Skin blood flow as a predictor of intraventricular hemorrhage in very-low-birth-weight infants.

BACKGROUND: Cardiovascular instability immediately after birth is associated with intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants. For circulatory management, evaluation of organ blood flow is important. In this study, the relationship between peripheral perfusion within 48 h after birth and IVH was evaluated in VLBW infants. METHODS: In this prospective observational study involving 83 VLBW infants, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a laser Doppler flowmeter. Blood flow was compared between infants with and without IVH. Multivariate logistic regression analysis was performed to identify the risk factors for IVH. RESULTS: IVH developed in nine infants. In eight of these patients, IVH occurred after 24 h. LBF was lower in infants with IVH at 18 and 24 h and increased to the same level as that of infants without IVH at 48 h. Multivariate logistic regression analysis identified a correlation only between LBF and IVH at 18 h. CONCLUSION: These findings were consistent with the hypoperfusion-reperfusion theory, which states that IVH develops after reperfusion subsequent to hypoperfusion. We speculate that measurement of skin blood flow in addition to systemic and cerebral circulation may be helpful in predicting IVH.

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model.

BACKGROUND: Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. METHODS: A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-P1/fl 30 min after CLP (ETR-P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6 h after CLP. RESULTS: CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group. CONCLUSION: ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model.

Oxidative and Inflammatory Markers Are Higher in Full-Term Newborns Suffering Funisitis, and Higher Oxidative Markers Are Associated with Admission.

The aim of this study was to assess whether oxidative and inflammatory mediators in the cord blood of newborns with funisitis and chorioamnionitis can serve as indicators of their inflammatory status, and whether there is a positive association between higher mediator levels and an increased risk of admission to the neonatal intensive care unit (NICU). This study was conducted prospectively in a neonatology department of a university hospital. In total, 52 full-term newborns were evaluated, including 17 funisitis cases, 13 chorioamnionitis cases, and 22 control newborns without funisitis or chorioamnionitis. Cord blood samples were measured for oxidative stress and inflammatory status markers. The oxidative stress markers included the total nitric oxide (NO), total hydroperoxide (TH), biological antioxidant potential (BAP), and TH/BAP ratio, comprising the oxidative stress index (OSI). Inflammatory markers included interleukin (IL)-1b, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNFα), interferon γ (IFNγ), and complement component C5a. TH, OSI, IL-1b, IL-6, and IL-8 concentrations were higher in the funisitis group than in the chorioamnionitis and control groups. C5a was higher in the funisitis and chorioamnionitis groups than in the control group. Among all enrolled newborns, 14 were admitted to the NICU. Multiple logistic regression analysis showed that elevated umbilical cord blood levels of OSI and TH were associated with a higher risk of admission to the NICU (OSI: R = 2.3, 95% CI 1.26-4.29, p = 0.007 and TH: R = 1.02, 95%CI = 1.004-1.040, p = 0.015). In conclusion, OSI and TH in cord blood from full-term newborns can provide an index of inflammatory status, and higher levels are associated with the risk of admission to the NICU and, therefore, could serve as an early indicator of inflammatory conditions in newborns.

Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury.

The hypoxia-responsive cytokine erythropoietin (EPO) provides neuroprotective effects in the damaged brain during ischemic events and neurodegenerative diseases. The purpose of the present study is to evaluate the EPO/EPO receptor (EPOR) endogenous system between astrocyte and oligodendrocyte precursor cell (OPC) under hypoxia. We report here elevated EPO mRNA levels and protein release in cultured astrocytes following hypoxic stimulation by quantitative RT-PCR and ELISA. Furthermore, the EPOR gene expressions were detected in cultured OPCs as in astrocytes and microglias by quantitative RT-PCR. Cell staining revealed the EPOR expression in OPC. To evaluate the protective effect of endogenous EPO from astrocyte to OPCs, EPO/EPOR signaling was blocked by EPO siRNA or EPOR siRNA gene silencing in in vitro study. The suppression of endogenous EPO production in astrocytes by EPO siRNA decreased the protection to OPCs against hypoxic stress. Furthermore, OPC with EPOR siRNA had less cell survival after hypoxic/reoxygenation injury. This suggested that EPO/EPOR signaling from astrocyte to OPC could prevent OPC damage under hypoxic/reoxygenation condition. Our present finding of an interaction between astrocytes and OPCs may lead to a new therapeutic approach to OPCs for use against cellular stress and injury.

