Multiple control and dynamic response of the Xenopus melanotrope cell.

Some amphibian brain-melanotrope cell systems are used to study how neuronal and (neuro)endocrine mechanisms convert environmental signals into physiological responses. Pituitary melanotropes release alpha-melanophore-stimulating hormone (alpha-MSH), which controls skin color in response to background light stimuli. Xenopus laevis suprachiasmatic neurons receive optic input and inhibit melanotrope activity by releasing neuropeptide Y (NPY), dopamine (DA) and gamma-aminobutyric acid (GABA) when animals are placed on a light background. Under this condition, they strengthen their synaptic contacts with the melanotropes and enhance their secretory machinery by upregulating exocytosis-related proteins (e.g. SNAP-25). The inhibitory transmitters converge on the adenylyl cyclase system, regulating Ca(2+) channel activity. Other messengers like thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH, from the magnocellular nucleus), noradrenalin (from the locus coeruleus), serotonin (from the raphe nucleus) and acetylcholine (from the melanotropes themselves) stimulate melanotrope activity. Ca(2+) enters the cell and the resulting Ca(2+) oscillations trigger alpha-MSH secretion. These intracellular Ca(2+) dynamics can be described by a mathematical model. The oscillations travel as a wave through the cytoplasm and enter the nucleus where they may induce the expression of genes involved in biosynthesis and processing (7B2, PC2) of pro-opiomelanocortin (POMC) and release (SNAP-25, munc18) of its end-products. We propose that various environmental factors (e.g. light and temperature) act via distinct brain centers in order to release various neuronal messengers that act on the melanotrope to control distinct subcellular events (e.g. hormone biosynthesis, processing and release) by specifically shaping the pattern of melanotrope Ca(2+) oscillations.

Dynamics and plasticity of peptidergic control centres in the retino-brain-pituitary system of Xenopus laevis.

This review deals particularly with the recent literature on the structural and functional aspects of the retino-brain-pituitary system that controls the physiological process of background adaptation in the aquatic toad Xenopus laevis. Taking together the large amount of multidisciplinary data, a consistent picture emerges of a highly plastic system that efficiently responds to changes in the environmental light condition by releasing POMC-derived peptides, such as the peptide alpha-melanophore-stimulating hormone (alpha-MSH), into the circulation. This plasticity is exhibited by both the central nervous system and the pituitary pars intermedia, at the level of molecules, subcellular structures, synapses, and cells. Signal transduction in the pars intermedia of the pituitary gland of Xenopus laevis appears to be a complex event, involving various environmental factors (e.g., light and temperature) that act via distinct brain centres and neuronal messengers converging on the melanotrope cells. In the melanotropes, these messages are translated by specific receptors and second messenger systems, in particular via Ca(2+) oscillations, controlling main secretory events such as gene transcription, POMC-precursor translation and processing, posttranslational peptide modifications, and release of a bouquet of POMC-derived peptides. In conclusion, the Xenopus hypothalamo-hypophyseal system involved in background adaptation reveals how neuronal plasticity at the molecular, cellular and organismal levels, enable an organism to respond adequately to the continuously changing environmental factors demanding physiological adaptation.

Functional organization of the suprachiasmatic nucleus of Xenopus laevis in relation to background adaptation.

The process of background adaptation in the toad Xenopus laevis is controlled by neurons in the suprachiasmatic nucleus (SC) that inhibit the release of alpha-melanophore-stimulating hormone from the neuroendocrine melanotrope cells in the pituitary gland. We have identified the structural and functional organization of different neuropeptide Y (NPY)-containing cell groups in the Xenopus SC in relation to background adaptation. A ventrolateral, a dorsomedial, and a caudal group were distinguished, differing in location as well as in number, size, and shape of their cells. They also show different degrees of NPY immunoreactivity in response to different background adaptation conditions. In situ hybridization using a Xenopus mRNA probe for the exocytosis protein DOC2 revealed that melanotrope cells of black-adapted animals have a much higher expression of DOC2-mRNA than white-adapted ones. This establishes that the degree of DOC2-mRNA expression is a good parameter to measure cellular secretory activity in Xenopus. We show that in the ventrolateral SC group, more NPY-positive neurons express DOC2-mRNA in white- than in black-adapted animals. In contrast, NPY-positive neurons in the dorsomedial group have a high secretory activity under the black-adaptation condition. We propose that in black-adapted animals, NPY-positive neurons in the ventrolateral group, known to inhibit the melanotrope cells in white-adapted animals synaptically, are inhibited by NPY-containing interneurons in the dorsmedial group. NPY-positive neurons in the caudal group have similar secretory dynamics as the dorsomedial NPY neurons, indicating that they also play a role in background adaptation, distinct from that exerted by the ventrolateral and dorsomedial group.

