Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke

Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFβ1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB-431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFβ1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke. SIGNIFICANCE STATEMENT The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. We assessed whether microglial cells preserve neurovascular integrity after neonatal stroke. In neonatal rats, microglial depletion or pharmacological inhibition of TGFbr2/ALK5 signaling in microglia triggered hemorrhages in injured regions. The effect was not associated with additional changes in expression or intracellular redistribution of several tight junction proteins or collagen IV degradation induced by stroke. Consistent with observations in neonatal rats, microglial depletion in neonatal mice exacerbated stroke injury and induced hemorrhages. The effects were independent of infiltration of monocytes into injured regions. Thus, microglia protect neonatal brain from ischemia-induced hemorrhages, and this effect is consistent across two species.

Comparison of IgG concentrations by radial immunodiffusion, electrophoretic gamma globulin concentrations and total globulins in neonatal foals

REASONS FOR PERFORMING STUDY: Failure of transfer of passive immunity (FTPI) in foals is associated with a risk of infection and death. The current diagnostic gold standard is quantification of immunoglobulins using radial immunodiffusion (IgG-RID). Routine diagnosis is often performed using semi-quantitative tests. Concentrations of serum electrophoretic gamma globulins (EGG) and total globulins may be useful to assess FTPI, but few studies have investigated their use. OBJECTIVES: To assess agreement between IgG-RID and EGG, and evaluate the accuracy of total globulin concentration to diagnose FTPI based on both IgG-RID and EGG. STUDY DESIGN: Prospective study. METHODS: 360 serum samples were harvested at 6-24 hours post natum from 60 German Warmblood foals. Concentrations of EGG, IgG-RID and total globulin concentration (calculated from total proteins and albumin) were measured. Agreement between EGG and IgG-RID was assessed using Bland-Altman plots and Passing-Bablok regression. The accuracy of total globulin concentration was assessed using rank correlation and ROC curve analysis. RESULTS: Good agreement was found with slightly lower EGG than IgG-RID concentrations (Bland-Altman systemic bias, -1.9 g/L) which was more pronounced at higher concentrations (regression equation: IgG-RID = -0.78 +1.28xEGG). Correlations between total globulin concentration and EGG, and total globulin concentration and IgG-RID were 0.93 and 0.79, respectively. The area under the curve was 0.982 and 0.952 for EGG <4 g/L and <8 g/L, and 0.953 and 0.899 for IgG-RID <4 g/L and <8 g/L. Sensitivities and specificities of total globulin concentration in the diagnosis of FTPI were comparable to commonly used screening tests, but cut-offs could be selected to achieve sensitivities of >95% with 71.2% (IgG-RID) and 90.5% (EGG) specificity for <4 g/L, and >90% with 66.0% (IgG-RID) and 87.9% (EGG) specificity for <8 g/L. CONCLUSIONS: There is good agreement between EGG and IgG-RID, with slightly more conservative estimates of immunoglobulins obtained using EGG. Total globulins may be a useful and economic quantitative screening test with cut-offs achieving high sensitivities, but analyser-specific cut-offs may be necessary. This article is protected by copyright. All rights reserved. KEYWORDS: IgG; electrophoresis; foal; globulins; horse; radial immunodiffusion. This article is protected by copyright. All rights reserved.

National training course, emergency medical technician - paramedic. Instructor's lesson plans. Module XII: pediatrics and neonatal.

Mode of access: Internet.

Neonatal respiratory adaptation : proceedings of the Interdisciplinary conference..., December 6-9, 1963, Princeton, New Jersey /

"This conference was sponsored by the National Institute of Child Health and Human development."

Research on diseases of neonatal calves,

Mode of access: Internet.

Finite mixture regression model with random effects: application to neonatal hospital length of stay

A two-component mixture regression model that allows simultaneously for heterogeneity and dependency among observations is proposed. By specifying random effects explicitly in the linear predictor of the mixture probability and the mixture components, parameter estimation is achieved by maximising the corresponding best linear unbiased prediction type log-likelihood. Approximate residual maximum likelihood estimates are obtained via an EM algorithm in the manner of generalised linear mixed model (GLMM). The method can be extended to a g-component mixture regression model with the component density from the exponential family, leading to the development of the class of finite mixture GLMM. For illustration, the method is applied to analyse neonatal length of stay (LOS). It is shown that identification of pertinent factors that influence hospital LOS can provide important information for health care planning and resource allocation. (C) 2002 Elsevier Science B.V. All rights reserved.