Edaravone, a hydroxyl radical scavenger, ameliorates the severity of pulmonary hypertension in a porcine model of neonatal sepsis.

Systemic infection in the newborn (neonatal sepsis) is the most common cause of neonatal mortality. Neonatal sepsis is complicated by pulmonary hypertension. In this study, we analyzed the effect of edaravone, a free radical scavenger that is known to reduce the production of inflammatory mediators, such as tumor necrosis factor α (TNFα), on pulmonary hypertension. Experimental and sham groups were drawn from 19 three-day-old piglets; 5 underwent a modified procedure of cecal ligation and perforation (CLP) (CLP group), 8 underwent CLP followed 30 min later by edaravone intravenous administration (edaravone group), and 6 did not undergo CLP and did not receive edaravone (sham group). To evaluate the pulmonary blood pressure despite the sepsis-induced low cardiac output, mean arterial blood pressure (mABP), mean pulmonary arterial pressure (mPAP), and comparative pulmonary hypertension ratio (mPAP/mABP) were determined. Serum TNFα levels were measured before the procedure and at 1, 3, and 6 h after. The mPAP levels were higher in the CLP group at 9 h compared to the edaravone group. The mPAP/mABP ratio was lower in the edaravone and sham groups compared to the CLP group at 6 and 9 h. TNFα in the edaravone and sham groups were lower at 1 and 3 h compared to that in the CLP group. In all animals, mPAP/mABP at 6 h correlated with serum levels of TNFα at 1, 3, and 6 h. These findings suggest that edaravone ameliorates the severity of pulmonary hypertension in a neonatal sepsis model by reducing serum TNFα levels.

Pediatric patients receiving ABO-incompatible living related liver transplantation exhibit higher serum transforming growth factor-ß1, interferon-γ and interleukin-2 levels.

BACKGROUND: ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival. PURPOSE: To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper. MATERIALS AND METHODS: A clinical outpatient study measuring serum transforming growth factor (TGF)-ß1, interferon (IFN)-γ, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients' regular follow-up visits. RESULTS: There were no differences between the ABO-c and ABO-i groups in terms of recipient's age [mean 12.6 vs. 11.1 years (y)], post-LTx duration (mean 7.3 vs. 7.3 y), donor's age (mean 35.5 vs. 34.6 y), body weight (28.9 ± 2.9 vs. 27.9 ± 6.9 kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-ß1, IFN-γ and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher γGTP levels in the ABO-i group, but this difference did not reach significance. CONCLUSION: ABO-incompatible LRLTx patients have higher serum TGF-ß1, IFN-γ and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely.

Oxidative stress after living related liver transplantation subsides with time in pediatric patients.

BACKGROUND: Oxidative stress has been suspected to influence graft survival and prognosis in pediatric recipients of living related liver transplantation (LRLT). PURPOSE: We determined the oxidative status of pediatric LRLT recipients during their regular outpatient follow-up visits, and looked for a relationship between oxidative status and post-liver transplantation (post-LTx) duration. PATIENTS: The study included 43 patients (20 males and 23 females) between the ages of 1.6 and 25.1 years (median 10.7 years) who had undergone LRLT from 5 months to 17.5 years (median 7 years) prior to the study, between the ages of 1.2 and 14.4 years (median 3.5 years). METHODS: Serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), gamma-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), direct bilirubin and choline-esterase were measured as part of the patients' regular follow-up visits. Serum total hydroperoxide (TH) and biological antioxidative potential (BAP) were measured using the free radical analytic system which requires 20 µl of serum and 10 min of processing time for each sample. Oxidative stress index (OSI) was calculated as the ratio of TH to BAP. RESULTS: Serum OSI correlated positively with serum levels of GOT, GPT, LDH, ALP, γ-GTP and direct bilirubin. Serum OSI, TH, LDH, ALP and GOT correlated negatively with post-LTx duration. Serum BAP correlated positively with post-LTx duration. Serum TH correlated positively with serum GOT and γ-GTP, but negatively with serum BAP. CONCLUSIONS: (1) The OSI, which can be calculated based on data acquired through a simple outpatient procedure, can serve as an index of our patients' laboratory results and oxidative status. (2) The LRLT recipients in our study were at risk for oxidative stress early in the post-operative period, but this risk subsided with time.

