Confounding factors associated with oral mucositis assessment in patients receiving chemoradiotherapy for head and neck cancer.

PURPOSE: The aim of this study was to identify patient-centered, mucositis-associated adverse impact factors and events that might confound physician-assessed oral mucositis (OM) in head and neck cancer (HNC) patients receiving chemoradiotherapy. METHODS: This was a post hoc analysis of a previously conducted randomized trial to determine the efficacy of 5% phenylbutyrate mouthwash in preventing chemoradiotherapy-induced OM. This analysis identified patient-centered symptomatic, observable, and measurable factors that may confound physician scoring of the severity of OM during chemoradiotherapy. Confounding factors were then combined with physician-rated OM scores according to World Health Organization (WHO) and OM Assessment Scale (OMAS) criteria to investigate the therapeutic implications of OM treatment. RESULTS: The original analysis found no significant differences between experimental and placebo groups with respect to the cumulative incidence of physician-recorded severe OM (WHO ≥3 or OMAS ≥2), patient-reported adverse events, and opioid use. However, patients in the experimental arm had relatively lower rates of OM-associated adverse clinical issues including unplanned short radiation breaks, skipping of chemotherapy, nausea/vomiting, late loss of body weight, and early opioid use, all of which could potentially interfere with physician-assessed OM scoring. When WHO OM grade (functional impact and pain), OMAS ulceration size (organic impact), and prolonged radiation treatment time (cancer treatment impact) were combined, there were significantly fewer interruptions of chemoradiotherapy treatment in symptomatic OM patients in the experimental compared to the placebo group. The benefits conferred by reducing the amount of chemoradiotherapy-related, OM-associated adverse impacts in the experimental group were reflected by better 5-year locoregional recurrence-free survival. CONCLUSIONS: This exploratory study raises questions as to whether the severity reflected by physician-rated OM scores is in concordance with OM-induced adverse impacts on HNC patients. Further investigations are warranted to identify patient-related and cancer-associated symptom burdens that may affect tolerance, compliance, and outcome of chemoradiotherapy and confound the evaluation of therapeutic effects on chemoradiotherapy-induced OM.

Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury.

Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects. OBJECTIVE: We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor. METHODS: PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment. RESULTS: EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3(+) T regulatory suppressor cells, which inhibited T helper cell proliferation. CONCLUSIONS: Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions.

Epigenetic therapy using the histone deacetylase inhibitor for increasing therapeutic gain in oral cancer: prevention of radiation-induced oral mucositis and inhibition of chemical-induced oral carcinogenesis.

In addition to genetic changes, epigenetic aberrations also play important roles in radiation- and chemical-induced disorders and carcinogenesis. The present study investigated whether epigenetic therapy with a histone deacetylase (HDAC) inhibitor has dual benefits for radiation-induced oral mucositis and chemical-induced oral carcinogenesis, which should be treated at the same time. The HDAC inhibitor phenylbutyrate was first tested to determine if it influences DNA damage repair and survival in irradiated normal cells in vitro by investigating the patterns and dynamics of phospho-gammaH2AX foci, Rad51 foci and phospho-gammaH2AX/Rad51 colocalization and using the comet and clonogenic assays. Oral mucositis or carcinogenesis was induced in hamsters using radiation or 7,12-dimethylbenz[a]anthracene (DMBA) irritation to the cheek pouch. The ability of phenylbutyrate formed in proper carriers to prevent radiation-induced oral mucositis and inhibit chemical-induced oral carcinogenesis was assessed. The treated or untreated irradiated or DMBA-irritated oral tissues or mucosal epithelia were subjected to the studies of histology, immunohistochemistry, gene expression, comet assay, HDAC activity or oxidative stress. We found that phenylbutyrate promoted DNA repair and survival in normal cells after radiation. Compared with blank or vehicle-treated hamsters, the irradiated mucosa treated with phenylbutyrate had significantly lower oxidative stress and tumor necrosis factor-alpha expression and less severe oral mucositis of a shorter duration. A reduction of the oral tumor incidence, burden and progression by phenylbutyrate correlated with the suppression of oncomiRs and Rad51 overexpression, the upregulation of differentiation markers and the decrease of intracellular HDAC activity and oxidative stress during DMBA-induced oral carcinogenesis. Thus, epigenetic therapy using the HDAC inhibitor as an adjuvant to radiotherapy for chemical-induced oral cancer may provide a promising strategy combining the prevention of radiation-induced oral mucositis and the inhibition of oral carcinogenesis.

Relationship between functional evaluation measures and self-assessment in nonacute low back pain.

