Improving Faculty Teaching Practices: Fostering the "Ideal ICU Teacher" Using a Positive Deviance Strategy.

We describe an innovative approach to medical education, using "positive deviants," or faculty who emerge as role models, despite responsibilities that compete with teaching efforts. In small group sessions, "positive deviants" taught effective strategies, resulting in faculty implementing new strategies.

Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm.

OBJECTIVES: Evidence-based care of extremely preterm infants (<28 weeks' gestation) depends heavily on research in which a primary outcome is infant neurodevelopmental impairment (NDI), yet it is unclear how well NDI in infancy predicts long-term NDI. In this study, we aim to assess the relationship between 2- and 10-year neurodevelopment using a well-known 2-year definition and a 10-year definition developed by an expert panel. METHODS: Using data from the Extremely Low Gestational Age Newborn Study cohort, we classified 2-year NDI using definitions developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. We classified 10-year NDI using definitions developed by an expert panel, which added epilepsy and ASD at 10 years. RESULTS: Of 1506 infants, 80% survived. Data sufficient to classify severity of NDI at both 2 and 10 years were available for 67% of survivors (n = 802). Among children classified as having moderate to severe NDI at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. Cohen's κ statistic indicated minimal to fair agreement between NDI at 2 and 10 years (0.34, P < .001). CONCLUSIONS: NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.

Teamwork, communication and resident leadership at resident-attended, neonatal delivery room resuscitations.

OBJECTIVE: Determine if a NICU resident delivery room (DR) skills educational curriculum is associated with changes in neonatal resuscitation team characteristics, including teamwork, communication and leadership. STUDY DESIGN: This prospective, observational study of resident-attended neonatal resuscitations utilized team questionnaire, video assessment and chart review. Each resident NICU block included a curriculum consisting of two educational programs focusing on NRP knowledge and skills with additional emphasis on teamwork and communication strategies. RESULTS: Ninety-nine resuscitations met inclusion criteria. Comparing behaviors at the beginning versus end of a NICU block, residents demonstrated increased frequency of initiating leadership (31% vs. 93%, p < 0.001) and maintaining leadership (19% vs. 79%, p < 0.001) at low-risk, resident-attended DR resuscitations. Overall measurements of teamwork and communication were unchanged. CONCLUSIONS: A NICU DR skills educational curriculum is associated with increased resident leadership at low-risk DR resuscitations over the course of NICU blocks, without compromising measurements of teamwork or communication.

Effect of Routine, Screening Head Ultrasounds on Clinical Interventions for Premature Infants.

OBJECTIVE: This article assesses whether routine, screening head ultrasound (HUS) studies performed at 7 to 14 postnatal days for premature infants are followed by clinical interventions. STUDY DESIGN: This retrospective cohort study included all inborn infants delivered at < 30 weeks' gestational age (GA) between January 1, 2012 and December 31, 2015 at a single center who had a routine, screening HUS performed between 7 and 14 postnatal days (n = 303). We defined "clinical intervention" as a 7 to 14 postnatal day HUS that was followed by neurosurgical intervention prior to a 36- to 40-week postmenstrual age (PMA) HUS or elective withdrawal of critical care within 30 days of a positive HUS finding. RESULTS: Four infants (1.3%) had neurosurgical intervention prior to a 36- to 40-week PMA HUS; all four had a diagnostic HUS performed prior to postnatal day 7 to assess for an intraventricular hemorrhage (IVH) due to clinical instability. No infant had critical care electively withdrawn following a 7 to 14 postnatal day HUS. CONCLUSION: Clinical intervention rarely followed routine, screening HUS studies performed at 7 to 14 postnatal days for inborn infants delivered at < 30 weeks' GA. In no case did clinical intervention related to HUS results occur when a 7 to 14 postnatal day HUS was the initial HUS performed.

Transitions in Care for Infants with Trisomy 13 or 18.

