Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways.

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

Patterns of academic achievement among patients treated early with phenylketonuria.

UNLABELLED: This paper provides a review of recent studies investigating the academic achievement of patients treated for phenylketonuria. These studies consistently indicate that these patients demonstrate mild academic difficulties, primarily with mathematics but with reading and spelling skills as well. In addition to the review of previous studies, academic achievement results are presented for a sample of 32 school-age, early-treated patients with phenylketonuria. CONCLUSION: Consistent with previous studies, results from the current study suggest that patients in this sample demonstrate mild difficulties with basic spelling and basic mathematical calculation skills.

Eating disorders in patients with cystic fibrosis.

This study was designed to examine rates of eating disorders and psychopathology in patients with cystic fibrosis (CF). Fifty-eight CF patients and 43 healthy control participants were evaluated using structured psychiatric interviews and rating scales. Two control participants and no CF patients were diagnosed with an eating disorder. Additionally, 11 CF patients were diagnosed with one or more psychiatric disorders. Group means on the rating scales did not show clinically meaningful elevations in either group. These data indicate no evidence for elevated rates of eating disorders in CF patients. Similarly, rates of other psychiatric disorders in the CF group were not greater than the prevalence reported in the general population.

Outcome at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study.

CONTEXT: Untreated maternal phenylketonuria (PKU) increases risk for developmental problems in offspring. The extent to which this risk is reduced by maternal dietary therapy at various stages of pregnancy is not known. OBJECTIVE: To determine whether dietary treatment during pregnancy of women with PKU affects developmental outcomes of offspring. DESIGN: The Maternal PKU Collaborative Study, an ongoing, longitudinal prospective study begun in 1984. SETTING: A total of 78 metabolic clinics and obstetrical offices in the United States, Canada, and Germany. PARTICIPANTS: A total of 253 children of women with PKU (n = 149), with untreated mild hyperphenylalaninemia (n = 33), or without known metabolic problems (comparison group; n = 71) were followed up to age 4 years. INTERVENTION: Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine < or =10 mg/dL [< or =605 micromol/L]). Women with mild hyperphenylalaninemia, who had plasma phenylalanine levels of no more than 10 mg/dL (605 micromol/L) on a normal diet, were not treated. MAIN OUTCOME MEASURES: Children's scores on cognitive and behavioral assessments (McCarthy Scales of Children's Abilities, Test of Language Development, Achenbach Child Behavior Checklist, Vineland Adaptive Behavior Scales, and Home Observation for Measurement of the Environment), compared by maternal metabolic status at 0 to 10 weeks', 10 to 20 weeks', and after 20 weeks' gestation. RESULTS: Scores on the McCarthy General Cognitive Index decreased as weeks to metabolic control increased (r = -0.58; P<.001). Offspring of women who had metabolic control prior to pregnancy had a mean (SD) score of 99 (13). Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 SDs below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems. CONCLUSIONS: Our data suggest that delayed development in offspring of women with PKU is associated with lack of maternal metabolic control prior to or early in pregnancy. Treatment at any time during pregnancy may reduce the severity of delay.

Phenylketonuric patients decades after diet.

Nineteen early-treated phenylketonuric patients, whose diet was discontinued between 4.5 and 13 years of age, and who have been off the diet for 12-28 years, were reassessed in 1992-93. There was little change in mean IQ between end of diet and follow-up, less than one IQ point on the average, with no change for any individual exceeding 12 IQ points. Both prior and current IQ correlated slightly negatively with mean phenylalanine (Phe) concentration, and positively with parents' education. The phenylalanine level at follow-up was significantly lower on average by about 900 mumol/L. Five of the subjects (26%) have evidence of mental disease. However, the data suggest that the discontinuation of the diet did not cause intellectual deterioration. Nonetheless, the patients' intellect cannot be the only consideration for maintenance of diet. The occurrence of psychopathology among phenylketonuric patients and the possible unknown effects of toxic elevation of phenylalanine during their lifetime suggest the need to maintain the diet. The use of DNA for diagnostic and prognostic purposes might assist in decisions about dietary quality and duration, and in anticipation of psychopathology.

Long-term outcome of Hurler syndrome following bone marrow transplantation.