STUDY DESIGN: The correlations between objective biomechanical indicators of function and self-assessment scores were examined retrospectively for 91 subjects with nonacute low back pain. OBJECTIVES: To examine the correlation between self-assessment, trunk range of motion (ROM), velocity, and complex mechanical coordination patterns of the spine in nonacute low back pain. SUMMARY OF BACKGROUND DATA: In low back pain, there is often little concordance between pain, physical impairment, and disability. Use of range of motion and velocity to enhance objectivity in impairment evaluations has been ineffectual. In this study, two hypotheses were examined: range of motion and velocity are controllable and inherently correlated with self-assessment; complex spinal coordination patterns such as range of lordosis cannot be controlled and are independent of self-assessment. METHODS: Self-assessment questionnaires were administered, and indexes of spinal motion and coordination were measured through skin marker kinematics. The correlation between self-assessments and biomechanical measures was determined. RESULTS: Self-assessments of function were significantly correlated with parameters prone to regulation: range of motion, velocity, and load lifted. In contrast, little correlation was found with measures of complex spinal coordination less susceptible to conscious or affective regulation, namely, range of lordosis and estimated segmental mobility. This effect was magnified with increased load. Self-assessment scores were significantly poorer among insurance referrals, regardless of functional status. CONCLUSIONS: Simple parameters of the functional examination, such as range of motion and velocity, are strongly correlated with cognitive state, and thus the information they supply is less than ideal. Complex spinal coordination is a better indicator of the degree of spinal dysfunction and enhances the process of differentiating between pain, disability, and functional impairment.

Improving the evaluation of benign low back pain.

STUDY DESIGN: A prospective, blind study was conducted to investigate the factors underlying the decisions of expert clinicians in diagnosis of acute, benign low back pain, compared with results obtained with an automated physical examination by machine. From the results, a strategy to significantly improve clinical diagnosis in cases of discordance was determined. OBJECTIVES: To identify factors in the clinical assessment of low back pain that indicate when independent diagnostic testing would be useful. SUMMARY OF BACKGROUND DATA: The clinical evaluation of low back pain is often dominated by subjective reports of pain. Published medical literature has underscored several inherent weaknesses of the clinical examination, and concerns have been raised about its effectiveness for assessing patients with low back pain. Thus, it has been proposed that objective measures to complement the clinician's examination would be beneficial in the formulation of dependable diagnoses. METHODS: Randomly designated subjects, who in describing their conditions were objective or role playing, were assessed by clinicians and a machine for diagnosis of low back pain assessment versus normal backs. Each subject's pain assessment was compared with a gold standard that was established by experts in low back pain. Components of the clinical examination were analyzed to assess which were the most informative in making a reliable diagnosis. The information content of the machine assessment was also analyzed and a strategy to complement the clinical diagnosis with the machine diagnosis determined. RESULTS: Discordance among the various components of the clinical examination was a strong indicator of when the efficacy of the clinical examination dropped below a random level of decision making. When there was discordance, incorporating the functional evaluation by machine into the clinical diagnosis improved the performance of the clinician. Notably, in nonobjective subjects, the accuracy of diagnosis was enhanced by as much as 69%. CONCLUSIONS: It is possible to improve the accuracy of clinical diagnosis by incorporating a functional evaluation by machine when there is discordance between physical examination findings and reported pain.

Evaluation of clinician and machine performance in the assessment of low back pain.

STUDY DESIGN: A prospective blind study to test and compare the performance of clinicians (evaluators) with that of an automated machine (the Spinoscope) in conducting an examination on randomly designated simulators/dissimulators and honest subjects to assess acute benign low back pain. OBJECTIVES: To test the impact of reported pain and history on the clinical examination and to compare the ability of clinicians and the machine to recognize normal findings in a controlled group of subjects with and without benign low back pain. BACKGROUND: The literature raises serious questions regarding the efficacy of the clinical examination for patients with low back pain. METHODS: A "gold standard" (clinical examination by experts in low back pain) was established against which the clinical examination by the evaluators and the machine assessment (incorporating weight-lifting ability) of honest subjects and simulators/dissimulators were compared using the receiver operating characteristic technique. The selection of subjects was performed according to strict inclusion and exclusion criteria. RESULTS: The evaluators were more accurate with the honest subjects, the machine more accurate with the simulators/dissimulators, and, for the entire population tested, the they were equivalent in accuracy (71% vs. 72% concordance). Results from the machine's expert system and from clinician readers of the machine data compared favorably. The machine's concordance with the gold standard increased with increasing loads lifted by the subject. CONCLUSION: By relying primarily on the subject's self-presentation, often to the exclusion of objective findings, the clinician may err in evaluating low back function when the patient does not report his or her true condition. The additional functional analysis provided by the machine offers the clinician objective, pertinent information to complement the findings from the clinical examination.

