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Long-term course of adolescent schizophrenia.

Our study investigated premorbid functioning, course, and outcome in early-onset schizophrenia. All inpatients with DSM-III-R diagnoses of schizophrenia (n = 101) consecutively admitted between 1983 and 1988 to the Department of Child and Adolescent Psychiatry at the University of Marburg in Germany were included. To assess premorbid adaptation and precursor symptoms, we administered the Instrument for the Retrospective Assessment of the Onset of Schizophrenia, which we modified to assess children and adolescents. Symptomatology was measured by the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, and the Brief Psychiatric Rating Scale. In addition, the Global Assessment of Functioning was applied. Followup data for 81 patients (80.2%) were available. The mean duration of schizophrenia at followup was 9.5 +/- 2.2 years. Assessment of the highest level of adaptive functioning revealed very good or good outcome in 19.8 percent of the patients, fair or poor outcome in 38.2 percent, and very poor outcome and gross impairment in 42.0 percent. Premorbid adjustment was the best predictor of outcome in our schizophrenia sample. A poor prognosis was found in patients with premorbid developmental delays and those who were introverted and withdrawn before their psychotic state.

Adolescent↗

Respiratory distress and neonatal lethality in mice lacking Golgi alpha1,2-mannosidase IB involved in N-glycan maturation.

There are three mammalian Golgi alpha1,2-mannosidases, encoded by different genes, that form Man5GlcNAc2 from Man(8-9)GlcNAc2 for the biosynthesis of hybrid and complex N-glycans. Northern blot analysis and in situ hybridization indicate that the three paralogs display distinct developmental and tissue-specific expression. The physiological role of Golgi alpha1,2-mannosidase IB was investigated by targeted gene ablation. The null mice have normal gross appearance at birth, but they display respiratory distress and die within a few hours. Histology of fetal lungs the day before birth indicate some delay in development, whereas neonatal lungs show extensive pulmonary hemorrhage in the alveolar region. No significant histopathological changes occur in other tissues. No remarkable ultrastructural differences are detected between wild type and null lungs. The membranes of a subset of bronchiolar epithelial cells are stained with lectins from Phaseolus vulgaris (leukoagglutinin and erythroagglutinin) and Datura stramonium in wild type lungs, but this staining disappears in lungs from null mice. Mass spectrometry of N-glycans from different tissues shows no significant changes in global N-glycans of null mice. Therefore, only a few glycoproteins required for normal lung function depend on alpha1,2-mannosidase IB for maturation. There are no apparent differences in the expression of several lung epithelial cell and endothelial cell markers between null and wild type mice. The alpha1,2-mannosidase IB null phenotype differs from phenotypes caused by ablation of other enzymes in N-glycan biosynthesis and from other mouse gene disruptions that affect pulmonary development and function.

Animals↗

Influence of antral follicle size on oocyte characteristics and embryo development in the bovine.

The developmental competence of bovine oocytes isolated from antral follicles of different sizes was assessed in three European laboratories (Belgium, UCL; Denmark, DIAS; France, INRA). Using the same protocol for in vitro production of embryos, the oocytes isolated from follicles with a diameter > or = 6 mm always gave a higher blastocyst rate than oocytes from follicles < 4 mm (UCL: 42% versus 14%, DIAS: 50% versus 35%, INRA: 39% versus 22%; P < 0.05). Blastocyst cell number was not affected by follicle size. Several parameters were investigated for these oocytes. The energy metabolism of cumulus-oocyte-complexes and of denuded oocytes was assessed by the oxygen and pyruvate uptake and by lactate release both at the beginning and the end of the maturation. No effect of follicle size could be detected but lactate release increased after maturation. The global profile of transcripts, the pattern of protein neosynthesis and the kinetics of meiosis resumption were not affected by follicle size. The developmental kinetics of derived embryos was also analysed. Whatever the follicle size, viable embryos had a shorter first and third embryonic cell cycle. Among the viable embryos, the size of the follicle interfered with the fourth cell cycle duration. A higher percentage of blastocysts issued from large follicle presented a short fourth cell cycle (9h) (35% versus 6%; P < 0.05). Beside, blastocysts derived from small follicles had a delayed cavitation and expansion. Thereby, a higher developmental competence for oocytes from follicle > or = 6 mm versus < 4 mm was demonstrated in three laboratories although no differences could be displayed directly at the oocyte level.