Previous reports suggested a therapeutic response of lysosomal storage diseases such as Hurler syndrome following bone marrow transplantation. However, a clearer understanding of outcome has awaited long-term follow-up. We evaluated prospectively 11 consecutive patients with Hurler syndrome receiving marrow from an HLA-identical sib donor between September 1983-October 1988. Follow-up evaluations included assessment of donor engraftment by restriction fragment polymorphism analysis, determination of leukocyte alpha-L-iduronidase level, measurement of lumbar cerebrospinal fluid (CSF) pressure, computerized tomography (CT) of the brain, and psychometric testing. In this series there was a survival rate of 9/11 (82%) with all survivors showing complete (7 patients) or partial (2 patients) donor engraftment. Prospective longitudinal evaluation of the 9 surviving children, now 3.8-8.9 years posttransplantation (median 5.5) demonstrated persistence of previously deficient leukocyte alpha-L-iduronidase at levels reflecting the donor genotype and degree of donor engraftment. Urinary glycosaminoglycan excretion declined to near-normal within 5 months of donor engraftment. Prior to treatment, 7 of 8 children studied were found to have occult intracranial hypertension (lumbar CSF pressure > 20 cm CSF); however, all surviving children attained normal or near-normal pressure within 18 months of donor engraftment. Longterm follow-up CT imaging of the brain did not show progressive volume loss (cerebral atrophy) after donor engraftment. Of 9 survivors, 4 children having a developmental quotient (DQ, Mental Development Index on Bayley Scales of Infant Development) above 80 prior to transplantation subsequently maintained IQ scores above this level. However, 5 patients with lower pretransplant DQ scores now have significant cognitive deficits and attention deficit hyperactivity disorder. Progressive brain damage resulting from communicating hydrocephalus may be prevented by successful engraftment. Early transplantation of children with Hurler syndrome who have normal intelligence is likely to have the clearest benefit because long-term intellectual outcome will be limited by brain damage which has occurred prior to treatment.

Effectiveness of preoperative sedation with rectal midazolam, ketamine, or their combination in young children.

To determine which of three types of rectal sedation was most effective preoperatively in facilitating parental separation and intravenous cannulation in young children, 100 children 3.0 +/- 1.7 (mean +/- SD) yr of age were randomly assigned to four equal groups. One group (M-K-A) received rectal midazolam (0.5 mg/kg), ketamine (3 mg/kg), and atropine (0.02 mg/kg). The other sedation groups received the same doses of midazolam and atropine (M-A) or ketamine and atropine (K-A) alone, and the control group (A) received only rectal atropine. Most children in either the M-K-A (100%) or M-A (92%) groups separated easily from their parents without struggling or crying, significantly more than in the K-A (60%) or A (64%) groups. However, more children in the M-K-A group (44%) were asleep during separation than in the M-A group (8%; P < 0.05). Only 20% of the children in the M-A or M-K-A groups cried during intravenous catheter placement, significantly less than in the K-A (56%) or A (92%) groups. Intravenous catheter placement was also successful significantly more often in the M-A (80%) and M-K-A (84%) groups than in the K-A (48%) or A (40%) groups. Complications were similar among the groups, but there was evidence that midazolam prolonged recovery time in some patients. Rectal midazolam with or without ketamine is a useful technique when intravenous catheter placement before induction of anesthesia is desired.

Children with phenylketonuria: the interface of family and child functioning.

Functioning and coping of 43 families with children with phenylketonuria (PKU) was investigated. A significant positive correlation was found among perceived family cohesion, dietary adherence associated with metabolic control, and child IQ. Parental education also significantly related to dietary adherence and to higher IQ level in the child. In addition, paternal perception of family adaptability was related to the child's IQ. Child depression as perceived by the parents was related to family functioning and coping variables. Functioning of PKU families is discussed in relation to current theories of family functioning under stress.

Psychosocial needs of long-term childhood cancer survivors: a review of literature.