Background and Objectives The scope of interventions offered to infants with trisomy 13 (T13) or trisomy 18 (T18) is increasing. We describe the spectrum of care provided, highlighting transitions in care for individual patients. Patients and Methods This is a single-center, retrospective cohort of infants with T13 or T18 born between 2004 and 2015. Initial care was classified as comfort care or intervention using prenatal counseling notes. Transitions in care were identified in the medical record. Results In this study, 25 infants were divided into two groups based on their care: neonates who experienced no transition in care and neonates who experienced at least one transition. Eleven neonates experienced no transition in care with 10 receiving comfort care. Fourteen neonates experienced at least one transition: three transitioned from comfort care to intervention and 11 from intervention to comfort care. The three initially provided comfort care were discharged home with hospice and readmitted. Among the 11 cases who transitioned from intervention to comfort care, 9 transitioned during the birth hospitalization, 6 had no prenatal suspicion for T13 or T18, and 5 experienced elective withdrawal of intensive care. Conclusion The spectrum of care for infants with T13 or T18 illustrates the need for individualized counseling that is on-going, goal directed, collaborative, and responsive.

Management of Pregnancy and Survival of Infants with Trisomy 13 or Trisomy 18.

Objective The objective of this study was to describe antenatal/intrapartum management and survival of liveborn infants with known trisomy 13 (T13) or trisomy 18 (T18) based on planned neonatal care. Study Design This is a retrospective cohort study of singleton pregnancies complicated by T13/T18 at a tertiary center from 2004 to 2015. We included pregnancies with antenatal or neonatal cytogenetic T13/T18 diagnosis and excluded those which were terminated or had a fetal demise < 20 weeks. We compared antenatal/intrapartum management and neonatal survival by planned neonatal care, defined as either neonatal intervention (INT), including neonatal cardiopulmonary resuscitative measures or comfort care (CC) without resuscitative measures. Results In this study, 32 women (10 with T13 and 22 with T18) met study criteria; 12 (38%) elected INT and 20 (62%) CC. Compared with those who elected INT, women who elected CC were more likely to undergo elective induction (40 vs. 0%, p = 0.01), have an intrapartum stillbirth (0 vs. 32%, p = 0.14), and deliver vaginally (25 vs. 63%, p < 0.01). In neonatal survival analysis (n = 26), median survival was longer in the INT group compared with CC group (64 days [interquartile range, IQR: 2, 155) vs. 3 days [IQR]: 0.3, 42), p = 0.28), but survival to hospital discharge was similar (53 vs. 57%, p = 0.95). Conclusion Regardless of desired level of neonatal INT, many women who continue pregnancies complicated by T13/18 have infants who survive beyond hospital discharge.

Development and validation of the Proxy-Reported Pulmonary Outcomes Scale for premature infants.

OBJECTIVE: Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures. STUDY DESIGN: Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool. RESULT: We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies. CONCLUSION: The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

Factors Influencing the Accuracy of Noninvasive Blood Pressure Measurements in NICU Infants.

OBJECTIVE: Compare invasive blood pressure (IBP) and noninvasive blood pressure (NIBP) measurement methods in the neonatal intensive care unit (NICU) across various gestational age and postmenstrual age (PMA), and determine the effect of gestational age and PMA on accuracy of NIBP measurements. STUDY DESIGN: Retrospective chart review of paired mean IBP and NIBP measurements from infants admitted to a single NICU from January 2008 through December 2010. Infants with congenital anomalies or receiving therapeutic hypothermia were excluded. Difference between paired measurements was analyzed using Bland-Altman method. We examined the association between PMA, sex, race, mechanical ventilation, medications, and axillary temperature, and the difference in measurements using a mixed effects linear regression model. RESULTS: Eighty-seven infants had 243 observations. The mean (range) gestational age at birth was 31.9 (23-41) weeks and PMA at time of measurement ranged from 26 to 52 weeks. We found poor agreement between IBP and NIBP measurements, with mean difference (95% limits of agreement) of -8.8 (11, -28.7) mm Hg. The mean blood pressure percent difference ( ± SD) was -28.3 ( ± 35.6%). A greater blood pressure percent difference between the two measurement techniques was associated with lower PMA and lower mean IBP. CONCLUSION: NIBP measurements overestimate IBP measurements particularly in smaller, sicker infants at lower IBP measurements.

