Tolerance to cadmium hepatotoxicity by metallothionein and zinc: in vivo and in vitro studies with MT-null mice.

The protective role of metallothionein (MT) in Cd-mediated hepatotoxicity was investigated in vivo and in vitro. Following injection of Cd (2 mg/kg, intraperitoneal or subcutaneous) hepatoxicity was significantly greater at 20 h in metallothionein-null (MT-/-) mice, compared with controls (MT+/+). The decrease in the blood and liver glucose concentrations correlated with the extent of hepatotoxicity, with blood glucose 43% lower in MT-/- mice. Zinc (50 microM) and/or Dex (1 microM) were used in hepatocyte cultures to raise MT 2-5-fold. When Cd at 10 microM was co-treated with Zn and/or Dex, lactate dehydrogenase (LD) leakage in the MT+/+ and MT-/- hepatocytes was reduced only when Zn was present. Cellular glutathione (GSH) was the same in control MT+/+ and MT-/- cultures and was uninfluenced by Zn and Dex. After treatment with 5 and 10 microM Cd, GSH levels were lower in MT-/- than MT+/+ hepatocytes in the control and Dex groups. Higher GSH concentrations were maintained in Zn co-treated cultures from both genotypes, indicating that the superior protective effect of Zn may in part derive from its influence on cellular GSH. Pre-treatment with Zn and/or Dex provided no further protection than co-treatment. Tolerance to brief (15 min) Cd exposure was also investigated in the presence of MT inducers including progesterone (100 microM). Zn, Dex and progesterone treated hepatocytes had less LD leakage than controls with Zn giving the greatest protection (LD leakage 18% of controls at 100 microM Cd). Zn pre-treated cells had higher cytosolic/particulate ratios of Cd. These findings demonstrate that MT protects primary cultures of mouse hepatocytes from short-term exposure to Cd. Zn enhances the protection through MT and non-MT mechanisms.

Multimethod psychoeducational intervention for preschool children with disruptive behavior: two-year post-treatment follow-up.

This paper describes the 2-year post-treatment follow-up of preschool children identified as having high levels of disruptive behavior at kindergarten entry. They were assigned to four treatment conditions: A no-treatment group, parent-training only, treatment classroom only, and the combination of parent training with the treatment classroom. Interventions lasted the entire kindergarten academic year. Initial post-treatment results reported previously indicated no effects for the parent-training program but some efficacy for the classroom intervention program. For this report, the disruptive behavior (DB) children were subdivided into those who did (n = 74) and did not (n = 77) receive the treatment classroom. Two-year post-treatment follow-up results indicated no differences between the classroom treated and untreated DB groups. These groups also failed to differ in the percentage of children using available treatments across the follow-up period. The DB children in both groups had significantly more symptoms of ADHD and ODD than a community control group (N = 47) at follow-up. They also received higher ratings of externalizing problems on the parent Child Behavior Checklist, more severe ratings of behavior problems at home, and ratings of more pervasive behavior problems at school, and had poorer academic skills. Results suggested that early intervention classrooms for DB children may not produce enduring effects once treatment is withdrawn, and that better approaches are needed for identifying those DB children at greatest risk for later maladjustment.

Multi-method psycho-educational intervention for preschool children with disruptive behavior: preliminary results at post-treatment.

Annual screenings of preschool children at kindergarten registration identified 158 children having high levels of aggressive, hyperactive, impulsive, and inattentive behavior. These "disruptive" children were randomly assigned to four treatment conditions lasting the kindergarten school year: no treatment, parent training only, full-day treatment classroom only, and the combination of parent training with the classroom treatment. Results showed that parent training produced no significant treatment effects, probably owing largely to poor attendance. The classroom treatment produced improvement in multiple domains: parent ratings of adaptive behavior, teacher ratings of attention, aggression, self-control, and social skills, as well as direct observations of externalizing behavior in the classroom. Neither treatment improved academic achievement skills or parent ratings of home behavior problems, nor were effects evident on any lab measures of attention, impulse control, or mother-child interactions. It is concluded that when parent training is offered at school registration to parents of disruptive children identified through a brief school registration screening, it may not be a useful approach to treating the home and community behavioral problems of such children. The kindergarten classroom intervention was far more effective in reducing the perceived behavioral problems and impaired social skills of these children. Even so, most treatment effects were specific to the school environment and did not affect achievement skills. These findings must be viewed as tentative until follow-up evaluations can be done to determine the long-term outcomes of these interventions.

Paracetamol hepatotoxicity in metallothionein-null mice.

The role of metallothionein (MT) in protecting the liver against paracetamol (PCT) toxicity was investigated in vivo and in vitro in mice lacking expression of MT-1 and MT-2 genes (MT -/-). In the fed, glycogen replete state, hepatotoxicity (PCT 300 mg/kg i.p.) at 6 h was significantly greater in MT -/- than MT +/+ mice. Plasma lactate dehydrogenase (LD) and alanine aminotransferase (ALT) were 5- and 13-fold greater respectively than in MT +/+ mice. Liver glycogen, glucose and zinc levels were significantly lower in MT -/- mice at this time. In contrast, hepatotoxicity (PCT 135 mg/kg i.p.) at 6 h was similar in both MT +/+ and MT -/- mice fasted 24 h, despite a doubling in liver MT in MT +/+ mice. No differences were found between MT -/- and MT +/+ mice in cytochrome P450 activity. Liver glutathione levels were the same in both groups of mice prior to fasting and were decreased to a similar extent (55-65%) following PCT treatment. Investigation of lower PCT doses (< or = 120 mg/kg) in fasted mice over 24 h demonstrated a greater susceptibility in female MT -/- mice with plasma LD, 2.4-fold and ALT, 7.5-fold greater than in MT +/+ mice at 120 mg/kg PCT. In male MT -/- mice, there was only a trend towards greater susceptibility at 110 mg/kg PCT compared to male MT +/+ mice, and at 120 mg/kg, both male genotypes were equally affected. Investigations with cultured hepatocytes supported the in vivo findings in that there was a trend towards greater toxicity (PCT at 1 and 5 mM for 24 h) in hepatocytes from fed MT -/- mice, with the difference diminished in association with greater hepatotoxicity in hepatocytes from fasted mice. Use of dexamethasone (Dex) to increase MT in the MT +/+ mouse hepatocytes protected from PCT toxicity. Zn alone was not protective. Zn plus Dex offered no protection despite higher MT levels. Generation of apo-MT with Dex may offer more protection than Zn-MT. In conclusion, MT -/- mice were more susceptible than MT +/+ mice to PCT toxicity in the fed state, but the increased susceptibility was much smaller, but still significant, when the effects of glycogen were minimised by fasting.

