Extreme hyperbilirubinaemia in Zimbabwean neonates: neurodevelopmental outcome at 4 months

As part of a prospective study of severely jaundiced Zimbabwean infants, the relationship between maximum total serum bilirubin (TSB) concentration in the neonatal period and neurodevelopmental outcome at the corrected age of 4 months was studied. Fifty infants with a TSB of > 400 micromol/l (23.4 mg/dl) were enrolled and screened with a neonatal neurological examination (NNE). The cause of jaundice was low birth weight in 22 (44%), ABO incompatability in 8 (16%), sepsis in 8 (16%) and congenital syphilis (6%) in 3 infants. In 9 infants a cause could not be determined. At 4 months, 2 infants had died and 3 were lost to follow up, leaving 45 infants for the infant motor screen (IMS) at 4 months of age. Mean TSB in the neonatal period was 485 micromol/l (28.2 mg/dl), and 7 infants received an exchange transfusion. Mean TSB of the infants with an exchange transfusion was 637 micromol/l (37.2 mg/dl) (range 429-865 micromol/l (25-50.3 mg/dl)) and of the infants without transfusion 459 micromol/l (26.8 mg/dl) (range 400 740 micromol/l (23.4-43 mg/dl)) (P < 0.0001). The TSB was not associated with birth weight, gestational age, gender or head circumference of the baby. On the IMS, 6 of 45 (13.3%) infants scored abnormal, 6 (13.3%) suspect and 33 (73%) scored normal. Three of the six (50%) remaining infants who received an exchange transfusion scored abnormal on the IMS while only 3 of the 39 (8%) infants without exchange transfusion were abnormal. CONCLUSION: More than 25% of infants with a TSB of > 400 micromol/l (23.4 mg/dl) scored abnormal or suspect at 4 months of age and half of these infants already showed irreversible neurological symptoms. All infants who scored abnormal or suspect on the IMS with bilirubin levels between 400 and 500 micromol/l (23.4 and 29.2 mg/dl) had haemolytic disease or were premature.     

Visual, cognitive, and neurodevelopmental outcome at 51/2 years in children with perinatal haemorrhagic-ischaemic brain lesions

To determine predictive values of early visual and neurocognitive assessment in children with perinatally acquired haemorrhagic or ischaemic brain lesions selected on the basis of ultrasound, 63 children (37 boys, 26 girls), who had been followed and examined until the age of 18 months, were reexamined at 5 1/2 years. Good correlations between visual and neurodevelopmental assessments at 18 months and at 5 1/2 years were found. When ultrasound abnormalities were combined with early visual and neurocognitive assessment data, good predictive values, especially for the group of children who had grade 2 to 4 leukomalacia, were found for visual acuity and neurodevelopment.     

Visual outcome at 5 years of newborn infants at risk of cerebral visual impairment

Among some 7500 respondents with known place of birth who had completed a nationwide questionnaire survey for multiple sclerosis (MS) in France in 1986, there were 260 born in former French North Africa (Algeria, Morocco, Tunisia). They had migrated to France between 1923 and 1986, but 66% came between 1956 and 1964. Two-thirds were from Algeria, where virtually the entire European population had emigrated in 1962 at the end of the Algerian war for independence. The migrants were younger at prevalence day (mean 43.4 years) and at onset (29.4 years) than the French-born MS (46.6; 31.3 years). Eight migrants lacked age information. The 225 migrants with onset more than 1 year after immigration presumably acquired their MS in France. They provided an age adjusted (US 1960) MS prevalence rate 1.54 times that for all France. If the latter is taken at 50 per 100,000 population their estimated adjusted rate is 76.8 with 95% confidence interval of 67.1 to 87.5. The other 27 with presumed acquisition in North Africa gave an estimated adjusted prevalence of 16.6 per 100,000 (95% CI 10.9-24.1). For those migrants with acquisition in France there was a mean interval of 13 years between immigration or age 11 and clinical onset, with a minimum of 3 years. This series provides further support for the theses: 1) that MS is primarily an environmental disease acquired after childhood; 2) that acquisition requires prolonged or repeated exposure (here 3 years for these medium-to-high MS risk migrants) followed by a prolonged latent or incubation period between acquisition and symptom onset (here 10 years); and 3) that this disease is most likely a widespread but unknown persistent infection which results in clinical MS in only a small proportion of those affected.     

