Immediate early genes and p21 regulation in liver of rats with acute hepatic failure

It has been observed that liver regeneration in acute hepatic failure (AHF) is suppressed [Eguchi et al. Hepatology 1996;24(6):1452-9]. The molecular mechanism regulating this inhibition is not known. We previously reported that in AHF rats, hepatocyte proliferation was significantly impaired with elevation in serum IL-6, TGF-beta1, and HGF [Kamohara et al. Biochem Biophys Res Commun 2000;273(1):129-35]. Following either 70% partial hepatectomy (PH) or liver injury, quiescent mature hepatocytes are "primed" to re-enter the cell cycle. The process of "priming" appears to be triggered by extracellular cytokines (IL-6 and TNF-alpha) and is characterized by expression of immediate early genes. Under the stimulation of growth factors such as HGF, "primed" hepatocytes exit the G1 phase of the cell cycle. G1-associated cyclins and their inhibitors play a pivotal role in G1/S cell cycle transition. Here, we demonstrate that immediate early gene (i.e. c-myc, c-fos) expression and AP-1 activity are preserved in AHF rat livers despite absence of hepatocyte proliferation. In contrast, p21 mRNA and protein are both over-expressed in AHF livers compared to livers from rats undergoing PH; this elevation leads to inhibition in Cdk2 activity, resulting in G1 cell cycle arrest and inhibition of regeneration.     

Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.     

Poly-lactic-glycolic acid microspheres: a biodegradable marker for the diagnosis of aspiration in hamsters

Aspiration is a major cause of lung disease in infants and young children. As the symptoms and signs of aspiration are not specific, the diagnosis is delayed due to a low index of suspicion and low sensitivity and specificity of the available diagnostic tests. In the present study, we evaluated the utility of microspheres composed of a degradable polymer, polylactic glycolic acid (PLGA), as a marker to diagnose aspiration in hamsters. Thirty hamsters underwent direct tracheal instillation of 0.1 mL of a suspension of PLGA. Eighteen other animals served as controls and underwent tracheal instillation of 0.1 mL of saline. Three animals served as naive controls and had no tracheal instillation. Five animals from the PLGA group and three from the saline group underwent whole-lung lavage (WLL) on days 1, 8, 15, 29, 43, and 58. PLGA microspheres were easily identified under light microscopy inside the alveolar macrophages obtained from WLL in all PLGA-instilled animals during all studied days. The number and size of PLGA microspheres within the alveolar macrophages decreased gradually with time with a 90% rate of disappearance of about 36 d. There was a marked neutrophilic response in lung lavage and a mild peribronchial neutrophil infiltration on the first day after tracheal instillation of PLGA which subsequently disappeared. We conclude that PLGA microspheres are a sensitive and specific marker for aspiration in hamsters. The usefulness of this test in diagnosing aspiration in humans should be further evaluated in clinical studies.     

Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy

PURPOSE: The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24- to 48-h fast. METHODS: Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST-KD) or gradual initiation (GRAD-KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3-month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3-month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher's exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed-effects models were used to look for trends in tolerability data over time. RESULTS: Forty-eight subjects, 24 in each arm, were randomized. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FAST-KD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD-KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and less-severe episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted. CONCLUSIONS: These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD.     

CT of hemangiomas of the upper airways in children

OBJECTIVE: Hemangiomas of the airways in infants are commonly diagnosed at bronchoscopy performed for the investigation of stridor or other respiratory symptoms. Occasionally on bronchoscopy the appearances are atypical or the entire extent of the suspected hemangioma cannot be appreciated. We report on the clinical usefulness of dynamic contrast-enhanced CT in the evaluation of suspected hemangiomas of the airways in infants. CT findings of 11 infants who underwent investigation for a suspected airway hemangioma were correlated with bronchoscopic findings. CONCLUSION: Dynamic contrast-enhanced CT is a valuable noninvasive method for the evaluation of airway hemangiomas. Although it can be used to confirm the diagnosis in patients with equivocal findings on bronchoscopy, we believe that CT findings are specific enough that CT can be recommended as the primary method of establishing the diagnosis. Multiplanar reconstructions illustrate the location, extent, and degree of luminal narrowing and any involvement of adjacent tissues.     

Special education services and school performance in a regional cohort of low-birthweight infants at age nine

Previous research has shown that low birthweight is a predictor of several adverse educational outcomes, including special educational placement, by middle school age. Most low-birthweight follow-up studies that have extended to school age have focused on very small infants-- < 1500 or < 1000 g; less is known of the school age outcomes for infants with only moderately low birthweight (1500-2000 g). This study examines the prevalence of special educational placement and the relationship of such placement to grade retention, verbal and performance scores on tests of general intelligence, reading and maths achievement scores and classroom hyperactivity among low-birthweight children. In a regional birth cohort of 1105 infants born between 1984 and 1987 and weighing 500-2000 g, 868 children were available for follow-up at age nine. Information on special education placement as well as grade retention, intelligence, academic achievement and classroom behaviour was available on 645 (74% completion rate). Nearly a third of the cohort was classified as needing special education. Special education placement followed a birthweight gradient, occurring among 29.3% of children with birthweights 1500-2000 g, among 32.5% in children 1000-1500 g and 49.4% in children < 1000 g. Among children in special education, a similar birthweight gradient was found for maths achievement and hyperactivity, but not for reading achievement or IQ scores. Among children not in special education, only maths achievement showed such a decline with birthweight. A substantial proportion of low-birthweight children, including those of moderate low birthweight, receive special education services, although the need is greatest among those with the lowest birthweights. Maths achievement declined with birthweight regardless of educational placement. The medical and social risk factors that accompany low birthweight and may account for these findings, require further study.