Animals↗

Pervasive developmental disorders among children and adolescents attending psychiatric day treatment.

OBJECTIVE: This study sought to determine the prevalence of pervasive developmental disorders (PDD) among children admitted to a state hospital day treatment service and to characterize the psychiatric disturbance of patients with PDD. METHODS: A total of 146 consecutively admitted patients were evaluated for PDD. Patients who had PDD were compared with a sample of age- and sex-matched patients in day treatment who did not have PDD. Psychiatric symptoms, family history, and developmental and educational histories were examined. RESULTS: Of the 146 patients, 20 (14 percent) met criteria for PDD. An additional five patients who had PDD were included, yielding a final sample of 25. Only two of an array of psychiatric symptoms were more prevalent among patients with PDD: engaging in unusual fantasy and talking to themselves, animals, or inanimate objects. Significantly more patients with PDD had a history of speech delay, language abnormalities, and inexplicable or lengthy episodes of crying or screaming. The groups did not differ significantly in IQ or global functioning. Seven patients with PDD (28 percent) met criteria for childhood-onset schizophrenia, and 19 (76 percent) had symptoms of a tic disorder. CONCLUSIONS: The study found that PDD is not rare and that children with PDD represent a significant subgroup of children with serious emotional disturbance referred for psychiatric treatment. The findings support the view that PDD may be easily missed because it may be mild and associated with psychiatric disturbances that are present among other severely ill youngsters.

Adolescent↗

Programming of sympathoadrenal function.

Environmental exposures at crucial points in development permanently alter sympathoadrenal function in mammals. The sympathetic innervation of peripheral tissues and the responsiveness of sympathetic nerves and adrenal medulla to standard stimuli are susceptible to modification by exposures in early life, such as environmental temperature, nutrition and stress. Because the sympathetic nervous system is composed of multiple, function-specific subunits, programming of sympathetic functions occurs on a regional rather than a global basis and can aid development of a phenotype adapted to the local environment. Under some circumstances, however, adaptations in early life might prove maladaptive in adulthood and, as a consequence, might provide a basis for developmental origins of pediatric and adult disease, such as sudden infant death syndrome and obesity.

Adrenal Medulla↗

Neonatal subependymal cysts detected by sonography: prevalence, sonographic findings, and clinical significance.

OBJECTIVE: Cranial sonography in neonates occasionally shows subependymal cysts. These cysts may be due to a variety of pathologic disorders, but they also occur as an "isolated" condition without an obvious cause in some patients. Assessment of the clinical significance of these lesions has been difficult because of the limited duration of follow-up, the informal nature of neurodevelopmental evaluation, and the heterogeneous cohort of patients previously reported. Accordingly, the purposes of this study were to provide more complete and longer neurodevelopmental followup and to describe the prevalence and sonographic characteristics of isolated subependymal cysts detected on cranial sonograms in neonates. MATERIALS AND METHODS: In a 4 1/2-year period, more than 4000 cranial sonograms were obtained at our institution. We retrospectively determined that 17 neonates (59 studies) had sonographic evidence of an isolated subependymal cyst. A high-resolution real-time mechanical sector transducer was used to obtain the sonograms. No subjects had clinical or sonographic evidence of intercurrent hemorrhage, infarct, infection, or congenital abnormalities. Neurodevelopmental outcome was independently determined. In particular, premature infants who weighed less than 1500 g at birth were longitudinally assessed by a multidisciplinary developmental team. A general quotient was derived in nine subjects by using the Griffith Mental Developmental Scales. RESULTS: Subependymal cysts were often tear shaped, 2-11 mm in size, and located either at the caudothalamic groove or along the anterior aspect of the caudate nucleus. Most subjects (n = 15) who had the cysts were born prematurely (mean gestational age, 31 weeks; range, 25-34 weeks). Results of follow-up were available in 14 infants 2-41 months old (mean, 22 months; median, 21 months). Development was considered to be normal in 13 of the 14 subjects; one term infant referred because of mild dysmorphic features had a mild global delay. The general quotient for corrected age, determined in nine subjects, had a mean of 111 (range, 103-120; normal, > 83). Fifteen neonates had at least two cranial sonographic examinations. In seven patients, serial examinations showed that cysts had resolved or diminished in size (on average 23 weeks after the initial sonographic study). In the other eight, no change in the size of the cyst was observed, but the mean interval between the first and last sonograms was only 14 days. CONCLUSION: Cranial sonograms of neonates occasionally show isolated subependymal cysts, usually in premature infants. In most cases, no serious neurodevelopmental complications occur. Many cysts resolve after a variable period.