P75 nerve growth factor receptor is important for retrograde transport of neurotrophins in adult cholinergic basal forebrain neurons.

The role of the p75 nerve growth factor receptor in the retrograde transport of neurotrophins in the adult CNS was investigated by comparing the transport of 125I-labeled neurotrophins by normal and p75 nerve growth factor receptor-deficient cholinergic septohippocampal neurons. In control mice, nerve growth factor was selectively transported from the hippocampal formation to the cholinergic neurons in the septum. Nerve growth factor labeling was found in three to four times as many septal cholinergic neuronal cell bodies than labeling for neurotrophin-3 or neurotrophin-4/5, and transported brain-derived neurotrophic factor was barely detectable. Cells were considered as labeled when the number of grains per cell exceeded five times background. In p75 nerve growth factor receptor-deficient mice, the number of cholinergic neurons labeled with each of the neurotrophins was reduced by 85-95%. Retrograde labeling of septohippocampal neurons with Fluorogold was not obviously reduced in p75 nerve growth factor receptor-deficient mice, suggesting that general transport mechanisms were not impaired. Despite the reduced neurotrophin transport, cholinergic neurons of p75 nerve growth factor receptor-deficient mice were larger than controls and had an apparently normal density of immunostaining for choline acetyltransferase. Since nerve growth factor is reportedly involved in size regulation and choline acetyltransferase expression, this raises the possibility that the retrograde transport itself is not essential for these events. Thus, p75 nerve growth factor receptor plays an important, although not exclusive, role in the transport of neurotrophins by cholinergic basal forebrain neurons, and retrograde transport of nerve growth factor may not be needed for regulating certain cellular processes.

Factors affecting cognitive, motor, behavioral and executive functioning in children with phenylketonuria.

We administered measures of cognitive, frontal lobe (executive), behavioral and motor functioning to 18 children with classical phenylketonuria, aged 12-101 months, in order to determine the relationship of age, current and lifetime average phenylalanine levels, and individual variation (standard deviation of lifetime average levels) to these functions. On measures of cognitive function, in children > or = 3 y of age lower current phenylalanine levels were associated with higher cognitive functioning. On a behavioral temperament scale designed for normal children, we found that higher current and average phenylalanine levels correlated with more difficult temperament. Motor function was also poorer in children with phenylketonuria, and was most impaired in children with current phenylalanine levels >360 micromol/l. We also identified a previously unreported correlation between increased individual variation and poorer executive function performance, a finding that may raise new management concerns about level fluctuations. Maintenance of phenylalanine levels <360 micromol/l may be necessary for optimal performance in children with phenylketonuria.

School-age follow-up of prophylactic versus rescue surfactant trial: pulmonary, neurodevelopmental, and educational outcomes.

BACKGROUND: Exogenous surfactant replacement has improved survival and reduced pulmonary complications of prematurity. Improved early outcomes for infants of <30 weeks' gestation treated with a strategy of prophylactic versus rescue surfactant, if needed, were demonstrated in a multicenter, randomized trial conducted between 1985 and 1988. We reevaluated a subset of survivors from this trial to determine the pulmonary and neurodevelopmental outcomes at school age. METHODS: At 4.5 to 8 years of age, all survivors from one of the three centers were located, and 96% were evaluated. The original randomization included stratification by center and followed an intention-to-treat methodology in assessing the efficacy of prophylactic versus rescue treatment with surfactant. The follow-up test battery included a health-assessment questionnaire, spirometry, 88% saturation test, neurologic examination, and the McCarthy Scales of Children's Abilities (MSCA) and the Conners' Parent Rating Scale-48. Educational achievement was determined by school class placement and teachers' reports of achievement. RESULTS: Of the 192 children originally enrolled, 154 survived. Evaluations were performed on 148 of these infants. An abnormal pulmonary history was found in 45 (30%) of the children: 16 (22%) in the prophylactic group and 29 (39%) in the rescue group. Formal pulmonary function was evaluated in 81 children; 29 (78%) in the prophylactic group and 33 (75%) in the rescue group were considered abnormal. No significant differences were found between the two groups on either cognitive or motor subscales of the MSCA, the Conners' Parent Rating Scale-48, the neurologic examination, the education services received in school, or the teacher ratings of below-average academic performance. Intelligence scores measured on the MSCA were low-normal for both groups. Some level of educational assistance was being provided to 72 (49%) of the cohort studied, and both groups had below average educational performance and increased needs for educational assistance. CONCLUSIONS: Prophylactic surfactant administration to infants of <30 weeks' gestation was associated with fewer long-term clinical pulmonary complications than assignment to rescue administration. Formal pulmonary testing at school age did not reveal significant differences between treatment groups in those infants who could be tested. There also were no group differences found on neurologic, cognitive, behavioral, or educational assessments at school age.

