Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis.

With the goal of identifying a potential intermediate biomarker in the multistep process of head and neck cancer development, we conducted immunohistochemical analyses for p53 expression in 33 patients with head and neck squamous cell carcinomas whose tissue sections contained adjacent normal epithelium, hyperplastic, and/or dysplastic lesions. Fifteen of 33 (45%) squamous cell carcinomas of the head and neck expressed p53, but none of four normal control patients (cancer-free nonsmokers) expressed detectable p53 in oral mucosa specimens. To determine when p53 expression is initiated during head and neck tumorigenesis, we examined the normal and premalignant lesions adjacent to the tumors. Five of 24 (21%) samples of normal epithelium adjacent to tumors, 7 of 24 (29%) samples of hyperplasia, and 9 of 20 (45%) samples of dysplasia expressed p53. Quantitative image analysis demonstrated not only a gradual increase in the amount of p53 expression as tissue abnormalities progressed but also a topological change in expression. Whereas p53 expression, when present, was limited to the basal layer in normal epithelium adjacent to tumor, the expression of p53 expanded into the parabasal and superficial layers in hyperplasia and dysplasia. We conclude that p53 expression can be altered in very early phases of head and neck tumorigenesis. Thus, it may be an excellent candidate for risk assessment and may serve as an intermediate biomarker in chemoprevention trials.

Head growth and neurodevelopment of infants born to HIV-1-infected drug-using women.

OBJECTIVE: To describe neurodevelopment and head growth in HIV-1-infected and exposed uninfected infants with and without in utero exposure to opiates and cocaine. METHODS: Using data from a multicenter cohort study of HIV-1-infected women and their children, the authors fit repeated measures regression models to estimate the effects of HIV-1 infection and in utero hard drug exposure on head circumference and Bayley Scales of Infant Development standard scores during the first 30 months. RESULTS: Of the 1,094 infants included in the analysis, 147 (13%) were HIV-1-positive and 383 (35%) were exposed in utero to opiates or cocaine (drug-positive). Mean 4- month Bayley mental scores were lower in infants with only HIV-1 positivity (HIV-positive and drug-negative) (-8.2 points, p < 0.0001) or only drug exposure (HIV-negative and drug-positive) (-4.4 points, p = 0.0001) and tended to be lower in infants with both factors (HIV-positive and drug-positive) (-3.7 points, p = 0.0596), compared with those who were HIV-1-negative and not drug exposed (HIV-negative and drug-negative). However, by 24 months of age, there was no longer a decrement among HIV-negative and drug-positive infants, whereas HIV-1 infection was still associated with a decrement relative to uninfected infants. Similar results were seen for Bayley motor scores and for head circumference Z scores. CONCLUSIONS: HIV-1 infection and in utero opiate and cocaine exposure decrease birth head circumference and slow neurodevelopment at 4 months. At 24 months of age, however, only HIV-1 infection is associated with decreased neurodevelopment and head circumference. There may be some postnatal recovery from the effects of in utero hard drug exposure. Importantly, the detrimental effects of HIV-1 positivity and maternal hard drug use on neurodevelopment at 4 months are not additive, although they are additive for birth head circumference.

Effect of perinatally acquired human immunodeficiency virus infection on neurodevelopment in children during the first two years of life.

OBJECTIVE: To determine the timing, extent, and magnitude of neurodevelopmental problems in children with perinatal HIV infection compared to similar uninfected children of HIV-infected women and controls. METHODS: Neurodevelopmental assessments during the first 24 months of life for 21 HIV-infected children born to HIV-infected mothers, 65 seroreverted children born to HIV-infected mothers, and 95 non-HIV-infected children born to non-HIV-infected mothers were analyzed. Neurodevelopment was assessed by using the Bayley Scales of Infant Development beginning at 3 months of age. Kent Scoring Adaptation was also utilized. A two-stage Hierarchical Linear Model was used for analysis of neurodevelopmental scores. RESULTS: In the initial comparison of these three groups, infected children had significantly lower scores on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) than the other two groups. The HIV-infected children were further classified into HIV-infected without Centers for Disease Control-defined AIDS, those with lymphoid interstitial pneumonitis (LIP) only as their AIDS-defining illness, and children with an AIDS-defining diagnosis other than LIP in the first 24 months. The children with LIP-only AIDS and the infected children without AIDS on average were not significantly different from the seroreverters or the controls on MDI or PDI, while the children with non-LIP AIDS had significantly lower scores after 3 months of age. Analysis of the Kent scores indicated that the decrement in the non-LIP AIDS children was seen in all five functional domains. CONCLUSION: Children with serious HIV symptomatology appear to be at very high risk for serious developmental impairments, HIV-infected children not highly symptomatic have relatively normal neurodevelopment, and uninfected children of HIV-infected mothers do not appear to be adversely affected by the mother's HIV infection.

Postnatal decline in pyridoxal phosphate and riboflavin. Accentuation by phototherapy.

Riboflavin is a cofactor in the conversion of pyridoxine (vitamin B6) to pyridoxal phosphate (PALP), an essential coenzyme in numerous metabolic pathways, including neurotransmitter synthesis. Riboflavin and pyridoxine are light sensitive in vitro, and conflicting results have been reported on the in vivo effects of phototherapy on riboflavin. We studied 25 full-term neonates receiving phototherapy and 16 healthy controls to evaluate their riboflavin and PALP status. Both vitamin cofactors decreased in both sets of infants, but significantly more so in the irradiated group. While the biologic or clinical importance of a modest biochemical decline in the level of PALP has not been established, it is possible that transient behavioral changes in irradiated, jaundiced neonates could be mediated by decreased availability of PALP. The mechanism for the postnatal decline and the desirability of routine supplementation with pyridoxine, especially in irradiated infants, require further study.

Early cognitive and motor development among infants born to women infected with human immunodeficiency virus. Women and Infants Transmission Study Group.

OBJECTIVE: To examine the frequency, timing, and factors associated with abnormal cognitive and motor development during the first 30 months of life in infants born to women infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Serial neurodevelopmental assessment was performed with 595 infants born to women infected with HIV-1 in a multicenter, prospective, natural history cohort study. Survival analysis methods were used to evaluate 6 outcome events related to abnormal cognitive and motor growth (time to confirmed drop of 1 SD, time to first score <69, and time to confirmed drop of 2 SD) in Bayley Scales of Infant Development Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores among infected (n = 114) and uninfected (n = 481) infants. Proportional hazards modeling was used to evaluate the effects of HIV infection status, prematurity, prenatal exposure to illicit drugs, maternal educational attainment, and primary language. RESULTS: HIV-1 infection was significantly associated with increased risk for all outcome events related to abnormal mental and motor growth. Differences between infected and uninfected infants were apparent by 4 months of age. Prematurity was associated with increased risk for MDI <69 and PDI <69. Maternal education of <9 completed years was associated with increased risk for MDI <69. Neither prenatal exposure to illicit drugs nor primary language other than English was associated with abnormal development. CONCLUSION: A significant proportion of infants with HIV-1 infection show early and marked cognitive and motor delays or declines that may be important early indicators of HIV disease progression. These abnormalities are independent of other risk factors for developmental delay.