Effects of long-chain PUFA supplementation in infant formula on cognitive function in later childhood.

BACKGROUND: Evidence is accumulating that a dietary supply of long-chain polyunsaturated fatty acids (LC-PUFAs) enhances the development of attention and efficient information processing in infants. However, it is uncertain whether LC-PUFAs in infancy influence cognitive development in later childhood. OBJECTIVE: The objective was to determine the effects of dietary LC-PUFAs in infancy on measures of cognitive function at age 6 y. DESIGN: Infants were randomly assigned to receive formula containing either docosahexaenoic acid and arachidonic acid or no LCPUFAs for a period of 4 mo. A reference breastfed group was also included. In a follow-up conducted at age 6 y, children received assessments of intelligence quotient (IQ), attention control (Day-Night Test), and speed of processing on the Matching Familiar Figures Test (MFFT). RESULTS: At follow-up there were 71 children in the LC-PUFA group, 76 in the control group, and 88 in the breastfed group. The formula groups did not differ on measures of Full-Scale IQ (LCPUFA mean = 98.0; control mean = 100.9) or attention control (LCPUFA mean = 12.7; control mean = 12.8). MFFT error scores were the same for both formula groups, but when making correct responses, the LC-PUFA group was significantly faster (mean = 6.2 s) than the control group [mean = 7.8 s; F(1, 131) = 6.09, P = 0.015]. CONCLUSIONS: IQ scores of children who were fed a formula containing either LC-PUFAs or no LC-PUFAs did not differ at age 6 y. However, children who received LC-PUFAs were faster at processing information compared with children who received unsupplemented formula. Variation in the dietary supply of LC-PUFAs in the first months of life may have long-term consequences for the development of some cognitive functions in later childhood.

Functional studies and proteomics in platelets and fibroblasts reveal a lysosomal defect with increased cathepsin-dependent apoptosis in ATP1A3 defective alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) is a rare syndrome with repeated hemiplegic episodes, paroxysmal events and global neurological impairment. Recently, heterozygous de novo ATP1A3 missense mutations have been identified in AHC patients, but the underlying pathogenesis mechanism remains unknown. Mutation analysis of ATP1A3 in 9 unrelated AHC cases revealed mostly D801N or E815K variants. As platelets represent a good cellular model to study defects in neuropathologies, morphological and functional experiments were performed in these subjects. Platelets from the AHC patients presented with structural and functional abnormalities of granules positive for the lysosomal marker CD63. Similar structural granule abnormalities were detected in patients' fibroblasts. Proteomic analysis of platelets and fibroblasts showed a total of 93 differentially expressed proteins in AHC mainly involved in metabolism. Interestingly, 7 of these proteins were detected in both cell types, including the lysosomal protein cathepsin. AHC fibroblasts revealed significantly increased levels of activated cathepsin B, which induces a stronger activation of apoptosis. Our study is the first to link ATP1A3 defects in AHC to a platelet and fibroblast lysosomal defect with evidence of increased apoptosis. Further studies are needed to define how this lysosomal defect is related to decreased ATPase activity. Biological Significance Only recently, the genetic cause of AHC was identified as heterozygous ATP1A3 mutations, but the underlying pathophysiological mechanism still remains unknown. By performing functional, morphological and proteomic studies in AHC patients we found a structural and functional granule defect in AHC platelets and fibroblasts that was specifically found in granules positive for the lysosomal marker CD63. In particular, proteomics identified several differentially expressed proteins in fibroblasts and platelets from AHC cases that are predicted to have an important role in cell function and maintenance, a pathway typically attributed to lysosomes. The lysosomal protein cathepsin was found to be differentially expressed in both platelets and fibroblasts of AHC patients, inducing a stronger activation of mainly the intrinsic apoptosis. Despite the precise mechanism for the increased lysosomal cathepsin B-dependent apoptosis detected in AHC in relation to impaired ATP1A3 deserves further studies, we could here show some evidence for a defective regulation of apoptosis in AHC, a disease that still has no biochemical or neuroradiological parameters for diagnosis.

Alternating hemiplegia of childhood: metabolic studies in the largest European series of patients.

Alternating hemiplegia of childhood (AHC) is a rare disorder with diagnosis based on clinical criteria, as no laboratory, neuroradiological or genetic markers are currently available. The pathogenic mechanisms are still an enigma. Some hypotheses have been proposed such as hemiplegic migraine variant, epileptic mechanism, channelopathy and mitochondrial disorder, but none of these has been confirmed. Our aim was to analyze the results of metabolic studies performed on a series of 157 European patients who fulfilled diagnostic criteria for AHC. We tried to find a common metabolic abnormality, related with AHC. We did not find significant abnormalities in basic metabolic screening, at different ages. Neurotransmitters in cerebrospinal fluid (n = 26) were normal in all of the patients. Mitochondrial respiratory chain enzyme activities were analyzed in 19 muscle biopsies; in 4 cases, different MRC enzyme deficiencies were demonstrated, ranging from mild-unspecific deficiencies to more profound and probably primary defects. Although we did not find specific metabolic markers in our series, some metabolic disorders such as pyruvate dehydrogenase deficiency, MELAS, cerebral glucose transporter defect and neurotransmitter deficiency can exhibit symptoms similar to those of AHC and need to be ruled out before a diagnosis of AHC can be established. Further studies including high-throughput diagnostic technologies seem necessary to elucidate the etiology of this severe and enigmatic disorder.

Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults.

Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials.

The effect of glycaemia on the cerebral oxygenation in very low birthweight infants as measured by near-infrared spectroscopy.

The cerebral tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) reflect the cerebral oxygenation. We studied the effect of glycaemia on the TOI and FTOE, as measured by near-infrared-spectroscopy (NIRS). We continuously measured TOI, glycaemia, mean arterial blood pressure (MABP), saturation (SaO(2)) and transcutaneous carbon dioxide pressure (tPCO(2)) for at least 4 h during the first week of life in neonates with gestational age (GA) < 32 weeks and weight < 1500 g. FTOE was calculated. 24 measurements in 11 neonates were analyzed. We found a significant negative correlation (r = -0.077; p = 0.0344) between glycaemia and TOI, also after correction for MABP, SaO(2) and tPCO(2) (r = -0.118; p = 0.002) and a significant positive correlation between glycaemia and FTOE (r = 0.147; p < 0.000) which remained significant after correction for MABP and tPCO(2) (r = 0.116; p = 0.001). Our results indicate that in neonates during the first days of life glycaemia - even within the normal ranges and after correction for MABP, SaO(2) and tPCO(2) - influences the cerebral oxygenation.

Use of tissue oxygenation index and fractional tissue oxygen extraction as non-invasive parameters for cerebral oxygenation. A validation study in piglets.

OBJECTIVE: To evaluate the relation between cerebral tissue oxygenation index (TOI), measured with spatially resolved spectroscopy (SRS), and the different oxygenation parameters. To evaluate the relation between a new parameter named fractional tissue oxygen extraction (FTOE) and the cerebral fractional oxygen extraction (FOE). METHODS: Six newborn piglets were measured at 33, 35, and 37 degrees C and in hypocapnia. Mean arterial blood pressure (MABP), haemoglobin (Hb), peripheral oxygen saturation (S(a)O(2)) and P(a)CO(2) were measured at each step. Cerebral blood flow (CBF) was measured by injection of coloured microspheres into the left atrium. Jugular bulb oxygen saturation (JVS), cerebral arterial and venous oxygen content (C(a)O(2) and C(v)O(2)) and FOE were calculated. TOI of the brain was calculated and FTOE was introduced as (S(a)O(2) - TOI)/S(a)O(2). The correlation was calculated with an ANCOVA test. RESULTS: There was a positive correlation (R = 0.4 and p = 0.011) between TOI and JVS. No correlation was found with CBF, MABP or Hb. There was a positive correlation between P(a)CO(2) and cerebral TOI (R = 0.24 and p = 0.03). FTOE correlated well with FOE (R = 0.4 and p = 0.016) and there was a negative correlation between FTOE and P(a)CO(2) (R = 0.24, p = 0.03). CONCLUSION: The measurement of TOI and FTOE by SRS correlated well with the cerebral venous saturation and FOE, respectively.

Variability in pain expression characteristics in former preterm infants.

OBJECTIVES: To document pain expression characteristics in former preterm infants in the first year of life in whom systematic evaluation and treatment of pain was provided. METHODS: Data on the Modified Behavioral Pain Scale (MBPS), Visual Analogue Scale (VAS, crying time and heart rate were collected during immunization. The effect of clinical characteristics {postconception and gestational age [PCA], surgery, ventilation, fentanyl, length of stay (LOS)} on bio-behavioral parameters was evaluated. RESULTS: 121 procedures were recorded in 49 infants. GA was 28 (25-32) weeks. PCA was 60 (34-90) weeks. Median MBPS was 8 (2-10), median crying time 44 (0-112) s. Median pre-procedural heart rate was 144 (103-201) and increased to 184 (147-220) afterwards, resulting in a relative increase of 29 (5-99)%. Median VAS score was 7 (1-10). Significant correlations of PCA with pre-procedural heart rate (r=-0.36) and with relative increase in heart rate (r=0.33) were identified. A correlation of LOS on crying time (r=0.37) was observed. CONCLUSIONS: Correlations of PCA with pre-procedural and relative increase in heart rate reflect the maturational decrease in heart rate. LOS had an effect on pain expression, potentially reflecting the impact of cumulative 'minor' procedural pain.

Measurement of the liver tissue oxygenation by near-infrared spectroscopy.