Brain Diseases↗

Abnormal electroretinogram associated with developmental brain anomalies.

PURPOSE: We have encountered abnormal ERGs associated with optic nerve hypoplasia, macular, optic nerve and chorioretinal colobomata and developmental brain anomalies. Brain anomalies include cortical dysgenesis, lissencephaly, porencephaly, cerebellar and corpus callosum hypoplasia. We describe six exemplar cases. METHODS: Scotopic and photopic ERGs adherent to international standards were performed as well as photopic ERGs to long-duration stimuli. CT or MRI studies were also done. The ERGs were compared to age-matched normal control subjects. RESULTS: ERG changes include reduced amplitude b-waves to blue and red stimuli under scotopic testing conditions. Implicit times were often delayed. The photopic responses also showed reduced amplitude a- and b-waves with implicit time delays. The long-duration photopic ERG done in one case shows attenuation of both ON- and OFF-responses. CONCLUSIONS: Common underlying developmental genetic or environmental unifying casualties are speculated to be at fault in causing these cases of associated retinal and brain abnormalities. No single etiology is expected. Multiple potential causes acting early in embryogenesis effecting neuronal induction, migration and differentiation are theorized. These occur at a time when brain and retinal cells are sufficiently undifferentiated to be similarly effected. We call these cases examples of Brain Retina Neuroembryodysgenesis (BRNED). Homeobox and PAX genes with global neuronal developmental influences are gene candidates to unify the observed disruption of brain and retinal cell development. The ERG can provide a valuable clinical addition in understanding and ultimately classifying these disorders.

Brain↗

Neonatal brain MRI and motor outcome at school age in children with neonatal encephalopathy: a review of personal experience.

The aim of this paper is to review (i) the spectrum of neuromotor function at school age in children who had been born full-term and presented with neonatal encephalopathy (NE) and low Apgar scores and (ii) the relation between the presence/absence of such difficulties and neonatal brain MRI. Motor outcome appears to be mainly related to the severity of basal ganglia and internal capsule involvement. Severe basal ganglia lesions were always associated with the most severe outcome, microcephaly, tetraplegia, and severe global delay, whereas more discrete basal ganglia lesions were associated with athetoid cerebral palsy, with normal cognitive development, or minor neuro-motor abnormalities. White matter lesions were associated with abnormal motor outcome only if the internal capsule was involved. Children with moderate white matter changes but normal internal capsule had normal motor outcome at school age.

Adolescent↗

Epilepsy related to hypothalamic hamartomas: surgical management with special reference to gamma knife surgery.

