Amplitude-integrated EEG and range-EEG modulation associated with pneumatic orocutaneous stimulation in preterm infants.

OBJECTIVE: Controlled somatosensory stimulation strategies have demonstrated merit in developing oral feeding skills in premature infants who lack a functional suck, however, the effects of orosensory entrainment stimulation on electrocortical dynamics is unknown. The objective of the study was to determine the effects of servo-controlled pneumatic orocutaneous stimulation presented during gavage feedings on the modulation of amplitude-integrated electroencephalogram (aEEG) and range electroencephalogram (rEEG) activity. STUDY DESIGN: Two-channel EEG recordings were collected during 180 sessions that included orocutaneous stimulation and non-stimulation epochs among 22 preterm infants (mean gestational age=28.56 weeks) who were randomized to treatment and control 'sham' conditions. The study was initiated at around 32 weeks post-menstrual age. The raw EEG was transformed into aEEG margins, and rEEG amplitude bands measured at 1-min intervals and subjected to a mixed models statistical analysis. RESULT: Multiple significant effects were observed in the processed EEG during and immediately following 3-min periods of orocutaneous stimulation, including modulation of the upper and lower margins of the aEEG, and a reorganization of rEEG with an apparent shift from amplitude bands D and E to band C throughout the 23-min recording period that followed the first stimulus block when compared with the sham condition. Cortical asymmetry also was apparent in both EEG measures. CONCLUSION: Orocutaneous stimulation represents a salient trigeminal input, which has both short- and long-term effects in modulating electrocortical activity, and thus is hypothesized to represent a form of neural adaptation or plasticity that may benefit the preterm infant during this critical period of brain maturation.

Frequency-modulated orocutaneous stimulation promotes non-nutritive suck development in preterm infants with respiratory distress syndrome or chronic lung disease.

OBJECTIVE: For the premature infant, extrauterine life is a pathological condition, which greatly amplifies the challenges to the brain in establishing functional oromotor behaviors. The extent to which suck can be entrained using a synthetically patterned orocutaneous input to promote its development in preterm infants who manifest chronic lung disease (CLD) is unknown. The objective of this study was to evaluate the effects of a frequency-modulated (FM) orocutaneous pulse train delivered through a pneumatically charged pacifier capable of enhancing non-nutritive suck (NNS) activity in tube-fed premature infants. STUDY DESIGN: A randomized trial to evaluate the efficacy of pneumatic orocutaneous stimulation 3 × per day on NNS development and length of stay (LOS) in the neonatal intensive care unit among 160 newborn infants distributed among three sub-populations, including healthy preterm infants, respiratory distress syndrome (RDS) and CLD. Study infants received a regimen of orocutaneous pulse trains through a PULSED pressurized silicone pacifier or a SHAM control (blind pacifier) during gavage feeds for up to 10 days. RESULT: Mixed modeling, adjusted for the infant's gender, gestational age, postmenstrual age and birth weight, was used to handle interdependency among repeated measures within subjects. A significant main effect for stimulation mode (SHAM pacifier vs PULSED orosensory) was found among preterm infants for NNS bursts per min (P=0.003), NNS events per min (P=0.033) and for total oral compressions per min (NNS+nonNNS) (P=0.016). Pairwise comparison of adjusted means using Bonferroni adjustment indicated RDS and CLD infants showed the most significant gains on these NNS performance indices. CLD infants in the treatment group showed significantly shorter LOS by an average of 2.5 days. CONCLUSION: FM PULSED orocutaneous pulse train stimuli delivered through a silicone pacifier are effective in facilitating NNS burst development in tube-fed RDS and CLD preterm infants, with an added benefit of reduced LOS for CLD infants.

The effects of vestibular stimulation rate and magnitude of acceleration on central pattern generation for chest wall kinematics in preterm infants.

OBJECTIVE: To examine the role of vestibular inputs on respiratory and oromotor systems in healthy preterm infants. STUDY DESIGN: A total of 27 preterm infants were quasi-randomly assigned to either the VestibuGlide treatment or control groups. VestibuGlide infants were held in a developmentally supportive position, given a pacifier and received a series of vestibular stimuli, counterbalanced across rate and acceleration conditions, 15 min 3 times per day for 10 days. The control infants were also held in a developmentally supportive position, given a pacifier for 15 min 3 times per day for 10 days but did not receive the VestibuGlide stimulation. RESULT: A multi-level regression model revealed that treatment infants increased their respiratory rate in response to vestibular stimulus, and that the highest level of vestibular acceleration delivered to the infants (0.51 ms(-2)) resulted in a significant increase in breaths per minute. CONCLUSION: Vestibular stimulation delivered to preterm infants before scheduled feeds effectively modulates respiratory rate and resets the respiratory central pattern generator.