The impact of inefficient clinical diagnosis on the cost of managing low back pain.

The clinical examination remains the pivotal factor in evaluating low back pain (LBP) for decisions concerning compensation and rehabilitation. Many practitioners believe it to be highly reliable, even though existing literature does not support this belief. Not only are there no data supporting the efficacy of clinical diagnosis for LBP, but also published data underscore its many inherent weaknesses. Healthcare risk managers need accurate clinical information to make decisions. If current clinical information is unreliable, then healthcare risk management strategies for LBP must be revised. This article reviews the work of many researchers in their attempts to unravel the problem of diagnosing LBP. The following conclusions were reached: The problem is significant and continues to increase. The problem is rooted in the clinician's strong dependency on reported pain, which may not always be a reliable source of objective information. Quantification of the impact of the objectivity of reported pain on clinical performance demonstrates the need for a independent source of functional data that can improve the diagnosis. Technology exists to complement the clinical examination, improve clinical performance, and thus reduce the cost associated with LBP management. The research results presented in this article unveil disturbing findings for healthcare risk managers. The strong bias clinicians reserve for reported pain may lead them to overrate pathology, treat patients inappropriately, prescribe unnecessary imaging tests, and generate unfounded medical opinions that are responsible for many disputes. Data are presented to demonstrate the financial benefits that result from the introduction of systematic objective controls via technology. These sound management principles allow the risk manager to determine the validity of claims and treatment proposals. Risk managers can then make informed decisions on contentious claims and regulate the large number of clinician-supported disability cases--decisions that represent significant savings.

The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania.

OBJECTIVE: To determine the independent contribution of changes in infant sleep position to the recent decline in sudden infant death syndrome (SIDS) rate in Tasmania. DESIGN: (1) A comparison of the whole population incidence of SIDS before and after an intervention to reduce the prevalence of prone sleeping position. (2) A within-cohort analysis of the contribution of sleep position and other exposures to the decline in SIDS after the intervention. SETTING: Tasmania, Australia. PARTICIPANTS: (1) All SIDS cases from 1975 through 1992. (2) A sample of one in five infants born in Tasmania who at perinatal assessment were scored to be at higher risk for SIDS since January 1988. Of 5534 infants included in the study, 39 later died of SIDS. INTERVENTIONS: Multiple public health activities to reduce the prevalence of the prone infant sleeping position in Tasmania and verbal information on the association between prone position and SIDS to cohort participants from May 1, 1991. MAIN OUTCOME MEASURE: Sudden infant death syndrome incidence. RESULTS: The Tasmanian SIDS rate decreased (P < .01) from 3.8 (95% confidence interval [CI], 3.5 to 4.2) deaths per 1000 live births from 1975 through 1990 to a rate of 1.5 (95% CI, 0.9 to 2.2) deaths per 1000 live births in 1991 through 1992. The SIDS mortality rate in the cohort by period of birth was 7.6 (95% CI, 4.9 to 10.3) deaths per 1000 live births for those born from May 1, 1988, through April 30, 1991, and 4.1 (95% CI, 1.3 to 7.0) deaths per 1000 infants for those born from May 1, 1991, through October 31, 1992. The prevalence of usual prone sleeping position at 1 month of age was 29.9% and 4.3% in these two cohorts, respectively (adjusted odds ratio, 0.11; 95% CI, 0.08 to 0.13). Logistic regression demonstrated that 70% of the SIDS rate reduction in the cohort could be accounted for by the decreased prevalence of the prone sleeping position. Other factors examined individually contributed to less than 10% of the SIDS rate reduction. CONCLUSIONS: The major contributing factor to the recent SIDS rate decline in Tasmania has been the reduction in the proportion of infants usually sleeping prone.

An assessment of the impact of public health activities to reduce the prevalence of the prone sleeping position during infancy: the Tasmanian Cohort Study.