OBJECTIVE: To study the relation between the liver tissue oxygenation index (TOI), transcutaneously measured with spatially resolved spectroscopy (a new method of near-infrared spectroscopy or NIRS), the mixed venous oxygen saturation and the blood flow in the different parts of the splanchnic circulation in newborn piglets. DESIGN: Tissue oxygenation index of the liver was measured in six newborn piglets at 33 degrees C, 35 degrees C, 37 degrees C and after a decrease in arterial carbon dioxide pressure (PaCO(2)). MEASUREMENTS: Mixed venous oxygen saturation, blood gas analysis and peripheral oxygen saturation were measured at each step. Gastric, proximal jejunal, midgut, distal ileal, splenic and hepatic arterial blood flow were measured by injection of coloured microspheres into the left atrium. NIRS optodes were attached to the skin over the liver and TOI was calculated. RESULTS: No significant changes of TOI of the liver were seen during the increase in temperature or change in PaCO(2). TOI correlated well with mixed venous oxygen saturation (r=0.85), the mid-ileal blood flow (r=0.57) and the distal ileal blood flow (r=0.72). CONCLUSIONS: Measurement of the TOI of the liver might be a non-invasive way to measure the distal ileal blood flow.

Measurement of tissue oxygenation index during the first three days in premature born infants.

No normal values of tissue oxygenation index (TOI) of the brain are known regarding premature born infants. We measured TOI, a measure for the cerebral hemoglobin oxygen saturation, on the head of 15 preterm infants with a median postmenstrual age of 28 weeks (interquartile range (IQR) between 26-29 weeks) with spatially resolved spectroscopy (NIRO 300, Hamamatsu) during the first three days of life. Infants with intra-ventricular hemorrhage or periventricular leucomalacia before the first measurement, as shown by ultrasound, were excluded. The first measurement was done within the first 6 hours of life, the second and third measurement at, respectively, 24 and 48 hours after this first measurement. The mean TOI was calculated if saturation did not change by more than 5% for at least 30 minutes. Other parameters measured were PaO2, PCO2, pH, mean arterial blood pressure, heart rate, hemoglobin, glycemia and peripheral oxygen saturation. There was a significant increase of TOI after 24 (p < 0.05) and 48 (p < 0.001) hours. The median TOI on the first day was 57% (95% CI: 54-65.7), 66.1% on the second day (95%CI: 61.9-82.3%) and 76.1% on the third day (95%CI 67.8-80.1%). No correlation was found between TOI and peripheral oxygen saturation, blood pressure, PaO2, PaCO2 and hemoglobin concentration after multiple regression analysis. TOI increases in the first three days in premature born babies. The increase of TOI is not due to an increase of oxygenation or mean arterial blood pressure. In our opinion, it reflects the increase in cerebral blood flow during the first three days.

Quantitation of the concordance between cerebral intravascular oxygenation and mean arterial blood pressure for the detection of impaired autoregulation.

Since some important forms of brain injury in premature infants are caused in considerable part by disturbances in cerebral blood flow (CBF), it is important to be able to detect whether the cerebrovascular autoregulation, the mechanism by which CBF is maintained constant despite alterations in mean arterial blood pressure (MAP), is working properly. A recent study suggested that concordant changes in MAP and cerebral intravascular oxygenation (HbD), measured non-invasively by near-infrared spectroscopy (NIRS) as the difference between the concentration changes of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (Hb), reflect impaired cerebrovascular autoregulation. Consequently, premature infants with impaired cerebrovascular autoregulation could be identified by simultaneous, continuous measurements of HbD and MAP. From several premature babies, MAP, HbD and arterial oxygen saturation (SaO2) were measured simultaneously at the University Hospital Leuven, Belgium. The concordance between MAP and HbD was quantitated using three different measures, among which a newly developed measure that looks for similarity of the dynamics between signals. Some preliminary results obtained from the measured data are given.

Polyarthritis and humeral epiphysial separation in an infant with acute disseminated histoplasmosis.

The case of an immunocompetent infant with disseminated histoplasmosis is described. The case is unusual in its clinical presentation in that it is dominated, apart from respiratory infection, by the presence of polyarthritis and complicated by epiphysial separation of both humeri. There was only little involvement of reticuloendothelial tissues. Treatment consisted of surgical correction and itraconazole.

Risperidone in the treatment of childhood autistic disorder: an open pilot study.

OBJECTIVE: To evaluate the tolerability and efficacy of risperidone in childhood autistic disorder. METHODS: A multicenter, open-label, dose-titration study involving seven autistic children (mean age 7.6 years) receiving risperidone for 4 weeks. RESULTS: Mean dose was 0.01 mg/kg/day on day 1, 0.019 mg/kg/day on day 7 (range 0.01-0.041 mg/kg/day) and 0.035 mg/kg/day on day 28 (range 0.014-0.064 mg/kg/day). Over the 4-week period, the Ritvo-Freeman Real Life Rating Scale total score measuring autistic behavior was significantly decreased (P = 0.019), as was the affectual reactions subscale (P = 0.029). Aberrant Behavior Checklist total score was significantly improved (P < 0.001), as were all subscales except inappropriate speech. Visual Analog Scale for individual target symptoms was significantly decreased (P = 0.001), and Clinical Global Impression severity of illness score was significantly improved (P = 0.006). The incidence of adverse effects was low, and no extrapyramidal symptoms were observed. No significant changes or clinically relevant abnormalities occurred in laboratory tests, vital signs or electrocardiograms. Plasma concentrations of the drug were similar to those in adult patients. CONCLUSIONS: These favorable results suggest that larger controlled trials of risperidone should be performed in autistic or mentally retarded patients with behavioral disturbances.