Acquired and introduced macroparasites of the invasive Cuban treefrog, Osteopilus septentrionalis.

Because shifts in host-parasite relationships can alter host populations, attention should be given to the parasites that introduced species take with them or acquire in their introduced range. The Cuban treefrog, Osteopilus septentrionalis, is a successful invasive species in Florida with its parasites in the native range being well-documented, but there is a void in the literature regarding what parasites were lost or introduced in its expansion. We necropsied 330 O. septentrionalis from Tampa, FL and compared their macroparasites to those of O. septentrionalis in their native range and to the parasites of anurans native to the Tampa, FL area to determine the species O. septentrionalis likely introduced or acquired in Florida. At least nine parasite species (Aplectana sp., Oswaldocruzia lenteixeirai, Cylindrotaenia americana, Physaloptera sp., Rhabdias sp., Centrorhynchus sp., unidentified trematode metacercariae, unidentified larval acuariids, and unidentified pentastomids) were isolated. We found no differences in parasite communities of adult male and female frogs, which averaged 19.36 parasite individuals and 1.39 parasite species per adult frog, and had an overall prevalence of 77.52%. Acuariid larvae were likely acquired by O. septentrionalis in FL because they are not found in their native range. O. lenteixeirai was likely introduced because it is commonly reported in O. septentrionalis' native range but has never been reported in FL-native anurans. Aplectana sp. is also likely introduced because it has been reported in several anurans in Cuba but only reported once in Florida. O. septentrionalis tended to harbor fewer of its native parasites in the introduced range, which is consistent with the enemy release hypothesis and potentially creates an immunological advantage for this invasive host. Because native populations can be threatened by introduced parasites, there is a need to further explore the frequency and rate at which non-native hosts introduce parasites.

Influence of neonatal practice variation on outcomes of late preterm birth.

OBJECTIVE: Examine variation in short-term outcomes of late preterm births (34(0/7)-36(6/7) weeks) between a university teaching hospital, teaching community hospital, and nonteaching community hospital. STUDY DESIGN: Review of maternal and newborn data from a random sample of late preterm births at three hospitals in North Carolina from 2008 to 2009. Outcomes included length of stay, neonatal intensive care unit (NICU) admission, respiratory support, antibiotic exposure, phototherapy exposure, and hypoglycemia. RESULTS: We analyzed data from 331 singleton late preterm newborns: 93 (28.1%) from a university teaching hospital, 110 (33.2%) from a teaching community hospital, and 128 (38.7%) from a nonteaching community hospital. Mean gestational age did not vary between hospitals. NICU admission, exposure to antibiotics, and phototherapy were more common at the university teaching hospital after controlling for risk factors, yet length of stay was shortest at the university teaching hospital and longest at the teaching community hospital after adjustment. CONCLUSION: Practice variation contributes to differences in length of stay, NICU admission, and exposure to antibiotics and phototherapy among late preterm newborns. Differences in practice during the birth hospitalization may affect outcomes and health care utilization (e.g., readmission) after discharge.

Regional variation in late preterm births in North Carolina.