Effect of polymyxin B-immobilized fiber hemoperfusion on respiratory impairment, hepatocellular dysfunction, and leucopenia in a neonatal sepsis model.

PURPOSE: Sepsis and septic shock remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Our aim was to study the effects of polymyxin-B direct hemoperfusion (PMX-DHP) therapy on sepsis-induced respiratory impairment, liver dysfunction and leucopenia in a neonatal cecal ligation and perforation (CLP) model. METHODS: Fourteen anesthetized and mechanically ventilated 3-day-old piglets underwent CLP and an arteriovenous extracorporeal circuit from 3 h until 6 h post-CLP, with a PMX column in the PMX-DHP treated group (7 piglets). Changes in oxygen saturation, PCO(2), base excess, white blood cell (WBC) count, platelet count, hematocrit (Hct%), serum glutamate pyruvate transaminase (SGPT), and serum glutamic oxaloacetic transaminase were measured before CLP and at 1, 3 and 6 h after. RESULTS: At 6 h, the PMX-DHP group showed lower Hct%, and SGPT in comparison to the control group, but higher oxygen saturation and WBC count. No effects on the platelet count were found. The survival times of the PMX-DHP group were longer than in control. CONCLUSION: PMX-DHP therapy limited the respiratory impairment, liver dysfunction and leucopenia in a neonatal septic model, which resulted in an improvement of survival time.

Developmental Evaluation of Infants Who Have Received Tadalafil in Utero for Fetal Growth Restriction.

To assess the long-term effects of tadalafil, a therapeutic agent for fetal growth restriction (FGR), we evaluated the developmental progress of 1.5-year-old infants whose mothers had taken tadalafil during pregnancy. Twenty-four infants were assessed. We evaluated infant body weight, height, and head circumference, and performed the Kyoto Scale of Psychological Development (KSPD) test, a standardized developmental assessment covering Postural-Motor (P-M), Cognitive-Adaptive (C-A), and Language-Social (L-S) functions. The sum score was converted to a developmental quotient (DQ). The mean gestational week of the included cases was 36.1 (29-39) weeks, and the mean birth weight was 1841 (874-2646) g. Twenty-one and 20 out of the 24 cases, respectively, attained body weight and height similar to those of age-matched normal infants (within the 3rd percentile); all cases caught up in head circumference. KSPD was performed for 18 cases at 1.5 years of corrected age. The mean DQ scores were 87 (in total): 82 in P-M, 90 in C-A, and 88 in L-S. The total DQ score in one case (5.6%) was less than 70, and ranged from 70 to 85 in five cases (27.7%), and was more than 85 in 11 cases (61.1%). The growth and development of infants born of tadalafil-treated mothers seem to show good progress at a corrected age of 1.5 years.

Longitudinal evaluation of patients with a homozygous R450H mutation of the TSH receptor gene.

