The health of children with cerebral palsy and stress in their parents

Title.  The health of children with cerebral palsy and stress in their parents.
Aim.  This paper is a report of a study conducted to describe the health of children with cerebral palsy and investigate predictors of stress in their parents.
Background.  Children with severe cerebral palsy tend to have poorer health than their able-bodied peers, and their parents are more likely to be stressed and have poorer health.
Method.  A cross-sectional survey with home visits using standard questionnaires was administered to parents in 2004–05. A total of 102/199 (51%) children and parents participated. The children were compared with a normative sample.
Results.  Children with cerebral palsy had poorer physical health, and 79% of parents reported that their child had moderate to severe pain. Their poorer health, in comparison with the normal sample and measured by the Child Health Questionnaire, was related to feeding problems and seizures, general health perceptions to intellectual and feeding impairment, and family activities with severe motor, intellectual and feeding impairment. Poorer psychological well-being on the hyperactivity domain of the Strengths & Difficulties Questionnaire was related to feeding difficulties, on the prosocial domain to more severe forms of all child impairments, and on the social impairment scale to intellectual impairment. Children with psychological problems had statistically significantly increased odds (OR = 7·2, 95% CIs 2·6–20·3) of having parents with high stress.
Conclusion.  Children with cerebral palsy and associated impairments are at higher risk of poorer health and family well-being. A family-centred approach to the care of children with cerebral palsy and their families is essential to ensure both receive adequate care and support.     

Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide

Thalidomide requires cytochrome P450 (CYP)-catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5'-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19(*)2, CYP2C19(*)3, CYP2C19(*)4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19(*)2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5'-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19(*)3 or CYP2C19(*)4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.     

Flavopiridol inversely affects p21(WAF1/CIP1) and p53 and protects p21-sensitive cells from paclitaxel

Resting cells are relatively resistant to microtubule-active drugs including paclitaxel (PTX). By causing p53-mediated arrest, pretreatment with low concentrations of doxorubicin (DOX) protected HCT116 cells from the cytotoxicity caused by PTX. Unlike DOX, flavopiridol (FL) did not protect HCT116 cells. Low concentrations of FL (50 nM) induced p21 but not p53. High concentrations of FL (500 nM) decreased levels of p21 and Mdm-2 but dramatically induced p53. Thus, FL reciprocally affects p21 and p53. In LNCaP, a prostate cancer cell line which is highly sensitive to p21-induced growth arrest (p21-sensitive), low concentrations of FL (50 nM) induced p21 (without induction of p53) and caused G1 and G2 arrest. This precluded mitotic arrest, Bcl-2 and Raf-1 phosphorylation, and diminished cell death caused by PTX. In contrast, FL did not protect PC3M, arrest-resitant and highly aggressive prostate cancer cells. Like LNCaP, HL60 and SKBr3 cells are known to be p21-sensitive. As predicted, low concentrations of FL antagonized PTX-mediated cytotoxicity in HL60 and SKBr3 cell lines. In summary, only low concentrations of FL can induce p21, and, in turn, only p21-sensitive cells are protected from PTX.     

The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women.

High levels of circulating insulin-like growth factor-I (IGF-I) and its major binding protein (IGFBP-3) at premenopausal ages have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in the breast increased with increasing serum levels of IGF-I (P for linear trend, P(t) = 0.05), IGF-II (P(t) = 0.08), and IGFBP-3 (P(t) = 0.01) only in premenopausal women. IGF-II and IGFBP-3 serum levels were associated with increases in the mammographically lucent area in both premenopausal (P(t) = 0.01 and 0.04, respectively) and postmenopausal women (P(t) < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (P(t) = 0.01) and postmenopausal (P(t) <0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors.     

Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.

The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.     

Methodologic Concerns Regarding Estimates of Physical Violence in Sexual Coercion: Overstatement or Understatement?

Self-report measures of sexual violence that ask women whether they have experienced threats of physical violence have attracted criticism in recent years; detractors claim that these measures lead researchers to overestimate the prevalence of sexual violence. Our study explored this issue by collecting data on the prevalence of threats versus force in the context of sexual aggression. Female undergraduates at two universities (n ₁ = 69; n ₂ = 111) were asked about their experiences with sexual coercion using a revised version of the Sexual Experiences Scale (Koss and Gidycz, 1985). Four of the original items were modified to distinguish between sexual contact that occurred as a result of a perpetrator using physical force and sexual contact that occurred because a perpetrator threatened physical violence. Analyses of the revised items revealed that the use of physical force was at least as likely as threats and that for some types of sexual acts, physical force was actually more likely than verbal threats. Furthermore, prevalence figures for three of the four types of sexual acts considered were not significantly altered by collapsing threat of force with use of force. Implications for future research on women's experiences of sexual coercion are discussed.     

Modulation of cytochrome P450 activity: implications for cancer therapy

Although metabolism mediated by cytochrome P450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, few clinical studies have investigated activity of cytochrome P450s and therapeutic outcome in people with cancer. Variability between individuals in the pharmacokinetics of cancer chemotherapy has important consequences in terms of therapeutic efficacy and safety. We discuss here the effect of drug metabolism mediated by cytochrome P450 on therapeutic outcome. As examples, the biotransformation pathways of cyclophosphamide, ifosfamide, tamoxifen, docetaxel, paclitaxel, and irinotecan are discussed. Since most anticancer agents are transformed by enzymes, better knowledge of their metabolic pathways could help improve treatment outcome and safety. Furthermore, a more complete understanding of the metabolism of anticancer agents through phenotyping and genotyping approaches will facilitate the prediction of interactions between drugs. More clinical evidence is needed on the metabolic transformation and drug interactions with these agents to improve cancer therapeutics.     

Molecular and phenotypic heterogeneity of metastatic prostate cancer

Metastatic prostate cancer remains a prevalent disease in the United States that requires detailed characterization of its pathobiology. In the December 2004 issue of Cancer Research, a comprehensive study by Shah et al. demonstrated that metastatic androgen-independent prostate cancer is a collective group of diseases even within the same patient. Understanding the molecular and phenotypic determinants of this heterogeneity is essential in assessing therapeutic outcomes in the management of prostate cancer progression.     

A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases

PURPOSE: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed. RESULTS: At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm. CONCLUSIONS: There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.