The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1.

Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate.

Mutations and common polymorphisms in interferon regulatory factor 6 ( IRF6) are associated with both syndromic and nonsyndromic forms of cleft lip/palate (CLP). To date, much of the focus on this transcription factor has been on identifying its direct targets and the gene regulatory network in which it operates. Notably, however, IRF6 is found predominantly in the cytoplasm, with its import into the nucleus tightly regulated like other members of the IRF family. To provide further insight into the role of IRF6 in the pathogenesis of CLP, we sought to identify direct IRF6 protein interactors using a combination of yeast 2-hybrid screens and co-immunoprecipitation assays. Using this approach, we identified NME1 and NME2, well-known regulators of Rho-type GTPases, E-cadherin endocytosis, and epithelial junctional remodeling, as bona fide IRF6 partner proteins. The NME proteins co-localize with IRF6 in the cytoplasm of primary palatal epithelial cells in vivo, and their interaction with IRF6 is significantly enhanced by phosphorylation of key serine residues in the IRF6 C-terminus. Furthermore, CLP associated IRF6 missense mutations disrupt the ability of IRF6 to bind the NME proteins and result in elevated activation of Rac1 and RhoA, compared to wild-type IRF6, when ectopically expressed in 293T epithelial cells. Significantly, we also report the identification of 2 unique missense mutations in the NME proteins in patients with CLP (NME1 R18Q in an IRF6 and GRHL3 mutation-negative patient with van der Woude syndrome and NME2 G71V in a patient with nonsyndromic CLP). Both variants disrupted the ability of the respective proteins to interact with IRF6. The data presented suggest an important role for cytoplasmic IRF6 in regulating the availability or localization of the NME1/2 complex and thus the dynamic behavior of epithelia during lip/palate development.

The effect of music-based imagery and musical alternate engagement on the burn debridement process.

Management of pain is a primary concern in the treatment of burn patients. The intent of this study was to test the efficacy of music-based imagery and musical alternate engagement in assisting burn patients in managing their pain and anxiety during debridement. Twenty-five patients, 7 years of age and older, who were admitted to the Comprehensive Burn Care Center were enrolled in the study, which used a repeated-measures design with subjects serving as their own control. Subjects were randomly assigned to 1 of 2 groups. Those placed in Group A received music therapy intervention during their first dressing change, and no music therapy on the following day. Group B received no music therapy intervention during their first dressing change and music therapy during their next dressing, on the following day. Data were collected at 4 intervals in the medical procedure; in the patient's room before transfer to the treatment room, in the treatment room during debridement, in the treatment room after debridement, and upon returning to the patient's room. The measurements taken were pulse, patients' self-report of pain, patients' self-report of anxiety, and the nurse's observation of patients' tension. There was a significant reduction in the self-reporting of pain in those who received music therapy in contrast to those who did not receive music therapy (P < .03). Music therapy is a valuable noninvasive intervention for the treatment of pain after burn injury.

The effect of contingent music to increase non-nutritive sucking of premature infants.

This study assessed music as reinforcement for non-nutritive sucking of 12 premature infants born at an average gestation of 29.3 weeks and an average birthweight of 1111.9 g. At the time of the study, the infants' average post conception age was 35.5 weeks, and their average weight was 1747.3 g. A pacifier was fitted with a pressure transducer so that a sufficient suck activated frequency and duration signals as well as 10 seconds of recorded music consisting of lullabies sung by female vocalists. A 14-minute ABAB study design included a silence baseline for 2 minutes, 5 minutes of contingent music, 2 minutes of silence, and 5 minutes of contingent music. Frequency data were recorded for each 5-second interval in which the duration light was activated for at least 3 seconds. Results demonstrated that sucking rates during the periods of contingent music were 2.43 times greater than baseline (silence) sucking rates. In this study, music contributed significantly to the development of non-nutritive sucking of premature infants.

The effect of music and multimodal stimulation on responses of premature infants in neonatal intensive care.

To assess the benefits of lullaby singing and multimodal stimulation on premature infants in neonatal intensive care, 40 infants in a Level III Newborn Intermediate Care Unit were divided into control (n = 20) and experimental (n = 20) groups by pair matching on the basis of gender, birthweight, gestational age at birth and severity of medical complications. Participants met these project criteria: (a) corrected gestational age > 32 weeks; (b) age since birth > 10 days; and (c) weight > 1700 g. All participants had been referred for developmental stimulation by the medical staff. Experimental infants received reciprocal, multimodal (ATVV) stimulation paired with line singing of Brahms' Lullaby. Stimulation was provided for 15-30 minutes, one or two times per week from referral to discharge. Dependent variables were (a) days to discharge, (b) weight gain/day, and (c) experimental infants' tolerance for stimulation. Results showed that music and multimodal stimulation significantly benefited females' days to discharge and increased weight gain/day for both males and females. Both male and female infants' tolerance for stimulation showed marked and steady increase across the stimulation intervals with females' tolerance increasing more rapidly than males.

Therapeutic effects of music and mother's voice on premature infants.

Aversive environment auditory stimuli is a common concern in neonatal intensive care. Recently, interest has developed regarding the use of music applications to mask such stimuli and to reduce the high risk for complications or failure to thrive. In this study of 20 oxygenated, low birth weight infants in a Newborn Intensive Care Unit of a regional medical center in the Southeastern United States, 10 infants listened to lullabies and 10 infants to recordings of their mother's voice through earphones for 20 minutes across three consecutive days. Oxygen saturation levels and frequency of oximeter alarms were recorded. Results indicated a differential response to the two auditory stimuli as listening time progressed. On Day 1, the infants listening to music had significantly higher oxygen saturation levels, but these effects disappeared by Days 2 and 3. On Days 2 and 3, however, the babies hearing music had significantly depressed oxygen saturation levels during the posttest intervals after the music was terminated. Infants hearing music had significantly fewer occurrences of Oximeter alarms during auditory stimuli than did those listening to the mothers' voice. Implications for the therapeutic use of auditory stimuli in the Newborn Intensive Care Unit are discussed.