OBJECTIVE: A large spectrum of surgical techniques can be proposed to young patients presenting with hypothalamic hamartomas (HH) associated with severe epilepsy. The aim of this report is to point on some clinical and anatomical parameters supposed to influence the choice of the surgical approach and to emphasize the specific role of radiosurgery. MATERIALS AND METHODS: We reviewed both our experience and the recent literature based on a Pubmed search. Lateral pterional, midline frontal through the lamina terminalis, transcallosal interforniceal approaches, endoscopic treatment through the foramen of Monro, disconnecting surgery, radiofrequency ablation, brachytherapy and gamma knife surgery (GKS) were all considered. Mortality, morbidity, and efficacy of each of these techniques were compared. Specific limits, difficulties, and constraints were taken into account. Our experience of radiosurgery is based on a prospective trial which enrolled 60 patients with HH and associated severe epilepsy between October 1999 and December 2005. RESULTS: Several surgical techniques can lead to a real reversal of the epileptic encephalopathy. The main factors for the decision-making process are the age, the size of the lesion and its anatomical type (according to our original classification), the severity of the epilepsy, and the severity of the cognitive/psychiatric comorbidity. In our prospective trial (GKS), 27 patients have a follow-up superior to 3 years. Among those, 59.2% have an excellent result with a dramatic behavioral and cognitive improvement and are completely seizure-free (37%) or have only rare non-disabling seizures (22.2%). No permanent neurological complication has been observed so far; three patients have presented a transient poïkilothermia. GKS is clearly the safer approach for these difficult patients. Young patients with severe epilepsy and comorbidity must be operated on using a curative approach as early as possible. Very large type VI or mixed type with a large component above the floor of the third ventricle must be disconnected and then the upper remnant can be ideally treated by GKS (staged surgery). Type V (rarely epileptic) and IV are frequently operable by disconnection. Type I HH deeply embedded in the hypothalamus are operated on by GKS efficiently and safely. Type II HH can be operated on either endoscopically or transcallosally or by GKS depending on the parents' choice and severity of epilepsy. In small type III HH, GKS is a safer procedure, due to the very close relationship to the fornix and mammillary bodies. In very large type III HH, transcallosal interforniceal approach is proposed but with significant risks especially concerning short-term memory. When the lesion is sufficiently small, GKS is globally offering the patient a rate of seizure cessation comparable to microsurgery with, however, a much lower risk (no neurological deficit reported till now). CONCLUSION: Our first results indicate that GKS is as effective as microsurgical resection and very much safer. GKS also allows avoiding the vascular risk related to radiofrequency lesioning or stimulation. The disadvantage of radiosurgery is its delayed action. Longer follow-up is mandatory for a reliable evaluation of the role of GKS. The early effect on subclinical discharges turns out to play a major role in the dramatic improvement of sleep quality, behavior, and developmental learning acceleration at school.

Epilepsy↗

The timing of compaction: control of a major developmental transition in mouse early embryogenesis.

The effect of protein synthesis inhibitors on compaction of the 8-cell mouse embryo has been investigated. The effects observed depended upon the duration and time of drug application and on the features of compaction scored. Continuous application from the late 2-cell or early 4-cell stages allowed cell flattening and surface polarization to occur in most embryos and advanced development of these features in many of them. Cell coupling developed only when drug addition was delayed until the mid 4-cell stage, and cytoplasmic polarization developed only when drug addition was delayed until the late 4-cell stage. We suggest that control over the timing of compaction is achieved at a post-translational level via a global permissive change within the blastomeres of the embryo.

Animals↗

A developmental study of scores of the Boston Qualitative Scoring System.

To elucidate developmental changes of the Summary Scores of the Boston Qualitative Scoring System (BQSS) for the Rey-Osterrieth Complex Figure (ROCF). One hundred healthy children aged 6-16 (average 9.7 +/- 2.4; 60 boys, 40 girls). The ROCF was administered and graded based on the BQSS. The subjects were classified in four age-groups: 6- and 7-year-olds; 8- and 9-year-olds; 10- and 11-year-olds; and 12- and 16-year-olds. The differences in Summary Scores were examined among age-groups. All BQSS Summary Scores except Delayed Retention showed clear developmental changes. The Copy Presence Accuracy, the Immediate Presence Accuracy, the Delayed Presence Accuracy, and the Immediate Retention showed continuous development throughout childhood, though some differences were noted in the age ranges during which each score showed the most rapid development. The Organization score showed a somewhat peculiar pattern, with rapid development during the age ranges of 8-9 and 10-11 and with no distinctive development before and after these ranges. Five of the six BQSS Summary Scores showed clear developmental changes with a different developmental pattern in each score. Especially, the Organization score was unique and was supposed to reflect a different underlying process than the other Summary Scores, which might relate to the local and global processing style. BQSS is a promising tool for the evaluation of higher brain functions in childhood.

Adolescent↗

The relationship between parental concerns and professional assessment in developmental delay in infants and children--a hospital-based study.

