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.

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.

Developmental delay in fetal aminopterin/methotrexate syndrome.

Maternal exposures to aminopterin and methotrexate have been associated with a pattern of malformation which includes prenatal-onset growth deficiency, severe lack of ossification of the calvarium, hypoplastic supraorbital ridges, small, low-set ears, micrognathia, and limb abnormalities. We report on a patient whose mother received methotrexate during the first trimester of pregnancy and who, in addition to the structural anomalies typical of maternal methotrexate exposure, has significant developmental delay. This is the third patient exposed to folic acid antagonists with mental retardation, providing further evidence that developmental delay is one feature of fetal aminopterin-methotrexate syndrome. Therefore, it is recommended that formal developmental testing be performed in all patients prenatally exposed to methotrexate.

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.

Experimental production and modulation of human cytotoxic dermatitis in human-murine chimeras.

Human dermatitis-involving cytotoxic interaction between effector lymphocytes and epithelial target cells has thus far been documented in vivo only as naturally occurring disease or as an iatrogenic complication of organ engraftment. In this report, we reproduce human cytotoxic dermatitis via local microinjection of heterologous human lymphocytes into human skin xenografted to mice with severe combined immune deficiency syndrome. Injection sites develop progressive T cell epidermotropism culminating in cytotoxic dermatitis resembling human lichen planus within 4 weeks. Effector T cells express a CD8+, TIA-1+ phenotype, proliferate locally, express interleukin-2 surface receptors, and demonstrate interferon-gamma mRNA induction after microinjection. Migration of these T cells into the epidermis is closely linked to experimental induction and coincident expression of intercellular adhesion molecule by keratinocytes. T cell apposition to keratinocytes is associated with endonuclease-mediated DNA fragmentation (apoptosis) in the latter cell type. Intraepidermal T cell migration and related lesion formation is partially abrogated by systemic administration of antisense oligonucleotide to ICAM-1 mRNA. These findings demonstrate that human cytotoxic tissue injury directed against epithelial targets can be produced and modulated in chimeric mice.

Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program.

OBJECTIVE: To reevaluate at age 8 years children who had participated during the first 3 years of life in a randomized clinical trial of special services for low-birthweight (LBW) premature infants. DESIGN: Follow-up of a randomized controlled trial of premature infants (< or = 37 weeks' gestation), stratified by 2 LBW groups (lighter [< or = 2000 g] and heavier [2001-2500 g]) and divided into intervention (n=377) and follow-up only (n=608) groups. SETTING: Eight sites serving diverse populations. PARTICIPANTS: At age 8 years, 874 children were assessed: 336 in the intervention group and 538 in the follow-up only group. INTERVENTION: The 3-year intervention consisted of home visits (birth to 3 years), child development center services (ages 1 to 3 years), and parent group meetings (ages 1 to 3 years). PRIMARY OUTCOME MEASURES: Cognitive functioning (Weschler Intelligence Scale for Children-III; Peabody Picture Vocabulary Test-Revised); academic achievement (Woodcock-Johnson Tests of Achievement-Revised); and parental reports of school performance, behavior (Child Behavior Checklist), and health (Child General Health Survey). RESULTS: At age 8 years, in the entire cohort and in the lighter LBW stratum, the intervention and follow-up only groups were similar on all primary outcome measures. Differences favoring the intervention group were found within the heavier LBW group: full-scale IQ score (4.4 points higher, P=.007), verbal IQ score (4.2 points higher, P=.01), performance IQ score (3.9 points higher, P=.02), mathematics achievement score (4.8 points higher, P=.04), and receptive vocabulary score (6.7 points higher, P=.001). On a physical functioning subscale, the whole intervention group received less favorable ratings, while the lighter LBW intervention group had lower maternal ratings assessing social limitations caused by behavior. CONCLUSION: Although at age 8 years there were modest intervention-related differences in the cognitive and academic skills of heavier LBW premature children, attenuation of the large favorable effects seen at 3 years was observed in both the heavier and lighter LBW groups. This indicates a need to develop additional intervention strategies for LBW premature children that can provide sustained benefits.

Social support in families of children with chronic conditions: supportive and nonsupportive behaviors.

We questioned parents of 182 young children with a variety of chronic health conditions concerning the amount of emotional, informational, and tangible social support they received from the family, community, and service providers. We also asked parents to describe nonsupportive or hurtful behaviors received from family or community members. Both mothers and fathers reported that family members provided the most emotional and tangible social support and service providers the most informational support. The amount of perceived support from all sources increased over time, but 78% of mothers and 60% of fathers reported at least one instance of nonsupport from these same sources, primarily from extended family members and health professionals. We encourage health professionals to show respect and to provide timely, accurate information in a sensitive manner to parents whose child has a chronic health condition and to assist parents in handling nonsupportive behaviors from family and friends.

Effect of incremental time experience on the results of in vitro fertilization with intracytoplasmic sperm injection (ICSI).

PURPOSE: Our objective was to determine the effect of experience on the results with intracytoplasmic sperm injection. METHODS: The quarterly outcome with both ICSI and traditional in vitro fertilization (IVF) in 1994 was analyzed in 475 patients under age 40 undergoing 595 oocyte retrievals. The data represent 307 patients undergoing 379 retrievals for IVF and 165 patients undergoing 216 retrievals for ICSI. RESULTS: Fertilization rates with ICSI improved significantly each quarter (52.96, 62.17, 70.17, and 74.87% in Q-I, Q-II, Q-III, and Q-IV, respectively), while the rate with IVF improved significantly between Q-I (69.9%) and Q-II (80.10%) and slightly but significantly between Q-II and Q-IV (82.88%). The implantation rate per embryo after ICSI improved significantly after Q-I (6.17%) compared to Q-II (10.70%) and Q-IV (12.14%). The pregnancy rate per transfer with ICSI increased steadily after Q-I (13.79, 21.88, 23.53, and 25.00% in Q-I through Q-IV), reaching statistical significance between Q-I and Q-III and between Q-I and Q-IV. CONCLUSIONS: Although acceptable results can be obtained with ICSI after a relatively short period of time, optimum results require substantial experience.

Early intervention for low-birth-weight premature infants: what can we achieve?

Low-birth-weight (LBW) premature infants are at increased risk for abnormal development. It is unclear whether intervention programs designed to prevent the disabilities in preterm children are efficacious. This paper reviews the settings in which interventions take place (e.g. nursery, home) and to whom they are directed (e.g. infant, parent). One intervention program, the Infant Health and Development Program (IHDP) is reviewed in detail. The IHDP was a multisite randomized clinical trial to evaluate the efficacy of combining developmental and support services along with paediatric follow-up to reduce the developmental problems seen among LBW preterm infants. Results from all studies suggest that preventive developmental interventions for LBW, premature infants have thus far demonstrated only modest success. Future research endeavours should investigate the type, duration, critical age onset, and intensity of the intervention as well as which subgroups of LBW infants most benefit from such programs.

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.

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.

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.