Music therapy research and applications in pediatric oncology treatment.

Music therapy is a profession which meets multiple physical, social, and psychological needs. Music therapists can facilitate health objectives by reducing the intensity or duration of pain, alleviating anxiety, and decreasing the amount of analgesic medication needed. Rehabilitative objectives can include activities which incorporate exercise, range of motion therapy, or gait training. Reduction of fear, anxiety, stress, or grief are common psychological objectives. Music therapy is particularly effective in promoting social objectives such as increased interaction, verbalization, independence, and cooperation; enhanced relationships with health care personnel and family members; and increased stimulation during long-term hospitalization or isolation. Counseling techniques are often paired with music to achieve emotional objectives such as expression, adjustment, stability, or locus of control. The purpose of this article is to synthesize the extant music/medical research literature and clarify how music therapy can provide a quintessential combination of physical, social, and psychological benefits to enhance the health care of pediatric oncology patients.

Training workers and supervisors in growth monitoring: looking at ICDS.

PIP: Integrated Child Development Service (ICDS) began in India in 1975 in order to improve the nutrition and health of women and young children. It currently covers 1600 out of 5000 total blocks throughout India (1 block = 100,000 population). ICDS gives food supplements, primary health care, and nutrition education to its constituents. There is 1 Child Development Project Officer (CDPO) per block; a Mukhya Sevika (MS) -- a science graduate -- assigned to 15-20 villages; and 1 Anganwadi Worker (AWW) per village (child care). Growth monitoring is not a program objective. ICDS has conducted field and research designed to evaluate and correct its performance. Studies from 19 blocks in Gujarat and Maharshtra show the following: Not many mothers attend the education sessions or understand the concept of weighing their child. AWW's do not fill in growth charts in the mothers' presence or try to involve them in the weighing or charting procedure. Charts weren't always maintained properly. Training of workers is by and large inadequate with too much emphasis on nutritional status and not enough hands on training. ICDS is reorganizing its training program to emphasize growth and skill. In May 1986 a workshop was held by the National Institute of Public Cooperation and Child Development (NIPCCD) to give workers more relevant training through practical experience. NIPCCD developed a growth monitoring manual from the results of the workshop. The manual is divided into a concept chapter, 4 specific task chapters, and a chapter on the organization of a growth monitoring system. Training must focus on practicalities, relationships between casual factors, and hands on experience. The manual and new style of training are currently being field tested. Appendices delineate instructional objectives and guidelines for trainers.^ieng

Music research in medical/dental treatment: meta-analysis and clinical applications.

This article is a comprehensive analysis and application of music therapy research in the general field of music in medicine, and consists of a thorough review of the literature and a meta-analysis of all empirical studies using music in actual medical/dental treatments. It also transfers research results to clinical applications of music therapy techniques and program development in a general hospital setting.

Electrophysiologic behavior modification of frontal EMG in cerebral-palsied children.

Four cerebral-palsied children participated in the following ABAB design: speech and motor pre-electrophysiologic behavior modification (EMB) evaluation; frontal EMG EMB, six weeks; speech and motor post-EBM evaluation; six weeks no training; speech and motor reevaluation; EMG EBM, four weeks; speech and motor evaluation. Auditory and visual feedback of frontal EMG was monitored by cumulative integration of frontal EMG voltage. The children were shaped by setting a cumulative voltage threshold (CVT). If the child's cumulative integrated frontal EMG voltage fell below the CVT at the end of each 60-sec epoch, a reward was automatically dispensed from a Universal Feeder. Frontal EMG decreased significantly over the initial twelve trials. Correspondingly, improvement was noted for the children in speech and motor skills. Follow-up six weeks later showed increased frontal EMG voltage and deterioration of speech and motor function. Reinstitution of frontal EMG EBM produced reacquisition of low frontal EMG and some recovery of speech and motor function. Collectively, these results indicate that frontal EMG EBM shows promise as an additional treatment modality in the habilitation of cerebral palsy children with spasticity.

Frontal EMG-biofeedback training of athetoid cerebral palsy patients: a report of six cases.

Six athetoid cerebral palsy patients participated in the following: speech and motor prebiofeedback training evaluation; frontal EMG biofeedback training, 6 wk; speech and motor postbiofeedback training evaluation. Frontal pretraining levels for the subjects averaged 28.9 muV p-p. Subjects' feedback consisted of an auditory signal (clicks) varying proportionately with frontal EMG activity. A visual meter display of the integrated EMG was also provided. Self-regulation of frontal EMG was evident for all subjects within session 1. Throughout all sessions, EMG levels of 2-4 mu V were often attained. Trend analysis of EMG acquisition curves showed significant reduction in frontal tension across sessions for all but one subject. Frontal posttraining levels averaged 13.0 muV p-p. Parents or subjects, or both, reported subtle improvements in various speech and motor functions, a finding confirmed by objective postbiofeedback training evaluation. Only the 2 most severely impaired subjects, JA and DS, failed to improve significantly on the speech measures. All subjects improved significantly on those measures that tapped fine and gross motor skills. Collectively, these results indicate that EMG biofeedback training shows promise as an additional treatment modality in the habilitation of cerebral palsy patients.