Severity of brain injury following neonatal extracorporeal membrane oxygenation and outcome at age 5 years

Neurodevelopmental evaluation in childhood provides an opportunity to study complex neurological compensation following documented neonatal brain injury, and furnishes important clinical information which may have an impact on patient care. We studied 152 term children treated with extracorporeal membrane oxygenation (ECMO) as neonates and who received routine neonatal neuroimaging and comprehensive neurodevelopmental evaluation at age 5 years. The cohort was divided into four groups based on an independent neuroimaging score: No lesion, N=88; Mild lesion, N=38; Moderate lesion, N=12; and Severe lesion, N=14. Standardized testing at age 5 included complete neuropsychological assessment, neurological evaluation, and assessment of motor function. All testing was conducted without knowledge of the neuroimaging score. The occurrence of disability by severity of neuroimaging was: No lesion=10%; Mild=13%; Moderate=33%; Severe=57%. The relative risk within the ECMO population for disability at age 5 after moderate or severe neonatal lesion was 4.3 (CI=1.0 to 17.5) and 11.7 (CI=3.3 to 41.3), respectively. The remaining non-disabled children who had moderate to severe lesions functioned within normal limits. Severity of neonatal neuroimaging was inversely associated with IQ scores, pre-academic skills, and neuromotor function. The effect size was small but the rank order was predictable. Our data identify in 5-year-old children an impact of brain lesion severity demonstrated on routine neonatal neuroimaging. The results indicate potential compensation following moderate and severe lesions, and suggest a subtle but consistent influence of even mild neonatal brain injury.     

Correlation of cerebral blood flow with outcome in head injured patients

In order to determine the relationship of cerebral blood flow (CBF) to the clinical outcome of head injury, serial determinations of CBF were performed by the intravenous Xenon technique in 24 patients. The patients were of mixed injury severity and were classified into four groups depending on the neurological exam at the time of each CBF study. All eight patients who were lethargic on admission demonstrated increases in their minimally depressed CBF as they improved to normal status. Eleven patients in deep stupor or coma ultimately recovered. Ten of these patients initially had moderate to profound decreases in CBF which improved as recovery occurred. The single exception was an adolescent whose initial CBF was high but became normal at recovery. Five comatose patients died. In four of these, already depressed CBF fell even lower, while one adolescent with initially increased CBF developed very low CBF preterminally. The data presented in this report demonstrated a good correlation between CBF and clinical outcome. In every one of the adult survivors, depressed CBF increased as the patient recovered to normal status. All adults who died showed a deterioration of CBF as the neurological status worsened. The only exceptions were two adolescents who initially showed high CBF values. In the adolescent who died, CBF dropped to low levels while in the survivor a normal CBF was achieved. Thus in adults a traumatic brain injury was associated with depressed CBF which increased with recovery or decreased further with deterioration while the reaction to injury was quite different in the younger brain.     

Morphometric and neurodevelopmental outcome at age five years of the offspring of women who continued to exercise regularly throughout pregnancy

