Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

The immune system and psychiatric disease: a basic science perspective.

Mental illness exerts a major burden on human health, yet evidence-based treatments are rudimentary due to a limited understanding of the underlying pathologies. Clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi-cellular resident immune system that interacts with peripheral immunity and impacts behavior. In this perspective, we highlight evidence of immune involvement in human psychiatric disease and review data from animal models that link immune signaling to neuronal function and behavior. We propose a conceptual framework for linking advances in basic neuroimmunology to their potential relevance for psychiatric diseases, based on the subtypes of immune responses defined in peripheral tissues. Our goal is to identify novel areas of focus for future basic and translational studies that may reveal the potential of the immune system for diagnosing and treating mental illnesses.

Antibodies to a nucleolar protein are localized in the nucleolus after red blood cell-mediated microinjection.

To determine whether red blood cell-mediated microinjection of antibodies can be used to study nuclear protein localization and function, we microinjected antibodies that have been shown to react specifically with nucleolar acidic phosphoprotein C23 into Walker 256 cells. The intracellular distribution of microinjected anti-C23 antibodies and preimmune immunoglobulins were determined by immunofluorescence. At 3 h after microinjection, affinity-purified anti-C23 antibodies were localized in the cytoplasm and nucleolus. At 17 h after microinjection, the affinity-purified antibody was localized to those nucleolar structures previously shown to contain protein C23. Furthermore, the antibody remained localized in the nucleolus for at least 36 h after microinjection. In contrast to the results obtained with specific antibodies, preimmune immunoglobulins remained in the cytoplasm 36 h after microinjection. These results indicate that red blood cell-mediated microinjection of antibodies can be used to study nucleolar and nuclear antigens.

Effect of low-fat diet on female sex hormone levels.

The hypothesis that dietary fat acts as a promotional agent for the development of breast cancer by influencing sex hormone levels was tested in a dietary intervention study. Thirty-three women in good health were randomly allocated to commence either a standard diet (deriving 40% of their energy from fat) or a low-fat diet (deriving 20% of their energy from fat). After 2 months, the women were crossed over to the alternative diet for another 2 months. Serum hormone and lipid levels were measured in the middle and at the end of each dietary period. In premenopausal women, the low-fat diet appeared to decrease levels of both non-protein-bound estradiol (1.48 down to 1.27%; P = .07) and non-protein-bound testosterone (1.06 down to 0.86%; P = .11). Cholesterol levels were lowered by the low-fat diet and were significantly associated with estradiol, testosterone, and dehydroepiandrosterone. High-density lipoprotein (HDL) cholesterol was associated with estradiol and prolactin. For the postmenopausal women, the low-fat diet lowered cholesterol and HDL cholesterol levels, but there were not the same associations with the hormones. These findings add weight to the concept that attention to diet may be a means of reducing the incidence of breast cancer in our community.

Diet and female sex hormone concentrations: an intervention study for the type of fat consumed.

A possible mechanism by which dietary fat may influence the development of breast cancer is by influencing the concentration of female sex hormones. This study investigated the effect of alteration in the type of fat consumed on concentrations of female sex hormones in serum. Female volunteers were randomly assigned to continue on their usual meat-eating diet, change to a vegetarian diet, or change to a diet that was predominantly vegetarian but where fish was consumed at least three times per week. Change to the vegetarian or fish diet had little effect on diet total hormone concentrations; however, the amount of estradiol was significantly decreased in the vegetarian group. When nutrient consumption was correlated with hormone concentrations, prolactin was directly associate with fat consumption, sex-hormone-binding globulin was inversely associated with fat consumption (particularly cholesterol consumption), and the proportion of nonprotein-bound estradiol was directly associated with complex carbohydrate consumption.

An improved procedure for the 'dot immunobinding' analysis of hybridoma supernatants.

The recently introduced dot immunobinding assay is well suited as a rapid and sensitive procedure for the analysis of those hybridoma clones that are producers of a specific antibody. We present a modification of the dot immunobinding assay which utilizes a single nitrocellulose sheet for up to 96 assays. By using a single nitrocellulose sheet, sample manipulation is greatly reduced, reaction conditions can be better standardized and a comparison of background reactivities is provided. Results are presented which demonstrate the effectiveness of this modified dot immunobinding assay.

Birth weight less than 800 grams: changing outcomes and influences of gender and gestation number.