With improved medical treatment for childhood cancer, many patients are enjoying long disease-free remission or cure. It is important to address the psychosocial adjustment of the survivor's life. There are two approaches to the study of psychosocial adjustment: study of psychiatric disturbances and assessment of quality of life. Incidences of psychiatric disturbances were reviewed with the most commonly reported difficulties being depression, anxiety and chemical dependency for older survivors and school attendance problems and learning difficulties for school age survivors. The assessment of quality of life focused on school performance, social adjustment, employment status, independent living and marital status. In addition, family coping has received increasing emphasis with regard to the effects on marital relationship and financial difficulties, although there is no consistent evidence to suggest an increased divorce rate in these families. Healthy siblings of cancer survivors are also subject to vulnerability. However, there is evidence to suggest most siblings will resolve their feelings of jealousy, fear of abandonment and establish a normal sibling relationship with the survivor.

Successful renal transplantation accelerates development in young uremic children.

To examine the impact of renal transplantation on subsequent development of children with chronic renal failure, 37 children undergoing primary renal transplantation at or before 30 months of age whose allograft functioned for at least 1 year were prospectively studied. Psychometric tests were performed an average of 4 months before transplantation; reevaluation was done an average of 14 months after surgery. Comparison of individual pretransplantation and posttransplantation mental development scores in 33 patients, assessed by either Bayley Mental Development Index or Stanford-Binet Intelligence Quotient, revealed an average increase of 12.6 (P less than .001). After transplantation, there was a significant improvement in mental performance in 12 of 18 patients (P less than .02) from the range of mild delay (Mental Development Index or Stanford-Binet IQ score = 50 to 69) to the range of normal mental development (greater than or equal to 70). The Bayley Psychomotor Development Index scores were frequently lower than Mental Development Index scores and also increased an average of 14.4 (P less than .01) after transplantation in all 12 patients with paired data. Significant individual improvement in occipital-frontal circumference standard deviation score (P less than .001) was noted in 24 children after transplantation. It is concluded that successful renal transplantation in young children with chronic renal failure is often associated with significant improvements in cognitive and psychomotor function, as well as improved cephalic growth.

Catch-up growth, muscle and fat accretion, and body proportionality of infants one year after newborn intensive care.

We studied catch-up growth, muscle and fat accretion, and body proportionality at 4 and 12 months of age corrected for prematurity in 30 very low birth weight (VLBW) (less than 1500 gm), 30 low birth weight (LBW) (1500 to 2499 gm) and 30 normal birth weight (greater than or equal to 2500 gm) infants who required newborn intensive care. At 4 and 12 months, the VLBW infants had significantly lower mean weight and length (p less than 0.01), but not lower occipitofrontal circumference percentiles, than the LBW and normal birth weight groups, and showed no catch-up weight or length growth between 4 and 12 months. All three groups had significant increases in mean upper mid-arm circumferences, mid-arm muscle circumferences, and arm muscle areas between 4 and 12 months. Mean mid-arm muscle circumferences and arm muscle areas were similar among the three groups at 4 months but became significantly stratified by birth weight groups by 12 months, with VLBW infants having the lowest mean value. In contrast, analysis of fat stores by triceps skin-fold thickness and arm fat area demonstrated no significant increases in any group between 4 and 12 months, except for arm fat area in the LBW group. The VLBW infants had significantly less fat than normal birth weight infants at 4 and 12 months. All three groups had proportional growth at both visits, as assessed by mid-arm circumference/head circumference ratio and weight-length percentile for age. The VLBW infants were significantly lighter for their length than normal birth weight infants. We conclude that VLBW infants have no first-year catch-up growth, remaining smaller than higher birth weight infants, although appropriately proportional. Somatic growth during the first year is due more to muscle than to fat accretion, especially in VLBW infants.

Growth and development in infants after renal transplantation.

Between January 1, 1978, and August 31, 1985, 13 infants aged 6 to 11 months received primary renal transplants (12, living related donor; one cadaver) at the University of Minnesota. Twelve infants are alive with functioning grafts (10 primary and two second transplants) after 4 months to 7.5 years. To assess the long-term outcome, we analyzed growth and development in the first nine infants 2 to 7.5 years after receiving their first transplant. Before transplantation, head circumference and height standard deviation scores in six of nine infants were less than -2. Five had seizures; four had delayed mental development, and six delayed motor development. The mean increment in height standard deviation scores for six boys after transplantation was +1.4 (P less than 0.05), and one achieved complete catch-up growth. The mean difference in height standard deviation scores for three infant girls with primary hyperoxaluria was -2.1; nevertheless, two infants with oxalosis are currently alive 2.7 to 3.3 years later. All eight surviving children achieved normal head circumference (mean improvement +2.2 SDS, P less than 0.001), and no child had further seizures. Of seven infants reassessed with the Bayley Scales after transplantation, mental development was normal in all and motor development was normal in five. Our findings suggest that early living related renal transplantation is an important option in the management of end-stage renal disease in infants.