OBJECTIVE: To test the hypothesis that continuing regular, vigorous, sustained exercise throughout pregnancy adversely affects morphometric and neurodevelopmental outcome in offspring at 5 years of age. STUDY DESIGN: The offspring of 20 women who exercised were compared with those of 20 physically active control subjects. The women and their offspring were matched for multiple prenatal and postnatal variables known to influence outcome. All women were enrolled before the index pregnancy, monitored throughout, and had clinically normal antenatal, intrapartum, and postnatal courses. Morphometric measures were obtained at birth and at 5 years of age by a single, trained observer. Neurodevelopment was assessed by developmental psychologists masked to maternal exercise status. Data were analyzed with an unpaired Student t test. RESULTS: At birth, head circumference and length were similar, but the offspring of the exercising women weighed less (3.40 +/- 0.80 vs 3.64 +/- 0.70 kg) and had less fat (10.5% +/- 0.9% vs 15.1% +/- 0.6%). At 5 years of age, head circumference and height were similar, but the offspring of the women who exercised weighed less (18.0 +/- 0.5 vs 19.5 +/- 0.6 kg) and had a lower sum (sigma) of five site skinfolds (37 +/- 1 vs 44 +/- 2 mm). Motor, integrative, and academic readiness skills were similar. However, the exercise offspring performed significantly better on the Wechsler scales (125 +/- 2 vs 116 +/- 3) and tests of oral language skills (119 +/- 2 vs 109 +/- 3). CONCLUSIONS: These data refute the hypothesis and suggest that exercise during pregnancy reduces the subcutaneous fat mass of the offspring.     

Cerebrospinal fluid adenosine concentration and uncoupling of cerebral blood flow and oxidative metabolism after severe head injury in humans

OBJECTIVE: Uncoupling of cerebral blood flow (CBF) and oxidative metabolism is observed after severe head injury in comatose patients; however, the mechanism(s) involved remain undefined. Adenosine can produce cerebral vasodilation and reduce neuronal activity and is a possible mediator of uncoupling. We hypothesized that cerebrospinal fluid (CSF) adenosine concentrations would be increased during uncoupling of CBF and oxidative metabolism, defined as a narrow arterio-jugular venous oxygen difference [D(a-v)O2 4 vol%] after head injury. METHODS: Adenosine concentrations were measured using fluorescent-based high-pressure liquid chromatography in 67 CSF samples obtained from 13 comatose (Glasgow Coma Scale score 7) adult patients who sustained a severe closed head injury. At the time each sample was obtained, CBF was measured by the xenon-133 method, and blood samples were obtained for determination of D(a-v)O2. RESULTS: CSF adenosine concentration was negatively associated with D(a-v)O2 (P < 0.05, generalized multivariate linear regression model). In addition, CSF adenosine concentration was increased when D(a-v)O2 was 4 versus > 4 vol% (38.5 [3.2-306.3] versus 14.0 [2.7-795.5] nmol/L, respectively, median [range]; P < 0.025) and in patients who died versus survivors (40.1 [6.9-306.3] versus 12.9 [2.7-795.5] nmol/L, respectively, median [range]; P < 0.001). CONCLUSION: The association between increased CSF adenosine concentration and a reduction in global cross-brain extraction of oxygen supports a regulatory role for adenosine in the complex balance between CBF and oxidative and nonoxidative metabolism severe head injury in humans.     

Assessment of preterm infants in the intensive-care unit to predict cerebral palsy and motor outcome at 6 years

One hundred and fifty-three infants were assessed by a method specific to preterm infants and appropriate to the intensive-care nursery environment. The presence or absence of six atypical features (coarse jitters, dominant asymmetrical tonic neck reflex, paucity of movement, 'contradictory' development, hypotonia, or hypertonia) resulted in neonatal classification. There were 116 'usual' (an absence of atypical features with progressive development), 26 'unusual' (a transient occurrence of any atypical feature), and 11 'suspect' (dominance of one or more atypical features). At 6 years of age the motor subsystems of balance, coordination, fine and gross motor, and associated movements were assessed. Nine of 11 children with cerebral palsy had neonatal categories of 'suspect' (7) and 'unusual' (2), of the remaining four other 'suspect' children, two failed two motor subsystems and two failed motor items. A 'usual' neonatal assessment predicted normal motor outcome for 72 of 116 (62%) whereas a 'suspect' assessment predicted major motor dysfunction for seven of 11 of the children.     