BACKGROUND/AIM: The R450H mutation of the TSH receptor (TSHR) gene has been frequently observed in Japanese patients with resistance to TSH. The purpose of this study was to clarify the phenotype of patients with a homozygous R450H mutation of the TSHR gene; the mutant receptor has previously demonstrated moderately impaired function in vitro. METHODS: We performed a clinical investigation of 5 Japanese patients who had hyperthyrotropinemia as neonates, in whom a homozygous R450H mutation of the TSHR gene had been demonstrated by genetic sequencing analysis. RESULTS: The thyroid hormone levels of the patients were normal in early infancy, although their serum levels of TSH were mildly elevated. After supplemental treatment with levothyroxine sodium (L-T4) was started, we had to increase the dose to maintain the level of TSH within the normal range in all patients. Thyroid dysfunction became obvious in one patient at reexamination during adolescence when L-T4 treatment was stopped for 1 month. Four patients were examined for intelligence quotient and their scores were normal. CONCLUSIONS: Thyroid hormone replacement therapy should be considered based on biological data in patients with hyperthyrotropinemia who have a homozygous R450H mutation of the TSHR gene even if they do not exhibit obvious hypothyroidism in infancy.

Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions.

We have demonstrated that tadalafil facilitates fetal growth in mice with L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia (PE) with fetal growth restriction (FGR). Tadalafil is a selective phosphodiesterase 5 inhibitor that dilates the maternal blood sinuses in the placenta, thereby facilitating the growth of the fetus. The purpose of this study was to investigate the effects of tadalafil treatment for PE and FGR on the developing brain in FGR offspring using an L-NAME-induced mouse model of PE with FGR. A control group of dams received carboxymethylcellulose (CMC). L-NAME-treated groups received L-NAME dissolved in CMC from 11 days post coitum (d.p.c.). The L-NAME-treated dams were divided into two subgroups 14 d.p.c. One subgroup continued to receive L-NAME. The other subgroup received L-NAME with tadalafil suspended in CMC. Tadalafil treatment for PE with FGR reduced the expression of hypoxia-inducible factor-2α in the placenta and in the brain of the FGR fetus. Moreover, tadalafil treatment in utero shows improved synaptogenesis and myelination in FGR offspring on postnatal day 15 (P15) and P30. These results suggest that tadalafil treatment for PE with FGR not only facilitates fetal growth, but also has neuroprotective effects on the developing brain of FGR offspring through modulating prenatal hypoxic conditions.

Maturation of spontaneous arousals in healthy infants.

OBJECTIVE: The propensity to arouse from sleep is an integrative part of the sleep structure and can have direct implications in various clinical conditions. This study was conducted to evaluate the maturation of spontaneous arousals during the first year of life in healthy infants. DESIGN: Nineteen infants were studied with nighttime polysomnography on 3 occasions: aged 2 to 3 months, 5 to 6 months, and 8 to 9 months. Ten infants with a median age of 3 weeks were added to the main study to assess the maturation of arousals from birth. The infants were born full-term, were healthy at the time of study, and had no history of apnea. Sleep-state and cardiorespiratory parameters were scored according to recommended criteria. Arousals were differentiated into subcortical activations or cortical arousals, according to the presence of autonomic and/or electroencephalographic changes. Frequencies of subcortical activations and cortical arousals were studied at different ages in both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: During sleep time, the frequency of total arousals, cortical arousals, and subcortical activations decreased with age. The maturation of the arousal events differed according to sleep states and types of arousals. With age, cortical arousals increased in REM sleep (P = 0.006) and decreased in NREM sleep (P = 0.01). Subcortical activations decreased with age in REM (P < 0.001) and NREM sleep (P < 0.001). CONCLUSIONS: During total sleep time, the frequency of cortical arousals and subcortical activations decreased with maturation. However, the maturation process was different between cortical arousals and subcortical activations. This finding suggests a difference in the maturational sequence of the different brain centers regulating arousals.

Late circulatory dysfunction and decreased cerebral blood flow volume in infants with periventricular leukomalacia.