Risk assessment of food-contact materials: past experience and future challenges.

The tiered approaches used in the European Union and the USA for the risk assessment of substances in food-contact materials are based on the principle that the amounts of data required to establish safety-in-use depend on the extent of dietary exposure. Tiered approaches are increasingly recognized as sound approaches for chemical risk assessment, which not only offer consumers reasonable certainty of no harm, but also avoid unnecessary toxicological testing and focus scarce risk-assessment resources on substances of potential concern. Although the European Union and United States approaches were developed separately, their tiered testing recommendations are similar. This paper indicates the savings they have brought in the use of animals and suggests areas where testing recommendations for higher dietary exposures might be further refined. It also discusses some of the future challenges in risk assessment of food-contact materials.

Synthetic orocutaneous stimulation entrains preterm infants with feeding difficulties to suck.

BACKGROUND: Prematurity can disrupt the development of a specialized neural circuit known as suck central pattern generator (sCPG), which often leads to poor feeding skills. The extent to which suck can be entrained using a synthetically patterned orocutaneous input to promote its development in preterm infants who lack a functional suck is unknown. OBJECTIVE: To evaluate the effects of a new motorized 'pulsating' pacifier capable of entraining the sCPG in tube-fed premature infants who lack a functional suck and exhibit feeding disorders. METHODS: Prospective cohort study of 31 preterm infants assigned to either the oral patterned entrainment intervention (study) or non-treated (controls) group, matched by gestational age, birth weight, oxygen supplementation history and oral feed status. Study infants received a daily regimen of orocutaneous pulse trains through a pneumatically controlled silicone pacifier concurrent with gavage feeds. RESULTS: The patterned orocutaneous stimulus was highly effective in accelerating the development of non-nutritive suck (NNS) in preterm infants. A repeated-measure multivariate analysis of covariance revealed significant increases in minute rates for total oral compressions, NNS bursts, and NNS cycles, suck cycles per burst, and the ratiometric measure of NNS cycles as a percentage of total ororhythmic output. Moreover, study infants also manifest significantly greater success at achieving oral feeds, surpassing their control counterparts by a factor of 3.1 x (72.8% daily oral feed versus 23.3% daily oral feed, respectively). CONCLUSION: Functional expression of the sCPG among preterm infants who lack an organized suck can be induced through the delivery of synthetically patterned orocutaneous pulse trains. The rapid emergence of NNS in treated infants is accompanied by a significant increase in the proportion of nutrient taken orally.

Patterned orocutaneous therapy improves sucking and oral feeding in preterm infants.

AIM: To determine whether NTrainer patterned orocutaneous therapy affects preterm infants' non-nutritive suck and/or oral feeding success. SUBJECTS: Thirty-one preterm infants (mean gestational age 29.3 weeks) who demonstrated minimal non-nutritive suck output and delayed transition to oral feeds at 34 weeks post-menstrual age. INTERVENTION: NTrainer treatment was provided to 21 infants. The NTrainer promotes non-nutritive suck output by providing patterned orocutaneous stimulation through a silicone pacifier that mimics the temporal organization of suck. METHOD: Infants' non-nutritive suck pressure signals were digitized in the NICU before and after NTrainer therapy and compared to matched controls. Non-nutritive suck motor pattern stability was calculated based on infants' time- and amplitude-normalized digital suck pressure signals, producing a single value termed the Non-Nutritive Suck Spatiotemporal Index. Percent oral feeding was the other outcome of interest, and revealed the NTrainer's ability to advance the infant from gavage to oral feeding. RESULTS: Multilevel regression analyses revealed that treated infants manifest a disproportionate increase in suck pattern stability and percent oral feeding, beyond that attributed to maturational effects alone. CONCLUSION: The NTrainer patterned orocutaneous therapy effectively accelerates non-nutritive suck development and oral feeding success in preterm infants who are at risk for oromotor dysfunction.

Non-nutritive sucking recorded in utero via fetal magnetography.

Several studies in term and pre-term infants have investigated the rhythmic pattern of non-nutritive sucking (NNS) indicating correlations between the quantitative measures derived from sucking pressure variation and/or electromyographic (EMG) recordings and a range of factors that include age, perinatal stress and sequelae. In the human fetus, NNS has been reported from 13 weeks of gestation and has been studied using real-time Doppler ultrasonography exclusively. The present study indicates that NNS in fetus can be reliably recorded and quantified using non-invasive biomagnetic measurements that have been recently introduced as an investigational tool for the assessment of fetal neurophysiologic development. We show that source separation techniques, such as independent component analysis, applied to the high-resolution multichannel recordings allow the segregation of an explicit waveform that represents the biomagnetic equivalent of the ororhythmic sucking pressure variation or EMG signal recorded in infants. This enables the morphological study of NNS patterning over different temporal scales, from the global quantitative measures to the within burst fine structure characterization, in correlation with the fetal cardiac rhythm.

