the expression of early motor behavior. Previous research has cited extensive neural connections between the vestibular apparatus and the motor system. Accordingly, some therapists have implemented programs of supplemental vestibular stimulation to improve motor and cognitive abilities in children with delayed motor development. In the present study a quantifiable regimen of supplemental rotary vestibular stimulation was administered in a cross-over longitudinal design to nonhandicapped and Down syndrome infants. Time constants, considered a measure of habituation in the vestibular system, were derived from postrotary nystagmus. Results indicated that supplemental rotary vestibular stimulation produced no measurable gain in motor ability beyond that evident in control periods. In addition, it was determined that children exhibited greater gains in motor skills in the early phase of the study, regardless of experimental condition. A positive correlation was found between changes in time constant and motor development.