Periventricular leukomalacia is a major neuropathology in preterm infants associated with adverse motor and cognitive outcome. The cerebral blood flow volume of the internal carotid artery and the vertebral artery was measured by ultrasonography at the neck in 36 low-birth-weight infants with gestational age of 25-34 weeks in order to investigate the pathophysiology of cerebral white-matter injury: 30 infants, normal and 6 infants, diagnosed as PVL. The mean blood flow velocity and diameter of each vessel were measured at postnatal days from day 0 to day 70. The intravascular flow volume was determined by calculating the mean blood flow velocity and the cross-sectional area. The mean blood pressures were recorded and PaCO(2) was determined. The total blood flow volume was significantly lower in infants with PVL than in normal infants on days 0, 1, 21, 28, 35, 42, and 63. The mean blood pressure was significantly lower in infants with PVL than in normal infants on days 7, 14, 21, 28, and 42. We suggest that the total cerebral blood supply is decreased in cases of PVL in the few days after birth and from day 21 to day 42. The results of the present study suggest that a dip in the blood flow volume in the few days after birth might result in subsequent PVL.

Reduction in cerebral blood flow volume in infants complicated with hypoxic ischemic encephalopathy resulting in cerebral palsy.

Hypoxic ischemic brain can result in cerebral palsy, mental retardation, and learning disabilities in surviving children. The purpose of this study was to elucidate the cerebral blood flow volume in infants complicated with brain damage after the birth. Nine term infants with hypoxic ischemic encephalopathy and 41 normal term infants were studied. Four infants with HIE suffered from CP or mental retardation, and the other five infants exhibited normal neurodevelopment. The mean blood flow velocity and diameter of the internal carotid artery and the vertebral artery were measured for 28 days. The intravascular flow volume was determined by calculating the flow velocity and the cross-sectional area. The ejection fraction and cardiac output were obtained, and the mean blood pressures were recorded. The summed flow volumes in both the ICA and VA, and the total CBFV increased after the birth in both the normal infants and the infants diagnosed with HIE with no disability complications. The total blood flow volume was significantly lower in infants with HIE and CP than in normal infants on days 0, 2, 5, 7, 10, 21, and 28, and significantly lower in infants with HIE and CP than in normal infants with HIE on days 2, 4, and 7. The ejection fraction was significantly lower in infants with HIE than in normal infants only on day 0. Our results suggest that the total cerebral blood supply is decreased in infants with HIE in those complicated with brain damage.

Severity of virilization of external genitalia in Japanese patients with salt-wasting 21-hydroxylase deficiency.

Females with salt-wasting (SW) 21-hydroxylase deficiency (21OHD) may present with mild external genitalia virilization, despite complete or almost complete enzyme inactivation. We therefore analyzed genotype/phenotype correlation in 13 Japanese female patients with SW 21OHD. Criteria for classification into the SW phenotype included history of a salt-losing crisis with documented hyponatremia, hyperkalemia, and markedly elevated plasma renin activity. Urologists and pediatricians determined the Prader genital stage and classified the location of the vaginal entrance into the common urogenital sinus as low, moderate, or high. CYP21A2 gene, coding for 21-hydroxylase, was analyzed with Southern blotting and direct sequencing. Genotypes were categorized into four mutation groups, based on the degree of enzymatic activity (N, complete enzyme inactivation; groups A, < 2%, B, 3-7%, and C > 30%). Basal androgen levels were available from only six out of thirteen patients, so we could not relate androgen levels with the severity of external genitalia virilization. We compared the degree of external genitalia virilization with genotype. The severity of external genitalia virilization varied from Prader stage 1 to 4. One patient who presented with Prader 1 had a genotype consistent with Group B. In addition, discordance between Prader classification and the location of the vaginal entrance was noted; one patient classified as Prader 4 showed low vaginal entrance, while another patient classified as Prader 3 showed high vaginal entrance. The degree of the impairment of 21-hydroxylase activity does not correlate with the severity of virilization of the external genitalia in female patients with the SW type of 21OHD.

The sex differences of cerebrospinal fluid levels of interleukin 8 and antioxidants in asphyxiated newborns.