Prevalence of impairments 5 years after a head injury, and their relationship with disabilities and outcome

To determine what consequences cognitive, behavioural or somatic impairments had on disabilities and recovery after a head injury (HI), a population-based sample of 231 adult patients was studied 5 years after an HI. Eighty lower-limb-injured (LLI) patients were considered as controls. Sixty-four LLI and 176 HI patients were reviewed (114 minor, 35 moderate, and 27 severe HI). Prevalence values of headaches (44-54%), dizziness (26-37%), and anxiety (47-63%) were not significantly different in the three HI severity groups, but were significantly lower in patients with an isolated limb injury (12-15%). Memory problems and depressive mood increased with injury severity. Mental impairments were frequent in severe HI patients (18-40% of patients). In minor and moderate HI patients, most disabilities were related to associated injuries. According to the Glasgow Outcome Scale (GOS), recovery was not considered as good because of somatic, behavioural or cognitive complaints in 2.5%, 5.7% and 59.2% of surviving patients in each of the above HI groups. Somatic or behavioural complaints may have considerable consequences in some minor HI patients, and the long-term management of certain patients needs improvement because these impairments are misunderstood.     

Temperament profiles and their role in neurodevelopmental assessed preterm children at two years of age

CD26 antigen, a 110 kDa membrane glycoprotein with exopeptidase activity (DAP IV), is an activation marker of T lymphocytes preferentially expressed on CD4+ memory cells and involved in T cell proliferation and IL-2 production after antigenic stimulation. We employed cytochemical and immunocytochemical techniques to study DAP IV/CD26 expression in circulating lymphocytes from 40 hemophilic patients, chronically treated with coagulation factors, in order to verify the possible involvement of this molecule in the immunological alterations of hemophilia. In all the hemophiliacs DAP IV activity was significantly lower than in the controls, independently of the quantity of blood transfused and previous exposure to viruses. This reduction may be responsible for the impaired proliferative response of lymphocytes to antigens and mitogens, notoriously observed in hemophilia. Whereas in the group of HIV- patients CD26 expression was similar to that of normal controls, in the 8 HIV+ hemophilic patients both percentages of positive lymphocytes and intensity of staining were significantly lower. In only 4 of the 8 cases was this deficit associated with CD4+ cell depletion. The significant selective loss of CD26 expression observed in HIV+ patients is probably an early event after HIV infection and seems to occur even before CD4 cell depletion. In conclusion, evaluation of DAP IV/CD26 might be a useful option for monitoring the immunological alterations of all hemophilic patients, HIV positive or not, chronically treated with coagulation factors.     

Brief communication: effects of diagnostic irradiation during pregnancy on head circumference at birth

A historical cohort study was carried out to evaluate the effects in utero medical ionizing radiation on head circumference at birth. The nature of medical practice in Rochester, Minnesota, and the Mayo Clinic medical records linkage system enabled us to provide accurate estimates of medical radiation absorbed dose in 9,793 pregnancies of 2,980 women pregnant in Rochester between 1917 through 1973. Data were controlled for sex of the fetus, duration of pregnancy and congenital head abnormalities. It was found that medical ionizing radiation in the second and third trimesters of more than 300 mrad were related to significantly decreased head circumference. There was no significant effect of radiation exposure in the first trimester or periconceptional period. Medical ionizing radiation in the second and third trimesters of more than 300 mrad is related to a significant yet minimal, decreasing head circumference at birth. Maximum effects were seen during the midgestational and second trimester periods.     

Antenatal phenobarbital therapy and neonatal outcome. II: Neurodevelopmental outcome at 36 months

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.     

Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease

OBJECTIVE: Cerebral parietal hypometabolism and left-right asymmetry occur early in the course of Alzheimer disease (AD), and the apolipoprotein E type 4 allele (APOE epsilon 4) is a risk factor for familial AD. To determine if APOE epsilon 4 is associated with lowered brain function in nondemented relatives at risk for familial AD, we studied 12 relatives with APOE epsilon 4 and 19 relatives without APOE epsilon 4. We also compared them with seven patients with probable AD. DESIGN: After grouping subjects according to diagnosis and genotype, brain function measures were compared among groups. SETTING: University medical center. PATIENTS: At risk subjects had mild memory complaints, normal cognitive performance, and at least two relatives with AD. Subjects with APOE epsilon 4 did not differ from those without APOE epsilon 4 in mean age at examination (56.4 vs 55.5 years) or in neuropsychological performance (mean Mini-Mental State Examination score, 28.8 vs 29.3). MAIN OUTCOME MEASURES: Cerebral glucose metabolism was measured using positron emission tomography and fludeoxyglucose F 18. RESULTS: Parietal metabolism was significantly lower and left-right parietal asymmetry was significantly higher in at-risk subjects with APOE epsilon 4 compared with those without APOE epsilon 4. Patients with dementia had significantly lower parietal metabolism than did at-risk subjects with APOE epsilon 4. CONCLUSIONS: These results suggest that the inheritance of APOE epsilon 4 is associated with reduced cerebral parietal metabolism and increased asymmetry in non-demented relatives at risk for probable AD. Longitudinal study will determine if glucose metabolic measures provide a means to monitor experimental treatment responses during the early phases of the disorder.     

Correlation between regional cerebral blood flow and oxidative metabolism. In vivo studies in man

To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.     

Infant visual attention: Relation to birth status and developmental outcome during the first 5 years.

This study examined the relation of infant attention and memory to later cognition in two groups of low socioeconomic status (SES) subjects: 45 full-terms and 46 high-risk preterms (rs?=?.37–.65). A sum of dichotomized novelty scores was less strongly related to outcome, indicating that variation in the actual magnitude of the novelty score is important. Ability to sustain attention during familiarization also related to outcome: Infants who took longer to reach a looking criterion had lower MDI/IQ scores. By contrast, the 7-month Bayley MDI was significantly related to later MDI/IQ only in preterms and then mostly at younger ages. Novelty scores related to later MDI/IQ independently of 7-month MDI, SES, maternal education, and medical risk. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relation of operator volume and experience to procedural outcome of percutaneous coronary revascularization at hospitals with high interventional volumes

BACKGROUND: Although an inverse relation between physician caseload and complications has been conclusively demonstrated for several surgical procedures, such data are lacking for percutaneous coronary intervention, and the ACC/AHA guidelines requiring > or = 75 cases per year for operator "competency" are considered by some physicians to be arbitrary. METHODS AND RESULTS: From quality-controlled databases at five high-volume centers, models predictive of death and the composite outcome of death, Q-wave infarction, or emergency bypass surgery were developed from 12,985 consecutively treated patients during 1993 through 1994. Models had moderate to high discriminative capacity (area under ROC curves, 0.65 to 0.85), were well calibrated, and were not overfitted by standard tests. These models were used for risk adjustment, and the relations between both yearly caseload and years of interventional experience and the two adverse outcome measures were explored for all 38 physicians with > or = 30 cases per year. The average physician performed a mean +/- SD of 163 +/- 24 cases per year and had been practicing angioplasty for 8 +/- 5 years. Risk-adjusted measures of both death and the composite adverse outcome were inversely related to the number of cases each operator performed annually but bore no relation to total years of experience. Both adverse outcomes were more closely related to the logarithm of caseload (for death, r = .37, P = .01; for death, Q-wave infarction, or bypass surgery, r = .58, P < .001) than to linear caseload. CONCLUSIONS: In this analysis, high-volume operators had a lower incidence of major complications than did lower-volume operators, but the difference was not consistent for all operators. If these data are validated, their implications for hospital, physician, and payer policy will require exploration.     

Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables

AIM: To compare the growth of very low birthweight (VLBW) children in early adolescence with that of their normal birthweight peers; to examine the role of factors contributing to growth-parental height, perinatal variables, bone maturity and sexual maturation; to examine the correlation between head growth and cognitive and educational outcome. METHODS: Standing and sitting heights, weight, occipito-frontal circumference (OFC), skinfold thicknesses and pubertal staging were assessed in 137 VLBW children and 160 controls at 11-13.5 years of age. Ninety six (70%) of the VLBW children had their bone age assessed using the TW2 method. Reported parental heights were obtained by questionnaire. All children had standardised tests of cognitive and educational ability. Perinatal data had been collected prospectively as part of a longitudinal study. RESULTS: VLBW children had lower heights, weight, and OFC. Skinfold thicknesses were no different. The children's short stature was not accounted for by difference in parental height, degree of pubertal development, or by retarded bone age. Indeed, the TW2 RUS score was significantly advanced in the VLBW children. Using the bone ages to predict final adult height, 17% have a predicted height below the third centile and 33% below the tenth. Weight was appropriate for height, but there was a residual deficiency in OFC measurements after taking height into account. In the VLBW group smaller head size was associated with lower IQ and mathematics and reading scores. CONCLUSIONS: Growth problems persist in VLBW children and final heights may be even more abnormal than present heights suggest. VLBW children have smaller OFCs than expected from their short stature alone and this may be associated with poorer educational and cognitive outcomes.     

Developmental pattern of 3-oxo-delta 4 bile acids in neonatal bile acid metabolism

AIMS: To investigate whether a fetal pathway of bile acid synthesis persists in neonates and infants. METHODS: 3-oxo-delta 4 bile acids were determined qualitatively and quantitatively in the urine, meconium, and faeces of healthy neonates and infants, using gas chromatography-mass spectrometry. RESULTS: The mean percentage of 3-oxo-delta 4 bile acids in total bile acids in urine at birth was significantly higher than that at 3 or 7 days, and at 1 or 3 months of age. The concentration of this component in meconium was significantly higher than that in faeces at 7 days and at 1 or 3 months of age. CONCLUSIONS: The presence of large amounts of urinary 3-oxo-delta 4 bile acids may indicate immaturity in the activity of hepatic 3-oxo-delta 4-steroid 5 beta-reductase in the first week of postnatal life. Large amounts of this component in meconium may be due to the ingestion of amniotic fluid by the fetus during pregnancy.     

Arterial-jugular vein free amino acid levels in patients with head injuries: important role of glutamine in cerebral nitrogen metabolism

Traumatic brain injury is the single largest contributor of trauma center deaths. Injury to the brain cannot be considered as an isolated event, affecting only this organ. Profound hypoglutaminemia commonly seen in patients with head injuries may be caused by the diminished release of glutamine from the brain to the systemic circulation. To assess this hypothesis, we have simultaneously measured the free amino acid (AA) levels in systemic arterial (A, radial artery), cerebral venous (JV, jugular bulb), and systemic venous (PA, pulmonary artery) plasma in 11 adult patients with severe head injuries once within 48 hours of the initial injury before starting nutritional support and again after 3 to 4 days of enteral feeding. Cerebral organ (A-JV) changes of AA levels were compared with whole body systemic (A-PA) changes. Arterial total AA levels when compared with reported normal values are diminished by 46% in patients with isolated severe injuries. Cerebral outflow of glutamine is 6% of the total AA output compared with 73% in normals. The systemic outflow of glutamine in patients with brain injuries is 28% of total AA flow. Despite this high systemic output, significant hypoglutaminemia persists. Feeding for 3 days did not appreciably change the arterial plasma AA levels except that of glutamate and citrulline. A significant (p = 0.01) linear relationship between glutamine (product) and glutamate (precursor) was seen in JV samples but not in A or PA samples. The ratio of plasma glutamine to glutamate was decreased significantly only in JV during nutritional support, and this was caused mainly by an increase in glutamate levels. This may be owing to defective amidation to glutamine, inasmuch as gamma aminobutyric acid (GABA) levels were only minimally affected. Nutritional support improves the net release of glutamine from the brain. This suggests that supplementing the diet with glutamine may be beneficial to support systemic requirements in patients with severe head injuries.