BACKGROUND: An intervention to reduce the prevalence of the prone sleeping position during infancy was implemented in Tasmania particularly from 1991 onward. The purpose of this report is to assess the impact of public health activities in promoting avoidance of the prone infant sleeping position among cohort study participants. METHODS: The prospective cohort study involved the one-fifth of Tasmanian live births who are assessed perinatally as being at higher risk for Sudden Infant Death Syndrome (SIDS). From 1 January 1988 until 30 April 1992, 5,403 infants participated in the hospital (4 days postnatal age) and home interviews (5 weeks postnatal age) (88% of eligible infants). After the finding that cohort infants who usually slept prone were at significantly greater risk for SIDS, additional questions on awareness and choice of infant sleep position were asked. RESULTS: The proportion of infants usually sleeping prone declined from 29.9% in the cohort prior to publication of the cohort findings (1 May 1988-30 April 1991) to 5.4% in the post publication cohort (1 May 1991-30 April 1992), RR = 0.18 (0.15, 0.22). Teenage motherhood was associated with non-awareness (RR = 2.39 (1.41, 3.24)) of an association between prone position and SIDS. After adjusting for maternal age, nonawareness remained positively associated with maternal smoking, maternal education (< Year 12), and paternal unemployment, while mothers who read books to prepare for the baby and who were married were more likely to be aware. In the period after the cohort study publication, the most common reasons given for the usual prone position were that the baby preferred that position and slept better. CONCLUSION: Public health activities to reduce the prevalence of the prone sleeping position have had a significant impact, with a dramatic reduction in the proportion of cohort infants usually sleeping prone. The identification of characteristics of nonaware mothers and the reasons for choosing a particular sleeping position will be used to maintain and improve health education in this area.

Innervation of the canine cruciate ligaments. A neurohistological study.

A search for mechanoreceptors within the substance of the cruciate ligaments was undertaken using the modified gold-chloride technique. Abundant Pacinian, Vater-Pacini, Ruffini end organs and Ruffini-type receptors were found within the substance of the anterior and posterior cruciates. The receptors were innervated by axons of 5 to 10 micrometers in diameter penetrating from the synovium investing the ligaments. The findings support the contention that the cruciate ligaments have important mechanoreceptive and proprioceptive functions.

Prone sleeping position and SIDS: evidence from recent case-control and cohort studies in Tasmania.

The most recent data from the cohort and case-control studies of SIDS and prone position recently reported from Tasmania are reviewed. The cohort analysis was based on 4103 infants born between 1 January 1988 and 1 December 1990 assessed as being at high risk at birth, of whom 29 later died of SIDS. A matched analysis which controlled for infant birthweight and maternal age indicated that prone sleeping position was associated with an increased risk of SIDS (OR 3.92, 95% Cl [1.37-11.24]). The case-control study was based on all (n = 55) Tasmanian SIDS death from October 1989 to April 1991 and matched live controls. The unadjusted odds ratio for prone position and SIDS was 5.04 (95% Cl [2.29-11.11]). The population attributable risk percentage, based on the high risk cohort data, was 0.38 (95% Cl [0.35-0.41]), suggesting that a significant reduction in SIDS incidence might occur if the prevalence of the prone sleeping position in the infant population were reduced. Other factors which may be important for the development of any public health interventions to reduce SIDS based on these findings are discussed.

Use of prescription drugs in the first trimester and congenital malformations.

A prospective survey of prenatal use of prescription drugs in Tasmania yielded detailed information on drug exposure, delivery and outcome for 56,037 births from 1982 to 1989. First trimester drug use was reported by 30.9% of women, and 17.9% used only supplements of vitamins and/or minerals; 40% used alcohol during the first trimester, and 28.8% smoked cigarettes. There were 1,035 (1.85%) congenital malformations, of which 885 (85.5%) were major. The malformation rate was not significantly different in the following exposure categories: supplements only (1.62%); other pharmaceuticals (1.92%); smokers (1.88%); alcohol users (1.89%); and maternal age 35 or more years (1.95%). Adjusting for alcohol use, smoking, maternal age and diabetes mellitus, significant associations [expressed as adjusted odds ratio and 95% confidence intervals (CI)] were found between aspirin and hypospadias (3.5, 95% CI 1.4 to 8.8); dicyclomine and phocomelia (4.4, 95% CI 1.0 to 19.5); and between oral contraceptive use and pes cavus (9.7, 95% CI 2.3 to 40.4). Although significant, these associations were based on very few cases and no direct supporting evidence could be found from other data sources.

Prospective cohort study of prone sleeping position and sudden infant death syndrome.

Studies of the link between prone sleeping position and sudden infant death syndrome have been criticised on grounds of recall bias and for not taking into account possible confounding effects. To avoid recall bias and to allow measurement of important biological factors a prospective cohort study of the cause of sudden infant death syndrome (SIDS) is being conducted. The infants included are those at high risk of the syndrome as assessed by a perinatal score. Of the 3110 members of the cohort born between January, 1988, and end of March, 1990, 23 infants later died of SIDS. Sleep position information was available for 15 of these. Matched analysis to control for the confounding effects of infant birthweight and maternal age indicated that prone sleeping position was associated with an increased risk of SIDS (OR 4.47 95% Cl [1.30-15.43]). The findings are strengthened by the results of a concurrent retrospective case-control study of 42 SIDS cases in which the prone position was also associated with an increased risk of SIDS (unadjusted OR 3.45 [1.59-7.49]).