Late preterm (LPT) neonates (34 0/7th-36 6/7th weeks' gestation) account for 70% of all premature births in the United States. LPT neonates have a higher morbidity and mortality risk than term neonates. LPT birth rates vary across geographic regions. Unwarranted variation is variation in medical care that cannot be explained by sociodemographic or medical risk factors; it represents differences in health system performance, including provider practice variation. The purpose of this study is to identify regional variation in LPT births in North Carolina that cannot be explained by sociodemographic or medical/obstetric risk factors. We searched the NC State Center for Health Statistics linked birth-death certificate database for all singleton term and LPT neonates born between 1999 and 2006. We used multivariable logistic regression analysis to control for socio-demographic and medical/obstetric risk factors. The main outcome was the percent of LPT birth in each of the six perinatal regions in North Carolina. We identified 884,304 neonates; 66,218 (7.5%) were LPT. After multivariable logistic regression, regions 2 (7.0%) and 6 (6.6%) had the highest adjusted percent of LPT birth. Analysis of a statewide birth cohort demonstrates regional variation in the incidence of LPT births among NC's perinatal regions after adjustment for sociodemographic and medical risk factors. We speculate that provider practice variation might explain some of the remaining difference. This is an area where policy changes and quality improvement efforts can help reduce variation, and potentially decrease LPT births.

Delayed repair of hemitruncus in an extremely low birth weight infant.

We present a case of a premature female infant, with a delayed diagnosis of hemitruncus, who underwent primary repair at 105 days of life. There have been few published reports of premature infants with hemitruncus, and none to our knowledge who underwent repair that was significantly delayed.

Development of a proxy-reported pulmonary outcome scale for preterm infants with bronchopulmonary dysplasia.

BACKGROUND: To develop an accurate, proxy-reported bedside measurement tool for assessment of the severity of bronchopulmonary dysplasia (also called chronic lung disease) in preterm infants to supplement providers' current biometric measurements of the disease. METHODS: We adapted Patient-Reported Outcomes Measurement Information System (PROMIS) methodology to develop the Proxy-Reported Pulmonary Outcomes Scale (PRPOS). A multidisciplinary group of registered nurses, nurse practitioners, neonatologists, developmental specialists, and feeding specialists at five academic medical centers participated in the PRPOS development, which included five phases: (1) identification of domains, items, and responses; (2) item classification and selection using a modified Delphi process; (3) focus group exploration of items and response options; (4) cognitive interviews on a preliminary scale; and (5) final revision before field testing. RESULTS: Each phase of the process helped us to identify, classify, review, and revise possible domains, questions, and response options. The final items for field testing include 26 questions or observations that a nurse assesses before, during, and after routine care time and feeding. CONCLUSIONS: We successfully created a prototype scale using modified PROMIS methodology. This process can serve as a model for the development of proxy-reported outcomes scales in other pediatric populations.

Educational impact of a hospital-based neonatal resuscitation program in Ghana.

AIM OF THE STUDY: To assess midwives' baseline cognitive knowledge of evidence-based neonatal resuscitation practices, and short- and long-term educational effects of teaching a neonatal resuscitation program in a hospital setting in West Africa. METHODS: All midwives (n=14) on the labor ward at Ridge Hospital in Ghana were trained using materials modified from the American Academy of Pediatrics (AAP) Neonatal Resuscitation Program (NRP). This training program included didactic and practical teaching and was assessed by direct observation within delivery rooms and written pre- and post-test evaluations. Written and practical modules 9-12 months after the initial training session were also conducted to assess retention of NRP knowledge and skills. RESULTS: Fourteen midwives received NRP training on the labor ward. Both written and practical evaluation of neonatal resuscitation skills increased after training. The percentage of items answered correctly on the written examination increased from 56% pre-training to 71% post-training (p<0.01). The percentage of items performed correctly on the practical evaluation of skills increased from 58% pre-training to 81% (p<0.01). These results were sustained 9-12 months after the initial training session. CONCLUSION: After receiving NRP training, neonatal resuscitation knowledge and skills increased among midwives in a hospital in West Africa and were sustained over a 9-month period. This finding demonstrates the sustained effectiveness of a modified neonatal resuscitation training program in a resource constrained setting.

Neurodevelopmental outcome of infants with unilateral or bilateral periventricular hemorrhagic infarction.