School-age follow-up of a single-dose prophylactic surfactant cohort.

This study reports the school-age developmental and health status of a preventilatory surfactant cohort. The sample consisted of 39 surviving subjects (21 experimental and 18 controls) born at 25 to 29 weeks gestation who were studied at 6 and 12 months and 5 to 7 years of age. At 6- and 12-month follow-ups, the cohort was functioning close to the population normative mean. Although cognitive and motor assessments at school age also showed no group differences, 8 of 19 (42%) in the surfactant group and 9 of 17 (53%) in the normal saline group attained a McCarthy General Cognitive Index score of < or = 84 (abnormal range). On the Connors' Parental Questionnaire, both groups scored high on the Learning Disability Subscale. The surviving cohort at 5 to 7 years had no identified long-term sequelae due to surfactant therapy, yet both groups were at risk for neurodevelopmental and educational morbidity.

Characteristics of community-based individuals with mental retardation and aggressive behavioral disorders.

A cohort of 199 individuals with mental retardation referred for behavioral and psychiatric crisis intervention services was studied to determine attributes differentiating physically aggressive behavior from other behavioral problems. Individuals with aggressive and nonaggressive behavior had similar neurological histories and current medical status and similar levels of seizure disorders and CNS abnormalities. Aggressive individuals more often had psychiatric diagnoses of organic brain syndrome, but frequencies of this diagnosis in each group were small. Current aggression was predicted by gender, level of mental retardation, and history of previous institutional placement; the strongest predictor was history of aggression. These data suggest a complex equation to describe social inadequacy involving interactions between CNS functioning and developmental cognitive and social variables that are only partially defined at this time. Further work to characterize this interaction almost certainly must include a prospective longitudinal analysis of social and developmental functions early in life.

Characteristics of age-related language decline in adults with Down syndrome.

Age-related declines in language and other neuropsychological variables were examined in 60 adults with Down syndrome. Researchers have found that deterioration in functioning is present in most adults with Down syndrome if they live to be 35 years of age. Declines have typically been interpreted as symptoms of Alzheimer disease; however, the declines are not well-understood, and alternative explanations have been suggested. Our results showed significant relations between aging and language comprehension and aging and self-help skills. Verbal skills were not significantly related to aging and little variation occurred between the youngest and the oldest subjects. Guidelines for choosing appropriate criteria to examine the loss of language skills in this population were discussed.

Monitoring adult patients with sleep apnea.

It can be said that there are two methods of evaluating certain aspects of sleep. PSM is more traditional and uses older equipment to assess a full scope of sleep disorders in a rather expensive and inconvenient way. Computerized home monitoring is a more modern way of monitoring sleep using improving technology, probably most applicable to snoring with sleep apnea, in a less expensive way. A joint study group should co-ordinate and encourage progress in both traditional and computerized procedures to the greater good of all.

Keratosis obturans and external auditory canal cholesteatoma.

Keratosis obturans and external auditory canal cholesteatoma (EACC) have previously been considered to represent the same disease process. However, review of the literature and our cases reveal these to be two different clinical and pathological processes. Keratosis obturans presents as hearing loss and usually acute, severe pain secondary to the accumulation of large plugs of desquamated keratin in the ear canal. External auditory canal cholesteatoma presents as otorrhea with a chronic, dull pain secondary to an invasion of squamous tissue into a localized area of periosteitis in the canal wall. The treatment previously recommended for both of these conditions has been conservative debridement of the external canal and application of topical medication. While this remains the treatment of choice for keratosis obturans, surgery may be required to eradicate EACC.

Tenant participation in public housing.

This paper argues that tenant participation in the substance of the housing environment is a major avenue for developing and maintaining viable public housing communities. If tenants participate in shaping basic decisions, a healthy encounter can develop with management from which can flow an atmosphere of battle-tested mutual trust and respect. A successful effort of tenants at Columbia Point in Boston illustrates the effectiveness of tenant participation. The paper proposes the creation of a tenants' health council to negotiate a contract with a health agency to provide agreed-upon health services in a public housing community. Success of a tenants' council depends on inner resources of tenants themselves and willingness of the power elite to recognize an independent-even dissident-role for tenants' organizations.