Mortality and neurodevelopmental morbidity were compared in two cohorts of neonates with birth weights of less than 800 g. The neonates, born in the years 1977 through 1980 (original cohort) and 1983 through 1985 (current cohort), were patients in the same university intensive care nursery. Mortality was 80% in the original cohort and 64% in the current cohort (P = .01). In the current cohort, survival was significantly better for neonates with birth weights of more than 749 g (58% vs 27%; P = .001). Survival was also significantly associated with gender and with gestation number (female survival was 48% and male survival was 23%, P = .003; singleton survival was 41% and twin survival was 21%, P = .03). Prevalence of major central nervous system handicaps did not significantly differ between the two study groups, but severity of handicap was worse for the current study group. Morbidity in the current cohort was most severe for twins (67% with a major central nervous system handicap) and was least severe for singleton girls (4% with a major central nervous system handicap, P = .002). Delivery mode appeared to affect outcome. Although there were more nursery admissions and more survivors among neonates with birth weights of less than 800 g during the period 1983 through 1985 compared with the period 1977 through 1980, overall neurodevelopmental morbidity worsened.

Middle ear function in learning-disabled children.

To investigate the possible association of chronic otitis media and school learning problems, past and current middle ear status in 53 learning-disabled (LD) children was compared to that of 56 control children without learning problems. A history of recurrent otitis media was obtained in 23% of the LD children and in 9% of the control children. Thirty-eight percent of LD children and 16% of control children had hearing abnormalities on pure tone audiometry; 49% of LD children and 21% of control children had abnormal tympanometry. LD children had significantly more middle ear malfunction than control children. Chronic, undetected middle ear problems may play a role in the etiology of some school learning disabilities.

Outcome of infants weighing less than 800 grams at birth: 15 years' experience.

OBJECTIVE: Mortality and neurodevelopmental morbidity among infants weighing less than 800 g at birth are compared in three separate studies from the same intensive care nursery during an almost 15-year period. METHODS: The survival and neurodevelopmental outcome of 210 infants with birth weights less than 800 g admitted to the University of Washington neonatal intensive care unit between 1986 and 1990 are compared with those of two previous cohorts (1977 through 1980 and 1983 through 1985) of extremely low birth weight (ELBW) infants from the same nursery. RESULTS: Annual admissions of these ELBW infants nearly doubled from 1977 to 1990, whereas nursery survival rose from 20% between 1977 and 1980, to 36% between 1983 and 1985, to 49% in this current study of births between 1986 and 1990. The greatest increase in survival among the three studies occurred among infants with birth weights less than 700 g. Female survival was 20% higher than male survival in each of the time periods. The prevalence of major neurosensory impairments did not differ significantly among the three study groups (19%, 21%, and 22% respectively); male survivors were more commonly affected across time periods. There were no differences in mean cognitive test scores between the current 1986 through 1990 birth cohort (94) and the two previous cohorts (1977 through 1980, 98; 1983 through 1985, 89). CONCLUSIONS: The experience of our center with these ELBW infants over time seems reassuring to the extent that progressive increases in nursery survival have not resulted in increased neurodevelopmental morbidity.

Growth and development of infants weighing less than 800 grams at birth.

A prospective study of infants weighing less than 800 g at birth and cared for in a single neonatal intensive care unit between 1977 and 1980 was conducted. Neonatal mortality was 80%; neurodevelopmental outcome was assessed in 16 of the 18 survivors. Mean birth weight for these 16 was 730 g; mean gestational age was 26 weeks. Perinatal asphyxia, respiratory distress, apnea, mechanical ventilation, and chronic pulmonary disease were commonplace. Symptomatic intracranial hemorrhage, seizures, sepsis, or meningitis did not occur in survivors. Of the 16 infants, 13 (81%), including all three with birth weight less than 700 g, were without major CNS handicaps and were developing appropriately at 6 months to 3 years of age. Only one of the 16 had clearly subnormal mental development. None had a major visual or hearing impairment. Apgar scores at one and five minutes were significantly related to outcome; apnea, mechanical ventilation, and chronic pulmonary disease were not. These data suggest that a remarkably hopeful outcome is possible for the few survivors of extremely low birth weight.

Periventricular echodensities detected by cranial ultrasonography: usefulness in predicting neurodevelopmental outcome in low-birth-weight, preterm infants.