Psychiatric diagnosis and behavioral characteristics of phenylketonuric children.

This study evaluated the psychiatric characteristics and the behavioral effects of an acute load of phenylalanine on phenylketonuric children. The sample consisted of 13 normal-IQ children who were identified at birth as having phenylketonuria and were subsequently treated with a strict low phenylalanine diet. After baseline measurements, the subjects were loaded with placebo or phenylalanine following a double-blind design. Behavioral and metabolic variables were monitored at hourly intervals for five subsequent hours. The effects of acute loading were measured by changes in a standardized Continuous Performance Task (CPT). Psychiatric symptoms were compiled through a structured psychiatric interview of the child and the parent. Results demonstrated that phenylalanine loading, compared to placebo, caused a nonsignificant decrement in performance on CPT testing. Psychiatric disorders were found in six of the 13 subjects with three currently meeting criteria for attention deficit disorder (ADD). In addition, six other subjects were diagnosed in the past as having ADD using DSM-III criteria.

Cognitive deficits in iron-deficient and iron-deficient anemic children.

Eighteen- to 60-month-old iron-deficient anemic children given iron therapy (n = 25) and a control group matched for mother's educational level showed no significant difference in mean mental development score at baseline. The control group's mean score was increased significantly over baseline score at 3 and 6 months and was significantly higher than the experimental group's mean score at 3 months. Although the experimental group demonstrated hematologic correction over 6 months, mean mental development score showed no significant improvement. Scores for an iron deficient not anemic group given iron (n = 22), despite complete hematologic correction over the six months of observation, and for its control group, did not change significantly. Baseline scores for an iron-deficient not anemic placebo group (n = 23) and for its control group were not significantly different. At 3 months the control group score had increased significantly, whereas that for the experimental group had not. When experimental and control subjects were matched on baseline mental development score, the control subjects experienced increases in scores over time, further confirming an impaired ability to improve scores with repeated testing in the experimental groups. Behavioral rating data (responsiveness to examiner, responsiveness to environment, and emotional tone) revealed significant differences between the iron-deficient anemic group and its control group at 3 and 6 months, with the control group rated more responsive, suggesting that iron deficiency, alone or in association with anemia, may have some lasting effect on behavior and development. Group differences were also found between the mean number of occurrences of multiple stressful events. Failure to show improvement in scores in the iron-deficient anemic group may reflect the fact that those children were less testable than were children in the control group, despite repeated testings, a theory supported by the infant behavior rating data. This may be related to some irreversible behavioral deficit or to an adverse environmental milieu (e.g., stress).

Relationship between phenylalanine tolerance and psychological characteristics of phenylketonuric families.

The purpose of this study was to find out how genetic and biochemical limitations influence psycho-social performance and to partially test the validity of justification theory. The ability to convert phenylalanine to tyrosine was compared with intellectual and personality characteristics in PKU family members. Each of the tested persons was given an oral dose of phenylalanine, the Shipley-Hartford Intelligence Test, and the Minnesota Multiphasic Personality Inventory (MMPI). Only those persons with reading ability at the sixth grade level or higher were tested. Eighty-six persons were tested: fifteen PKUs, forty-three siblings, and twenty-eight parents. A comparison was made among parents, PKUs, and the siblings. Siblings with the higher 2/3's of P2/T ratios were contrasted with those with the lowest 1/3 of ratios on measures of intelligence and psychopathology. Statistical analyses of the data reflected a trend in support of the justification theory. PKUs had significantly lower intelligence than their sibs and parents. The PKUs' mean IQ was 95 (homozygotes born of heterozygotes), followed by the upper 2/3's sibling mean IQ of 105 (heterozygotes born of nonheterozygote mothers). The lower 1/3 siblings' mean IQ was 107 (nonheterozygotes born from heterozygote mothers), and finally, the parents' mean IQ was 109 (heterozygotes, among them 50% were born from nonheterozygote mothers). The latter three mean IQs are not significantly different from each other. The personality tests revealed a trend toward more abnormality in PKUs than in their heterozygote siblings. The lowest rate of abnormality occurred in the nonheterozygote sibling group; that rate was significantly lower than in all other groups. The parents had the highest absolute rate of personality abnormality, but statistically so compared to the low-ratio siblings.