Developmental toxicity evaluation of triclopyr butoxyethyl ester and triclopyr triethylamine salt in the CD rat.

Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid) is an herbicide used extensively in the control of woody plants and broadleaf weeds, and is often formulated as a triethylamine salt (T-TEA) or butoxyethyl ester (T-BEE). This study evaluated the developmental toxicity of T-TEA or T-BEE in time-mated CD rats gavaged on gestation days 6-15 with 0, 30, 100 or 300 mg/kg body weight(bw)/day. The doses of each compound were equimolar and equivalent to 22, 76, 216 mg/kg bw/day of triclopyr, based on prior studies indicating rapid cleavage of the salt or ester and equivalent pharmacokinetics for the active ingredient. T-TEA caused maternal toxicity, evidenced by the death of one high-dose dam, reduced body weight gain, increased relative liver and kidney weights (300 mg/kg bw/day), reduced feed consumption, and increased water consumption (100 and 300 mg/kg bw/day). Developmental effects were limited to slightly decreased fetal body weight and reduced skeletal ossification at the high dose level. T-BEE caused similar, albeit slightly more severe, maternal toxicity, with three maternal deaths at 300 mg/kg bw/day, and slight maternal effects at 30 mg/kg bw/day. Due to an equivocal increase in malformations, which were mainly clustered in litters from three high dose dams with marked maternal toxicity, the T-BEE study was repeated using 30 dams/group, investigator-blind fetal evaluations, and an additional dose group (5 mg/kg bw/day). In the repeat study, the only reproducible fetal effect was an increased incidence of 14th thoracolumbar rib at 300 mg/kg bw/day. Overall analysis of the two T-BEE studies suggested that the fetal malformations unique to the initial study likely reflected a combination of spontaneous events, exacerbated by marked maternal toxicity. The combined weight of evidence from these developmental toxicity studies, coupled with their known pharmacokinetic equivalence, indicates that T-BEE and T-TEA are not selectively toxic to the fetus. The respective maternal toxicity no-observed effect levels (NOEL) for T-BEE and T-TEA were 5 and 30 mg/kg bw/day, while the NOEL for developmental toxicity was 100 mg/kg bw/day for both compounds.

Hazard identification by methods of animal-based toxicology.

This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.

Review of risk factors for sudden infant death syndrome.

Sudden infant death syndrome (SIDS) accounts for the largest number of deaths during the first year of life in developed countries. The possible causes of SIDS are numerous and, to date, there is no adequate unifying pathological explanation for SIDS. Epidemiological studies have played a key role in identifying risk factors, knowledge of which has underpinned successful preventive programmes. This review critically assesses information on the main risk factors and causal hypotheses put forward for SIDS, focusing on research published since 1994. The overall picture that emerges from this review is that affected infants are not completely normal in development, but possess some inherent weakness, which may only become obvious when the infant is subjected to stress. Initially there may be some minor impairment or delay in development of respiratory, cardiovascular or neuromuscular function. None of these is likely to be sufficient, in isolation, to cause death and, provided the infant survives the first year of life, may no longer be of any significance. However, when a compromised infant is confronted with one or more stressful situations, several of which are now clearly identified as risk factors, and from which the majority of infants would normally escape, the combination may prove fatal.

Risk assessment of the use of deltamethrin on bednets for the prevention of malaria.

Risk assessments covering the use of the pyrethroid, deltamethrin, on bednets for the prevention of malaria have been conducted The toxicity of deltamethrin in humans and animals is reviewed following both dermal and oral exposure. The no-adverse-effect level (NOEL) for exposure via the dermal route was 1000 mg/kg body weight/day. From this an acceptable exposure level (AEL) of 10 mg/kg body weight/day has been derived. The NOEL for exposure via the oral route was 1 mg/kg body weight/day, with exposures above this causing neurotoxic effects in animals. This NOEL has been used to derive margins of safety compared with predicted exposures. While direct skin contact does not seem to cause systemic toxicity in humans, it can cause burning, numbness and tingling of the skin, which is a local effect. This too is taken into account in the risk assessments. The risk assessments cover those treating bednets, on an intermittent or regular basis, the washing of treated nets, sleeping under treated nets (infants, children and adults). Worst case scenarios for each of these situations show that dermal exposures are low (one-tenth or less of the AEL) and the margins of safety for systemic exposure derived from oral data are acceptable, ranging from 10 to 3300. The benefits of the use of treated bednets in reducing morbidity and mortality from malaria are considerable and it can be concluded that the risk:benefit ratio is very favourable.