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05-0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64-1.00] vs 11% [95% CI: 0.01-0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

Biophysical properties of CDAN/DOPE-analogue lipoplexes account for enhanced gene delivery.

Typically, cationic liposomes are formulated from the combination of a synthetic cationic lipid (cytofectin) and a neutral, biologically available co-lipid. However, the use of cationic liposome formulations to mediate gene delivery to cells is hampered by a paradox. Cationic lipids, such as N(1)-cholesteryloxycarbonyl-3-7-diazanonane-1,9-diamine (CDAN), are needed to ensure the formation of cationic liposome-DNA (lipoplex, LD) particles by plasmid DNA (pDNA) condensation, as well as for efficient cell binding of LD particles and intracellular trafficking of pDNA post-intracellular delivery by endocytosis. However, the same cationic lipids can exhibit toxicity, and also promote LD particle colloidal instability, leading to aggregation. This results from electrostatic interactions with anionic agents in biological fluids, particularly in vivo. One of the most commonly used neutral, bioavailable co-lipids, dioleoyl L-alpha-phosphatidylethanolamine (DOPE), has been incorporated into many cationic liposome formulations owing to its fusogenic characteristics that are associated with a preference for the inverted hexagonal (H(II)) phase-a phase typical of membrane-membrane fusion events. However, these same fusogenic characteristics also destabilize LD particles substantially with respect to aggregation, in vitro and especially in vivo. Therefore, there is a real need to engineer more stable cationic liposome systems with lower cellular toxicity. We hypothesize that one way to achieve this goal should be to find the means to reduce the mol fraction of cationic lipid in cationic liposomes without impairing the overall transfection efficiency, by replacing DOPE with an alternative co-lipid with fusogenic properties "tuned" with a greater preference for the more stable lamellar phases than DOPE is able to achieve. Herein, we document the syntheses of triple bond variants of DOPE, and their formulation into a range of low charge, low cationic lipid containing LD systems. The first indications are that our hypothesis is correct in vitro.

Insulin-like growth factor and interleukin-1beta levels and subsequent fetal size in response to chronic Porphyromonas gingivalis exposure in the pregnant rabbit.

OBJECTIVE: The purpose of this study was to describe maternal insulin-like growth factor, interleukin-1beta, and fetal size in a rabbit model of Porphyromonas gingivalis exposure. STUDY DESIGN: With the use of a previously described model, 8 New Zealand White rabbits were exposed to either P gingivalis or media during pregnancy and killed at term. Kit and placenta weight were compared between groups. Doe serum insulin-like growth factor system protein and interleukin-1beta levels were compared by analysis of variance for repeated measures; a probability value of <.05 was considered to be significant. RESULTS: No significant differences in kit and placental weights between exposed and unexposed groups were observed. Insulin-like growth factor system proteins increased significantly as pregnancy progressed, but there were no significant differences in insulin-like growth factor system proteins or interleukin-1beta between exposed and unexposed does. CONCLUSION: Chronic P gingivalis exposure does not disrupt insulin-like growth factor system proteins or systemic inflammation and does not impair fetal growth in the pregnant rabbit. Gestational age changes in doe insulin-like growth factor system proteins occur, and the timing of exposure to oral pathogens may influence fetal growth.

The facile preparation of primary and secondary amines via an improved Fukuyama-Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent.

An efficient modification of the Fukuyama-Mitsunobu procedure has been developed whereby primary or secondary amines can be synthesized from alkyl alcohols and the corresponding nosyl-protected/activated amine. Most importantly, the use of the DTBAD and diphenylpyridinylphosphine, as Mitsunobu reagents, generates reaction by-products that can be easily removed, providing a remarkably clean product mixture. This improved technique was implemented in the synthesis of a complex lipopeptide designed to target alpha9beta1-integrin proteins predominant on upper airway epithelial cells.