BACKGROUND: Developmental delay (DD) in infants and children is one of the chief complaints of parents. It has been established that the concerns of parents are as accurate as quality screening tests. Some kinds of concerns are particularly useful in the early detection of associated developmental problems. The purpose of this study was to investigate the relationship between the main parental concerns and the final diagnosis based on professional assessment of children who are suspected to have DD. METHODS: One-hundred and 1 infants or children were recruited into this study. The major concerns of parents were elicited and categorized by various developmental domains: speech, motor, behavioral, cognitive, global, and non-specific developmental problems. All children underwent comprehensive combined assessments by professionals in the hospital, and were classified into 6 subtypes: speech, motor, behavioral, cognitive, and global DD, and normal development. RESULTS: Our results revealed that parental concerns about speech, motor, and behavioral development yielded a high sensitivity to the final diagnosis of the same developmental domain (77-89%). However, concerns about cognitive and global DD had limited sensitivity (15-36%). On the other hand, concerns about global, speech, and motor DD had relatively higher positive predictive values (55-77%). Comparatively, cognitive or behavioral concerns had lower positive predictive values (25-33%). CONCLUSIONS: Such results indicate that parents play an important role in detecting speech, motor and behavioral DD in children. Parental concerns about cognition and behavior should be questioned in terms of their association with the real problem. This information may be useful in establishing trends in understanding the discrepancy or relationship between parental concerns and professional assessments in DD.

Child↗

Do pregnancy complications contribute to neurodevelopmental disability?

In the Dundee Development Screening Programme all children born in Dundee in 1974 and 1975 were screened at intervals during infancy and childhood. The obstetric and neonatal antecedent factors in 300 of the 322 singleton children with neurodevelopmental disability (index group) were compared with those of the 600 children of normal development born immediately before and after each child with disability (control group). Low social class was associated with mental retardation, global delay, speech delay, and behavioural disorder, but not with cerebral palsy or motor delay. With the exception of cerebral palsy, strong associations were found between all categories of disability and severe hypertension, unclassified antepartum haemorrhage, and preterm uterine activity. Cerebral palsy was not associated with antepartum complications, but was with fetal tachycardia during labour. Our data suggest that neurodevelopmental disability may, in many cases, originate during pregnancy and delivery.

Birth Weight↗

S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man.

This paper reports the third proven human case of deficient S-adenosylhomocysteine (AdoHcy) hydrolase activity. The patient is similar to the only two previously reported cases with this disorder in having severe myopathy, developmental delay, elevated serum creatine kinase (CK) concentrations, and hypermethioninaemia. Although he has been followed from infancy, the basic enzyme deficiency was established only at age 26 years. The diagnosis was based on markedly elevated plasma concentrations of both AdoHcy and S-adenosylmethionine, some 20% of the mean control activity of AdoHcy hydrolase activity in haemolysates of his red-blood cells, and two missense mutations in his gene encoding AdoHcy hydrolase. He had low values of erythrocyte phosphatidylcholine and plasma free choline and marginally elevated excretion of guanidinoacetate, suggesting that the elevated AdoHcy may have been inhibiting methylation of phosphatidylethanolamine and guanidinoacetate. His leukocyte DNA was globally more methylated than the DNA's of his parents or the mean extent of methylation measured in age-matched control subjects.

Adenosylhomocysteinase↗

Drawings by individuals with Williams syndrome: are people different from shapes?

Because it is unclear whether people with Williams syndrome produce drawings that are delayed or deviant, we examined these two possibilities in Draw a Person and figure copying tasks (VMI) in 28 persons with Williams syndrome, 28 with mixed etiologies, and 28 with Down syndrome. All human figures could be classified into discrete stages of drawing development, and in all groups, drawing tasks were significantly correlated with MA. Human figures from participants with Williams syndrome were no more deviant than their counterparts, nor did they show "local-global" differences. Draw a Person scores exceeded VMI scores in the Williams syndrome group, whereas the Down syndrome group showed relative strengths on both drawing tasks, and the mixed group had no profile. Developmental and phenotypic implications of findings are discussed.

Adolescent↗

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype.