Psychiatric and psychological morbidity as a function of adaptive disability in preschool children with aggressive and hyperactive-impulsive-inattentive behavior.

Children with high levels of aggressive-hyperactive-impulsive-inattentive behavior (AHII; n = 154) were subdivided into those with (n = 38) and without (n = 116) adaptive disability (+AD/-AD) defined as a discrepancy between expected versus actual adaptive functioning. They were compared to each other and a control group of 47 normal children. Both AHII groups were more likely to have attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, and conduct disorder than control children; more symptoms of general psychopathology; greater social skills deficits; more parental problems; and lower levels of academic achievement skills. Compared to AHII - AD children, AHII + AD children had (1) more conduct disorder; (2) greater inattention and aggression symptoms; (3) more social problems, less academic competence, and poorer self-control at school; (4) more severe and pervasive behavior problems across multiple home and school settings; and (5) parents with poorer child management practices. Thus, adaptive disability has utility as a marker for more severe and pervasive impairments in AHII children.

Excerpts from family-centered care for children needing specialized health and developmental services.

In 1994, Family-Centered Care for Children Needing Specialized Health and Developmental Services was published. This monograph is the third revision of the 1987 landmark publication titled Family-Centered Care for Children with Special Health Care Needs. The revision incorporates several changes: the key elements of family-centered care are reworded for clarity; the order in which the elements are presented is changed to better illustrate their inter-relationships; new understandings about family-centered care are integrated; program examples are updated; and research findings are incorporated. The revised key elements of family-centered care are listed and described here in material excerpted from the 1994 monograph.

Parent training for attention-deficit hyperactivity disorder: its impact on parent functioning.

This study examined changes in parent functioning resulting from parental participation in a behavioral parent training (PT) program specifically designed for school-aged children with attention-deficit hyperactivity disorder (ADHD). Relative to wait list controls, subjects who completed the nine-session PT program showed significant posttreatment gains in both child and parent functioning, which were maintained 2 months after treatment. In particular, there were PT-induced reductions in parenting stress and increases in parenting self-esteem, which accompanied parent-reported improvements in the overall severity of their child's ADHD symptoms. In addition to their statistical importance, these findings are discussed in terms of their clinical significance, utilizing methods developed by Jacobson and Truax (1991).

Driving-related risks and outcomes of attention deficit hyperactivity disorder in adolescents and young adults: a 3- to 5-year follow-up survey.

OBJECTIVE: To determine whether teenagers and young adults with attention deficit hyperactivity disorder (ADHD) have more motor vehicle citations and crashes and are more careless drivers than their normal peers. DESIGN: A comparison of two groups of teenagers and young adults (ADHD and normal) followed up 3 to 5 years after original diagnosis. SETTING: A university medical center clinic for ADHD patients. PATIENTS: Thirty-five subjects with ADHD and 36 control subjects between 16 and 22 years of age, all of whom were licensed drivers. MAIN OUTCOME MEASURES: Parent ratings of current symptoms of ADHD, oppositional defiant disorder, and conduct disorder, a survey of various negative driving outcomes, and a rating scale of driving behavior. RESULTS: Subjects with ADHD used less sound driving habits. This deficiency was associated with greater driving-related negative outcomes in all categories surveyed. Subjects with ADHD were more likely than control subjects to have had auto crashes, to have had more such crashes, to have more bodily injuries associated with such crashes, and to be at fault for more crashes than control subjects. They were also more likely to have received traffic citations and received more such citations than control subjects, particularly for speeding. The sub-group of teenagers with ADHD having greater comorbid oppositional defiant disorder and conduct disorder symptoms were at highest risk for such deficient driving skills/habits and negative driving-related outcomes. CONCLUSIONS: ADHD, and especially its association with oppositional defiant disorder/conduct disorder, is associated with substantially increased risks for driving among teenagers and young adults and worthy of attention when clinicians counsel such patients and their parents.

Parenting stress among families of children with attention deficit hyperactivity disorder.

Prior research has shown that parenting stress levels can be quite high among families of children with attention deficit hyperactivity disorder (ADHD). This study investigated the degree to which such stress was related not only to the child's ADHD, but also to various other child, parent, and family-environment circumstances. Multimethod assessments were conducted on 104 clinic-referred children with ADHD. Data collected from these subjects were entered into hierarchical multiple-regression analyses, utilizing the Parenting Stress Index as the criterion. The results showed that the child and parent characteristics accounted for a substantial portion of the variance in overall parenting stress. The child's oppositional-defiant behavior and maternal psychopathology were especially potent predictors. The severity of the child's ADHD, the child's health status, and maternal health status also emerged as significant predictors. These findings are discussed in terms of their impact upon the clinical management of children with ADHD.