Forty-eight low-birth-weight, preterm graduates of the University of Washington's neonatal intensive care unit who had received periodic, serial scanning by means of cranial ultrasonography during the first 4 to 6 weeks of life were longitudinally observed in an interdisciplinary neurodevelopmental follow-up program to a mean corrected age of 18 months. Mean birth weight for the sample was 1286 g; mean gestational age was 29 weeks. Periventricular echodensities were graded from 0 to 3, with 0 indicating no densities and 3 indicating cystic formation. Intracranial hemorrhage was graded in the conventional manner from 0 to IV. Neurodevelopmental outcome was assessed by means of a neurologic examination and the Bayley Scales of Infant Development. To synthesize the results, neurodevelopmental outcome for each subject was classified as normal, demonstrating minor abnormalities, or demonstrating major abnormalities. Multiple statistical analyses with various subgroupings of subjects consistently indicated severe intracranial hemorrhage (grades III and/or IV) to be a better predictor of overall neurodevelopmental outcome than grade of periventricular echodensity, including small cysts. These results suggest a wide range of outcomes after detection of periventricular echodensities and caution against communicating overly pessimistic prognoses in many cases.

Williams syndrome: features in late childhood and adolescence.

Nine children with the Williams syndrome were evaluated for physical, neurodevelopmental, and behavioral characteristics to record the natural history of this disorder. The study subjects, who ranged in age from 10 years to 20 years, generally showed lower than expected cognitive functioning with four of the nine functioning in the severely retarded range. However, all the children showed uneven developmental profiles, compared to measured IQ, with reading abilities exceeding the expected level and visual-motor skills deficient for overall performance expectations. All but one child had evidence of supravalvular aortic stenosis on echocardiography, but there was little morbidity from cardiovascular disease in this group of patients. Although all had grown at or below the fifth percentile in early childhood, seven now were above the fifth percentile for height. Personality attributes that characterize younger children with Williams syndrome persisted in this group of older children.

Vitamin and mineral supplementation in Down's syndrome.

The claim that large, nonspecific doses of vitamins and minerals improve the performance of mentally retarded children has recently reappeared in both the scientific literature and the public media. This hypothesis was examined in a double-blind, case-control study involving 20 home-reared children with Down's syndrome between 5 and 13 years of age. Children were randomly assigned by matched pairs to either a vitamin/mineral group or placebo group for an 8-month study period. No significant group differences or suggestive trends were found in any tested area of development or behavior, including intelligence (IQ), school achievement, speech and language, and neuromotor function. No group differences in appearance, growth, or health were seen. No support was found for the orthomolecular hypothesis in school-aged children with Down's syndrome.

Teaching developmental pediatrics to pediatric residents: effectiveness of a structured curriculum.

A national Task Force on Developmental Pediatrics was convened in 1979 to produce a curriculum for pediatric residents pertaining to the detection, assessment, and management of children with atypical development. During a 2-year period, the task force developed a structured curriculum composed of specific goals, educational objectives, and matched learning activities that identified and described the basic knowledge, skills, and attitudes of developmental pediatrics to be acquired during a pediatric residency. Subsequently, the curriculum was implemented and evaluated in 11 pediatric programs with a developmental pediatrics rotation. On a seven-point subjective scale, the mean resident (n = 64) rating of the curriculum's usefulness was 6.0 and of their perceived competence in the skills of developmental pediatrics was 5.2; the mean percent of this competence attributed to the curriculum-based rotation was 56.6. On an objective case management test, residents who used the curriculum scored significantly (P less than .005) higher than those who did not. These results suggest the efficacy of structured curricula in pediatric resident education.

Breaking the news. How families first learn about their child's chronic condition.

OBJECTIVE: To develop recommendations for effectively informing families about their child's chronic illness or disability. METHODS: The sample included 43 families of infants with Down syndrome and/or congenital heart disease who were participating in Project Resilience, which is a multisite longitudinal research project. Family interviews were transcribed verbatim and coded by two raters. Qualitative techniques were used to identify the factors that influenced family caregivers' reactions to learning that their child had been diagnosed as having a chronic condition. RESULTS: Family caregivers clearly distinguished their personal emotional reactions to the diagnosis from their reactions to how providers informed them about their child's condition. Families emphasized the quality of information that they received as well as the manner in which they were told about the condition. Although two thirds of the informing incidents were positive, families also reported negative reactions to outdated and inadequate information as well as to professionals who were insensitive to their needs. CONCLUSIONS: Resident and continuing education programs need to prepare physicians who can sensitively and effectively "break the news" to diverse families who have children with chronic conditions. At the time of diagnosis, clinicians need to PACE the news by (1) planning the setting, (2) assessing the family's background knowledge and experience, (3) choosing strategies that best fit the family's particular situation, and (4) evaluating the family's understanding of the information.