Newborn males are more sensitive to brain injury than newborn females are. The aim of the present study was to find an explanation for this. We used the neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) for the classification of 32 newborns (19 males and 13 females) on their fifth postnatal day. The NSE levels were higher than normal (8.4 +/- 1.6 ng/mL) in 10 newborn males and 6 females and were, respectively, considered asphyxiated male and female groups. The remaining newborns, 9 males and 7 females, had normal CSF levels of NSE and were considered normal newborn male and female groups. The CSF samples were measured for 12 cytokines, using a cytokine array kit, and for total hydroperoxide and biological antioxidant potentials (BAPs), using the free radical analytic system. Among the 12 cytokines measured, only interleukin 8 (IL-8) was properly detected. The CSF levels of IL-8 were higher in the asphyxiated newborn females than in the other three groups. The mean CSF levels of BAPs in the asphyxiated newborn females were higher compared with the other three groups, but significance was detected only in comparison with the BAP levels in the CSF samples of the normal newborn males. There were no differences in total hydroperoxide levels among the groups. There are sex-related differences in the CSF levels of IL-8 and antioxidants in asphyxiated newborns, with higher levels in newborn females; this might contribute in the sexual dimorphism regarding the fact that females have better protection from brain injury than the males.

Spontaneous arousability in prone and supine position in healthy infants.

STUDY OBJECTIVE: Compared with control infants, those who will be future victims of sudden infant death syndrome (SIDS) show a decreased arousability during sleep, with fewer cortical arousals and more-frequent subcortical activations. These findings suggest an incomplete arousal process in victims of SIDS. Prone sleep position, a major risk factor for SIDS, has been reported to reduce arousal responses during sleep. The present study was undertaken to evaluate whether the prone sleep position impairs the arousal process in healthy infants. METHODS: Twenty-four healthy infants were studied polygraphically during 1 night; 12 infants regularly slept supine and 12 infants regularly slept prone. Infants were matched for sex, gestational age, and age at recording. Arousals were differentiated into subcortical activations or cortical arousals, according to the presence of autonomic and/or electroencephalographic changes. Frequencies of subcortical activations and cortical arousals were compared in the prone- and the supine-sleeping infants. RESULTS: Compared with supine sleepers, prone sleepers had significantly fewer cortical arousals during rapid eye movement (REM) sleep (p = .043). There were no significant differences in cortical arousals between the 2 groups during non-REM sleep. No significant differences were seen in the frequencies of subcortical activations during both REM and non-REM sleep between supine and prone sleepers. The ratio of cortical arousal to subcortical activation showed no significant differences between the prone and the supine sleepers. CONCLUSIONS: Prone sleep position decreased the frequency of cortical arousals but did not change the frequency of subcortical activations, as has been previously found in SIDS victims. These results suggest specific pathways for impairment of the arousal process in SIDS victims.

Development and characterization of a novel porcine model of neonatal sepsis.

Sepsis and its sequela remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Many models of neonatal sepsis have been developed for investigating the pathophysiology of this disease and application of therapy, and a model with an infectious focus is closer to clinical reality. To establish an animal model that mimics the clinical characteristics of neonatal sepsis, the cecal devascularization and perforation procedure was implemented on 15 mixed-strain newborn piglets, which produced an infectious focus that acted as a continuous source of microorganisms to the peritoneal cavity. The mean survival time in animals with sepsis was 10.4 h (range 5.5-17.9 h), whereas all of the sham-operated control animals survived more than 24 h. Animals with sepsis showed a gradual significant decrease in the mean systemic blood pressure (mSBP; 71 +/- 3 mmHg in sepsis vs. 64 +/- 3 mmHg in control at 3 h, 38 +/- 7 mmHg in sepsis vs. 59 +/- 4 mmHg in control at 6 h, mean +/- SEM). They also showed an increase of serum levels of endotoxin (5.6 x 10 +/- 4.5 x 10 pg/mL in sepsis vs. 6.0 x 10 +/- 3.8 x 10 pg/mL in control at 6 h). Serum levels of TNF-alpha in the animals with sepsis became significantly higher than the control animals at 0 h (96 +/- 31 pg/mL in sepsis vs. 12 +/- 1 pg/mL in control) and remained significantly higher than all through the experiment. Serum levels of IL-6 in animals with sepsis showed a gradual increase (484 +/- 231 pg/mL in sepsis in its peak at 6 h vs. 24 +/- 5 pg/mL in control), however, there were no significant differences in serum IL-10 levels between the groups. Microorganisms detected in the blood of animals with sepsis were gram-negative enteric and anaerobic organisms. These results suggested that this model mimics the clinical state of neonatal sepsis and hence may have significant implications for the treatment of sepsis, including its use as a model in further investigations.