Mechanically evoked perioral reflexes in premature and term human infants.

Neurophysiological assessment of the preterm human neonatal oromotor system has been limited due to their fragile medical state, and methodological limitations. A new, noninvasive technology known as the actifier was developed and used to evoke perioral motor unit activity during non-nutritive suck in preterm infants. A significant ontologic trend for the early component of the perioral reflex (R1) was discovered in the context of spontaneous, centrally-patterned oromotor behavior.

Dilemmas facing regulatory and advisory bodies dealing with conflicting results.

Regulatory and advisory bodies have to take into account the possibility that conventional toxicological screening and testing methods may be failing to pick up relevant effects, with the implication that testing may need to go down to much lower exposure levels and use specifically designed studies. In the paper, attention is focused on the problems of understanding endocrine disrupting activity. The shape of the dose-response curve for endocrine disrupters may differ from that normally associated with toxic chemicals (the monotonic sigmoid curve). Thus, prediction of both the nature of the effects of potential endocrine disrupters and the intensity of those effects at different doses may be equally difficult. Endocrine effects are not currently amenable to analysis by a single apical assay. While existing toxicological tests can pick up many end-organ and functional effects that are relevant to endocrine disturbances, they are generally poor at exploring apparently subtle effects such as disturbances of brain endocrine homeostatic mechanisms which may be critical for normal development.

Dietary vitamin A and teratogenic risk: European Teratology Society discussion paper.

This review discusses the predictive value of animal models in assessment of possible risk from excess vitamin A consumption during pregnancy and the human evidence concerning risk of congenital malformations from excess vitamin A in the diet, consumed either as a constituent of normal foods or in the form of dietary vitamin supplements. Other sources of exposure to vitamin A include medicines (dermal and oral preparations) and cosmetics, but these are not further considered here. Conservative estimates of the likely safe intake of vitamin A during pregnancy are available, based on results from scientific research to date. However, current uncertainties are such that further research is needed to more clearly define intakes which may be on the borderline between those which are beneficial and those which may pose a risk to the developing embryo and fetus.

Intrinsic dynamics and mechanosensory modulation of non-nutritive sucking in human infants.

The human infant is endowed with a complex mechanism for the ingestion of nutrients that becomes functional in late fetal life. The sucking motor pattern is generally accepted to be under the control of pattern generating circuitry located in the brainstem reticular formation. Systems under the control of a central pattern generator (CPG) may use afferent feedback to allow for changing environmental conditions. Although it is clear that afferent pathways serving the orofacial region become responsive to mechanical stimulation early in fetal life, little is known about the integration of afferent information into the suck CPG. The actifier, a device for the mechanical stimulation of intraoral and perioral tissues, was designed and used to investigate the response properties of the human infant suck CPG to patterned mechanical stimulation. Sinusoid and square waveform stimuli elicited responses including modulation of jaw kinematics and synchronization [entrainment] of non-nutritive suck motor patterns to the mechanical stimulus. These data provide evidence that the suck CPG is responsive to mechanical stimulation of perioral and intraoral soft tissues.

Mechanosensory modulation of perioral neuronal groups during active force dynamics.

The spatiotemporal organization of the mechanically evoked perioral sensorimotor response was sampled from five normal females using a custom-designed linear motor operating under force feedback. Electromyographic activity was sampled from the superior and inferior segments of the orbicularis oris muscle during the production of a visually guided ramp-and-hold lip-rounding task. Brief mechanical inputs of approximately 0.45 N delivered to the left upper lip during the ramp-and-hold task produced a composite myogenic response characterized by phases of excitation and suppression. Modulation of the primary excitatory component (R1) of the mechanically evoked perioral response was found to be highly dependent upon the rate of force recruitment (1 N/s vs. 4 N/s) and the phase of force recruitment (20% vs. 50% vs. 80% of 1 N end-point force). Modulation of later occurring inhibitory (S1) and excitatory (R2) potentials were also found to be dependent upon differences in the rate and phase of force recruitment. The organization of the perioral sensorimotor response is considered in relation to speech motor control and the dynamic organization of neuronal groups subserving perioral sensorimotor activity.

The actifier: a device for neurophysiological studies of orofacial control in human infants.

A new device for the stimulation of intraoral tissues in human neonates is described. This instrument, known as an actifier, features a wide frequency range for mechanical stimulation, integrated multichannel electomyographic electrode pairs, and the capacity for transducing law compression during non-nutritive sucking behavior. The stimulus/recording interface consists of a modified pacifier. The actifier has been used to investigate the responsiveness of the sucking central pattern generator in human infants to mechanical perturbation.