Regulation of insulin-like growth factor (IGF)-binding protein expression by growth factors and cytokines alters IGF-mediated proliferation of postnatal lung fibroblasts.

Postnatal day 5 is the beginning of septation and the peak of postnatal fibroblast proliferation. The author and colleagues studied fibroblasts from this developmental time period to determine factors that regulate cell proliferation. Exposure of cells to insulin-like growth factor (IGF)-I for 48 hours increased cell number whereas exposure to epithelial growth factor (EGF), platelet-derived growth factor (PDGF)-BB, fibroblast growth factor (FGF)-7, FGF-2, tumor necrosis factor-alpha (TNF-alpha), or interleukin (L)-1beta did not alter cell number. Long[R3]IGF-I (a synthetic IGF analog with reduced affinity for IGF-binding proteins [IGFBPs]) was more potent than IGF-I, with half-maximal stimulation at a dose of 0.6 nM for long[R3]IGF-I compared to 1.5 nM for IGF-I, suggesting that IGFBPs in the conditioned medium (CM) inhibit IGF activity. Addition of exogenous IGFBP-3 inhibited the IGF-stimulated increase in cell number. Addition of IGFBP-4 did not alter IGF activity because IGF-I stimulated proteolysis of IGFBP-4. The expression of mRNA for PAPP-A (a known IGFBP-4 protease) suggests that the clearance of IGFBP-4 is mediated by pregnancy-associated plasma protein (PAPP)-A. Exposure of cells to TNF-alpha or IL-1beta increased IGFBP-3 mRNA abundance and IGFBP-3 protein in CM. PDGF-BB and IL-1beta increased IGFBP-4 protein abundance and PDGF-BB and dibutyryl cAMP increased IGFBP-4 mRNA. The increase in CM IGFBP-3 following TNF-alpha exposure blocked IGF-mediated cell proliferation, suggesting that the growth factor- and cytokine-mediated changes in IGFBP abundance regulate postnatal fibroblast cell proliferation.

Tumor necrosis factor-alpha regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathogenesis of several disorders and injuries in the central nervous system (CNS). Unlike IGF-I, which promotes CNS growth, TNF-alpha causes brain growth retardation and neural damage. Recently TNF-alpha has been shown to inhibit IGF-I signaling and actions in non-neural tissue. To investigate whether TNF-alpha deleteriously influences brain growth by altering the IGF-I system in vivo, we examined the expression of IGF-I, the type 1 IGF receptor (IGF1R) and IGF binding proteins (IGFBPs) in the brain of transgenic (Tg) mice with murine TNF-alpha overexpression. We show that overexpression of TNF-alpha reduces the weights of whole brain and all brain regions examined during development. In adult TNF-alpha Tg mice, cerebellum (CB) exhibited the greatest reduction in weight among the five brain regions examined, being approximately 77% of that in wild-type (WT) mice. IGF-I abundance was decreased in the CB, as well as in cerebral cortex and diencephalon, of TNF-alpha Tg mice. When compared to those in WT mice, CB IGF-I abundance in Tg mice was reduced by approximately 35%, approximately 45%, and approximately 40% at 2, 6, and 9 weeks of age, respectively. Of the IGFBPs studied the abundance of IGFBP-3 and IGFBP-4 was increased by 2-3.7-fold, and the abundance of IGFBP-5 was decreased by approximately 3-fold (as judged by Western immunoblot analysis). Histological analysis and immunocytochemical staining confirmed that TNF-alpha specifically increases IGFBP-3 and IGFBP-4 immunoreactivity, as well as that of the IGF1R, in radial glial and Purkinje cells. In addition, TNF-alpha alters CB cytoarchitecture, apparently by influencing granule cell migration. Our data indicate that TNF-alpha alters the expression of IGF-I system proteins in vivo, and suggest that altered expression of IGF-I system proteins may in part explain TNF-alpha deleterious actions on brain growth.