Arousal deficiency theory in sudden infant death syndrome with reference to neuronal plasticity.

OBJECTIVE: Among 27,000 infants studied prospectively to characterize their sleep-wake behavior, 38 infants died under 6 months of age (including 26 infant victims of sudden infant death syndrome (SIDS), five with congenital cardiac abnormalities, two from infected pulmonary dysplasia, two from septic shock with multi-organ failure, one with a prolonged seizure, one from prolonged neonatal hypoxemia and one from meningitis and brain infarction). METHOD: The frequency and duration of sleep apnea events recorded some 3-12 weeks before the infants' deaths were analyzed. Brainstem material from these 38 infants was studied in an attempt to elucidate the relationship between sleep apnea and neuronal pathological changes in the arousal pathway. The histochemical analyses included Bielschowsky staining and the immunohistochemical analyses included the evaluation of growth-associated phosphoprotein 43 (GAP43) and of synaptophysin as markers for synaptic plasticity. Neurofibrae with positive pathological reactions were quantitatively analyzed. Pathological and physiological data were linked for each infant. RESULTS: The correlation between sleep apnea and neuronal plasticity in the arousal pathway of the SIDS victims was not seen in the control infants and the correlation between sleep apnea and neuronal plasticity in the arousal pathway found in the control infants was not seen in the SIDS victims. CONCLUSION: These findings suggest that neuronal plasticity in the brainstem arousal pathway is related with SIDS.

Interaction between apnea, prone sleep position and gliosis in the brainstems of victims of SIDS.

Among 27,000 infants studied prospectively to characterize their sleep-wake behavior, 38 infants died suddenly and unexpectedly under 6 months of age. Of these, 26 died from sudden infant death syndrome (SIDS), 5 from congenital cardiac abnormalities, 2 from infected pulmonary dysplasia, 2 from septic shock with multi-organ failure, 1 from a prolonged seizure, 1 from prolonged neonatal hypoxemia, and 1 from meningitis and brain infarction. The frequency and duration of apneas recorded some 3-12 weeks prior to the infants' death were analyzed. The brainstem materials were collected and studied in an attempt to elucidate the relationship between sleep apnea, and prone sleep position and gliosis in some nuclei associated with cardiorespiratory characteristics, such as nucleus ambiguus in the medulla oblongata and the solitary nucleus, as well as structures associated with arousal phenomenon, such as the reticular formation, the superior central nucleus and the nucleus raphe magnus in the pons, the dorsal raphe nuclei in the midbrain and medulla oblongata, periaqueductal gray matter in midbrain, and locus ceruleus. Gliosis was estimated as the density of glial fibrillary acidic protein (GFAP)-positive reactive astrocytes. Variant-covariant analyses were carried out using the characteristics of apnea as an independent variable and sleep position and gliosis as dependent variables. A significant association was found only in the frequency of obstructive apnea and prone position (P<0.001) and gliosis in the raphe nuclei in the midbrain (P<0.001). Although prone position is a well-known risk factor for SIDS, the frequency of obstructive apnea has not been associated with the prone sleep position. The observed relation between prone sleep and the density of gliosis does not relate to epidemiological findings. Further studies are needed to investigate the unexpected statistical association.