Parents' perceptions of helpful vs unhelpful types of support in managing the care of preadolescents with chronic conditions.

OBJECTIVE: To identify parents' perceptions of helpful vs unhelpful types of social support received in managing the care of preadolescents with chronic conditions. DESIGN: Multimethod cohort study with 1-year follow-up. SETTING: General community. PARTICIPANTS: Volunteer, consecutive sample of parents of 124 preadolescents with a variety of chronic conditions. METHODS: In-depth, in-home interviews conducted with parents. Quantitative data from the Social Support Assessment questionnaire was used to assess and compare sources and types of helpful support at baseline and 1 year later. Content analytic methods were used to categorize unsupportive behaviors described by parents during the first interview. RESULTS: Both mothers and fathers reported that other family members were the primary source of helpful emotional and tangible support, while health care providers were the primary source of helpful informational support. The amount of perceived support from family members, community members, and service providers stayed relatively stable over time, except that fathers reported a significant increase in helpful emotional and informational support from extended family members from baseline to 1 year later. Also, 388 incidents of unsupportive behaviors were identified; the majority of these behaviors were attributed to health professionals and extended family members. CONCLUSION: While patterns of perceived support remained relatively stable over a 1-year period, reports of unsupportive behaviors suggest gaps in service and problems that must be addressed to improve the care that children with chronic conditions and their families receive.

Long-term perspective on premature infant outcome and contemporary intervention issues.

Despite improvements in survival rates for low birthweight (LBW) infants, the prevalence among survivors of major neurodevelopmental impairment seems relatively stable. Cerebral palsy, the most common major impairment, can usually be ruled out by 18 months corrected age. Minor impairments such as learning disabilities cannot be ruled out until much later. The efficacy of interventional services in this population was addressed by a national randomized trial. The intervention produced large treatment effects for heavier LBW infants and moderate effects for lighter infants. Five years later, modest residual effects were found for heavier LBW infants, but not for the lighter, suggesting that 0 to 3 services alone are not sufficient to prevent scholastic disadvantage in this population.

Preventive interventions with low birth weight premature infants: an evaluation of their success.

The outcome literature on low birthweight (LBW) premature children indicates that they are at risk for a variety of neurodevelopmental impairments throughout childhood. To prevent such disabilities, numerous interventions have been initiated with LBW children. Nineteen intervention programs designed for LBW preterms that have published study results dating from 1971 are reviewed. Included are interventions in the neonatal nursery, at home, and at centers as well as interventions that are both child-focused and parent-focused. One randomized clinical trial evaluating comprehensive intervention services, the Infant Health and Development Program, is described in detail. Conclusions from the studies reviewed indicate that intervention programs have had only modest success in altering neurodevelopmental outcomes, although parent-child interaction has often been facilitated. Future research on the effects of preventive intervention needs to examine long-term developmental competencies and to replicate positive findings in multiple settings.

Effectiveness of developmental intervention in the first five years of life.

Developmental intervention in the first 5 years of life is an expanding, complex enterprise. Documenting efficacy by traditional scientific methods has proven to be elusive for a number of practical reasons, e.g., target population heterogeneity, methodology variability, inadequate outcome measures, and cost of longitudinal cohort designs. Nevertheless, despite these shortcomings, there is accumulating research information as to which types of intervention approaches are likely to be most beneficial to specific groups of infants and children and their families. It is quite clear that preventive strategies for at-risk children and families are different than ameliorative strategies for children with established disabilities. It is also clear that comprehensive evaluation of effectiveness must include consideration of both functional child gains (e.g., social, communication, mobility, and adaptive skills) and enhancement of family function. It is the pediatrician's responsibility to be adequately informed about contemporary developmental interventions in order to balance parental hopes and needs with potential benefits.

Stimulant medication for the child with attention-deficit/hyperactivity disorder.

Stimulant medications have been used to manage the associated symptoms of ADHD including inattention, developmentally inappropriate levels of activity, distractibility, and impulsivity. To date, clinical trials clearly have established the efficacy of the stimulants on the core symptoms of ADHD and associated aggression. Although the stimulants improve classroom productivity and behavior, few data have demonstrated the effectiveness of the stimulants on academic achievement. Finally, there has been a paucity of data on the long-term efficacy and safety of stimulants. Recommendations are made for future research studies that examine the integration of stimulant medication with other psychosocial therapies, particularly behavior management.