AIMS/HYPOTHESIS: Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. A minority of patients also have neurological features. The identification of a KCNJ11 mutation has important therapeutic implications, as many patients can replace insulin injections with sulfonylurea tablets. We aimed to determine the age of presentation of patients with KCNJ11 mutations and to examine if there was a relationship between genotype and phenotype. SUBJECTS AND METHODS: KCNJ11 was sequenced in 239 unrelated patients from 21 countries, who were diagnosed with permanent diabetes before 2 years of age. RESULTS: Thirty-one of the 120 patients (26%) diagnosed in the first 26 weeks of life had a KCNJ11 mutation; no mutations were found in the 119 cases (0%) diagnosed after this age. Fourteen different heterozygous mutations were identified, with the majority resulting from de novo mutations. These include seven novel mutations: H46Y, R50Q, G53D C166Y, K170T, L164P and Y330S. All 11 probands with the most common mutation, R201H, had isolated diabetes. In contrast, developmental delay in addition to diabetes was seen in four of five probands with the V59M mutation and two of four with the R201C mutation. Five patients with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome had unique mutations not associated with other phenotypes. CONCLUSIONS/INTERPRETATION: KCNJ11 mutations are a common cause of permanent diabetes diagnosed in the first 6 months and all patients diagnosed in this age group should be tested. There is a strong genotype-phenotype relationship with the mutation being an important determinant of associated neurological features.

Amino Acid Substitution↗

Correlation between neonatal cranial ultrasound, MRI in infancy and neurodevelopmental outcome in infants with a large intraventricular haemorrhage with or without unilateral parenchymal involvement.

UNLABELLED: During a 7-year-period, 1625 infants of 34 weeks gestation or less were enrolled in a prospective ultrasound (US) study. One hundred and eleven (6.8%) infants developed a large intraventricular haemorrhage (IVH) with or without unilateral parenchymal involvement (PI). Fifty-six of these 111 infants survived (50.4%) and in 23 (41%) of them a magnetic resonance imaging (MRI) study was performed beyond 12 months corrected age. There appeared to be a good agreement between neonatal ultrasound findings and MRI changes noted in infancy. Of the 10 cases with a large IVH without PI (group A), seven had a VP shunt with complete decompression of previously enlarged ventricles. Six of these seven infants had periventricular hyperintensity (PVHI) but none developed cerebral palsy (CP). Two of the ten cases without a VP shunt had irregular ventricular enlargement (VE) with PVHI in one. Both developed CP. Seven cases showed thinning of the corpus callosum. Of the 13 cases with a large IVH associated with PI (group B), the site of the PI could still be recognised on MRI and the degree of communication of the porencephalic cyst (PC) with the lateral ventricles correlated well with neonatal US findings. On MRI, VE was present in only 6 cases. Wallerian degeneration was present in 9/13 infants and all but one developed a hemiplegia. In 12/13 cases there was thinning of the corpus callosum, either focal or diffuse. PVHI was present in all infants. In 6/13 PVHI was only present around the PC. Neurodevelopmental outcome differed for both groups. CP was only present in 2/10 infants in group A, compared to 11/ 13 in group B. Global delay, in the absence of CP, was more common in infants with a large IVH than in those with associated PI. CONCLUSION: Combining neonatal US with MRI in infancy enhances our understanding of the long-term effects of severe haemorrhagic brain lesions, occurring in preterm infants.

Brain↗

Language acquisition in special populations: a comparison between Down and Williams syndromes.

To investigate the relationship between language acquisition and cognition, we evaluated linguistic abilities in 12 Italian-speaking children with Williams syndrome (WS) and 12 with Down syndrome (DS) of comparable global cognitive level. Another control group included 12 typically developing (TD) children, matched for mental age. Linguistic measures included a parent questionnaire to assess vocabulary, a verbal comprehension test, a sentence repetition test and MLU calculated on spontaneous production. No dissociation was evident between lexical and cognitive abilities, but specific morphosyntactic difficulties emerged both in comprehension and production in children with DS. Individuals with WS, albeit less compromised than DS, also had difficulty in the phrase repetition task and, particularly, using content words. Our results demonstrate that the linguistic abilities of infants with WS are not above their cognitive level and that language development in these special populations is not only delayed, but follows a different developmental trajectory.

Child↗