Behavioural and EEG responses to auditory stimuli during sleep in newborn infants and in infants aged 3 months.

Two studies were conducted in order to assess EEG and behavioural responsiveness to auditory stimuli as a function of sleep state in infants. The subjects in the first experiment were 11 infants aged 3 months, and in the second study the responsiveness of 8 infants aged 3 months was compared with that of 8 newborn infants. The stimuli ranged in intensity from 36 to 90 dB and were presented using a modification of the method of constant stimuli. The occurrence and intensity of behavioural responses were recorded by a trained observer. Electroencephalogram (EEG) responses were defined as EEG desynchronization and were identified by a Fast Fourier Transform algorithm. The results of the two studies showed that infants were more responsive during active sleep (AS) than during quiet sleep (QS) and gave behavioural responses at lower stimulus intensities than EEG responses. Behavioural responsiveness and EEG responsiveness during AS increased as a function of age, while EEG responsiveness during QS decreased. The marked suppression of EEG responsiveness during QS at 3 months of age is thought to be a consequence of developmental changes in sleep mechanisms--an effect which may have clinical implications.

The development of a model for predicting infants at high risk of sudden infant death syndrome in Tasmania.

A statutory 'Notification of Birth' form, containing obstetric and perinatal information, has been routinely collected for Tasmanian deliveries since 1974. For the period 1980 to 1984, birth notification data was collected for over 99% of Tasmanian deliveries. This data was examined for the 130 cases of sudden infant death syndrome (SIDS) that occurred from 1980 to 1984 and for 610 controls. It was then used to construct an at-birth scoring system to predict infants at higher risk of SIDS in the postneonatal period. A predictive model of the relative risk of SIDS was developed by fitting a binomial/logistic generalised linear model to the binary 1980-1984 case control data with birth variables used as predictors. The final predictive model contained five variables (maternal age, infant sex, birth weight, month of birth and feeding practice) and had a sensitivity of 62% and specificity of 73%. The model was then tested on independent birth cohorts from 1985 and 1986 and found to have a sensitivity of 47% and specificity of 77%. The risk of SIDS in the group of infants classified as high risk was 7.9 per 1000 live births and in the group at low risk it was 2.5 per 1000 live births. In addition, the model predicted 74% of neonatal deaths occurring during these 2 years. This compares well with other predictive models developed elsewhere. The predictive model will be used to identify infants at high risk for SIDS in a prospective cohort study.

Neuro-ophthalmologic manifestations of Lyme disease.

Lyme disease is a tick-borne spirochetal infection characterized by skin rash, neurologic, cardiac, and arthritic findings. The authors report six patients with Lyme disease who had neuro-ophthalmologic manifestations. One patient had meningitis with papilledema, two had optic neuritis, and one had neuroretinitis. Three patients had sixth nerve paresis, two of whom cleared quickly, whereas multiple cranial nerve palsies and subsequent optic neuropathy developed in another. Early recognition of neuro-ophthalmologic findings can help in the diagnosis and treatment of Lyme disease.

Arousal deficit: mechanism of the sudden infant death syndrome?

Polygraphic tracings of 13 normal infants were recorded in a morning sleep at 1 and 2 weeks of age and 1, 2, 3, 4, and 6 months of age. A vibrotactile stimulus graded at 25, 50 and 100 Hz (frequency) and amplitudes of 1, 2 and 3 mm (intensity) was used, each combination being applied twice at 30 s intervals to the hand of the sleeping infant during active sleep (AS) and quiet sleep (QS). The results were analysed as percentages of failure to arouse (FTA) in relation to the number of stimulus trials, the criteria for FTA being the absence of a response in heart or respiratory rate, electroencephalogram, or chin electromyogram. The percentages of FTA from QS did not change significantly from 1 week to 6 months of age, irrespective of frequency or intensity. The percentages of FTA from AS fell sharply and significantly from 1 week to 2 months of age (P less than 0.001). At 3 months of age there was a significant increase followed by a significant decrease at 4 months of age, both changes showing a significant difference at P less than 0.05. Apart from the first week of age, the numbers of FTA from QS were greater than from AS for all stimulus trials. It is concluded that there is an arousal deficit in QS from 1 week to 6 months of age and the temporary deficit in AS at 3 months of age could explain the peak incidence of SIDS at this time.