Personality, behavior, family environment, family social status and hypertension risk factors in children. The Minneapolis Children's Blood Pressure Study.

To assess the relationship of psychosocial variables to risk factors for hypertension in children, we administered instruments designed to measure aspects of children's personality, behavior, family environment and family social status to 1505 school children aged 7-10 years. Children's blood pressure was significantly related only to mother's occupation, the children of unskilled employees having higher blood pressure than children of higher status workers. Children's body mass index was directly related to scores on the conformity scale of the personality inventory and inversely related to scores on the intellectual-cultural orientation scale of the family environment instrument and to social class. Social status but not measured dimensions of children's personality, behavior and family environment may influence the risk of hypertension in children.

Efficacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy.

Twenty-three newborn infants with severe bilateral pulmonary disease and persistent pulmonary hypertension received mechanical ventilation to pH greater than 7.55 and PaCO2 less than 25 torr. Response, as defined by attainment of a PaO2 greater than 100 torr, occurred in 87% of patients. Analysis of sequential arterial pH determinations revealed a linear increase in the number of infants responding as arterial pH increased. However, individual patients varied greatly in the optimal pH necessary to correct hypoxemia (range pH 7.50 to 7.75). Sixteen patients who had received mechanical hyperventilation were observed for 11.1 +/- 2.3 months. Virtually all had normal growth and development on follow-up physical and neurologic examinations, often despite profound or prolonged alkalosis and hypocarbia. In 11 infants at a corrected gestational age of 1 year, Bayley Scales of Infant Development revealed normal mental developmental indices (mean 106.2 +/- 15.4) and normal, but significantly lower, psychomotor developmental indices (93.2 +/- 11.7) (P less than 0.005). Although response and short-term outcome of neonatal hyperventilation appear favorable, this technique should be reserved for critically ill infants, because its long-term effects on the central nervous system are unknown.

Growth development and its relationship to intellectual functioning of children with phenylketonuria.

Growth measurements, including weight, height, and head circumference, of 67 early treated children with phenylketonuria (PKU) were compared to normal standards from infancy up to six years of age. Children with PKU, both girls and boys, achieved growth parameters that were similar to those of normals. Head circumference of the boys at six years of age and of the girls at three and four years of age correlated positively with IQ scores. Weight/height (W/H) ratios at one year of age correlated positively with IQ scores for boys. Similar correlations between IQs and weight/height ratios were found for girls at one, two, and three years of age.

Recent life events in school children: race, socioeconomic status, and cardiovascular risk factors. The Minneapolis Children's Blood Pressure Study.

During a study of children's blood pressure, recent life events were measured to determine their occurrence in elementary school children and to determine their relationship to blood pressure and other possible precursors of adult hypertension. Data about life events for a one-year period were obtained from a stratified sample of 1505, 6- to 9-year-old children enrolled in Minneapolis public schools. Children's age and sex were not related to life events. Parental education, employment, and income were related to the child's life event frequency. Indian and black children tended to experience significantly more undesirable life events than white children. Life events frequency was not related to baseline or to follow-up blood pressure or to obesity or other risk factors for adult hypertension.

Factors affecting attachment between infants and mothers separated at birth.

A sample of 24 healthy Neonatal Intensive Care Unit (NICU) survivors separated from their mothers for a period of more than 10 days after birth were studied at approximately 1 year postconceptional age to assess mother-infant attachment. The 24 infants were classified into secure-attached (N = 17) and insecure-attached (N = 7) groups according to Ainsworth categories. No differences were found between the groups in birth weight, gestation, length of NICU hospitalization, Bayley developmental scores, and 1-year physical measurements. Secure-attached infants, however, tended to be from younger, working mothers and had more day-care experiences. The data do not support the hypothesis that prolonged neonatal separation has detrimental effects on later mother-child interaction.