Gastroschisis: determinants of neonatal outcome

This retrospective study elicits information regarding the dependence of neonatal outcome in gastroschisis upon: (1) the mode of delivery, (2) place of birth, (3) time for birth to surgery, (4) method of closure, (5) time from operation to commencement of first enteral feeds. The neonatal intensive care database from five major tertiary centres was used to identify 181 neonates with gastroschisis from 1990 to 2000. There were 8 deaths. There were no significant differences in outcome for infants delivered vaginally (102) versus Caesarean section (79), those born near the tertiary centre (133) as compared to infants born away (48), ones operated within 7 hours (125) compared with those operated after 7 hours (56), with delayed closure (30) versus primary closure (151). Neonates fed within 10 days of operation (85) had significantly lower incidence of sepsis, duration of TPN and hospital stay when compared to those fed after 10 days (96). Early commencement of feeds decreases the incidence of sepsis, duration of total parenteral nutrition (TPN) and hospital stay. Place of delivery, mode of delivery, time to surgery and type of closure do not influence neonatal outcome.

Primary trabeculodysgenesis in association with neonatal Marfan syndrome

We present the clinical and ophthalmological findings in two infants with neonatal Marfan syndrome (nMFS) and primary trabeculodysgenesis (PT). Fibrillin 1 (FBN1) mutations were confirmed in both cases. Numerous eye anomalies have been recognized in infants with nMFS, but PT has not been reported previously. Our report expands the phenotype of nMFS, and highlights the importance of early and careful ophthalmological assessment of these infants. (C) 2004 Wiley-Liss, Inc.

Loss of glial glutamate transporters and induction of neuronal expression of GLT-1B in the hypoxic neonatal pig brain

The homeostasis of glutamate is critical to normal brain function; deficiencies in the regulation of extracellular glutamate are thought to be a major determinant of damage in hypoxic brains. Extracellular levels of glutamate are regulated mainly by plasmalemmal glutamate transporters. We have evaluated the distribution of the glutamate transporter GLAST and two splice variants of GLT-1 in the hypoxic neonatal pig brain using this as model of neonatal humans. In response to severe hypoxic insults, we observe a rapid loss of two glial glutamate transporters from specific brain regions, such as the CA1 region of the hippocampus, but not the dentate gyrus. The spatial distribution of loss accords with patterns of damage in these brains. Conversely, we demonstrate that hypoxia evokes the expression of a splice variant of GLT-1 in neurons. We suggest that this expression may be induced in response to elevated extracellular glutamate around these neurons, and that this splice variant may represent a useful marker for direct quantification of the extent of likely neuronal damage in hypoxic brains. © 2004 Elsevier B.V. All rights reserved.

Inhibition of 19-kDa C-terminal region of merozoite surface protein-1-specific antibody responses in neonatal pups by maternally derived 19-kDa C-terminal region of merozoite surface protein-1-specific antibodies but not whole parasite-specific antibodies

Immunizing pregnant women with a malaria vaccine is one approach to protecting the mother and her offspring from malaria infection. However, specific maternal Abs generated in response to vaccination and transferred to the fetus may interfere with the infant's ability to respond to the same vaccine. Using a murine model of malaria, we examined the effect of maternal 19-kDa C-terminal region of merozoite surface protein-1 (MSP1(19)) and Plasmodium yoelii Abs on the pups' ability to respond to immunization with MSP1(19). Maternal MSPI,g-specific Abs but not A yoelii-specific Abs inhibited Ab production following MSP1(19) immunization in 2-wk-old pups. This inhibition was correlated with the amount of maternal MSP1(19) Ab present in the pup at the time of immunization and was due to fewer specific B cells. Passively acquired Ab most likely inhibited the development of an Ab response by blocking access to critical B cell epitopes. If a neonate's ability to respond to MSP1(19) vaccination depends on the level of maternal Abs present at the time of vaccination, it may be necessary to delay immunization until Abs specific for the vaccinating Ag have decreased.

Neonatal calyceal dilation and renal fibrosis resulting from loss of Adamts-1 in mouse kidney is due to a developmental dysgenesis

Background. A disintegrin and metalloproteinase with thrombospondin motifs 1, Adamts-1, is important for the development and function of the kidney. Mice lacking this protein present with renal lesions comprising enlarged calyces, and reduced cortex and medulla layers. Our current findings are consistent with the defect occurring due to a developmental dysgenesis. Methods. We generated Adamts-1 null mice, and further investigated their kidney phenotype in a time course study ranging from E18.5 to 12 months of age. Immunohistochemistry was used to assess the localization of type IV collagen, TGF-beta and F4/80-positive macrophages in the kidneys of Adcants-1 null mice compared to wild-type control animals. The expression of Adamts-1 mRNA was determined in metanephric kidney explants by in situ hybridization. Results. Adamts-1 null mice have a gross kidney defect. At day 18.5 of gestation, the Adcants-1 null kidney has a normal appearance but at birth when the kidney begins to function, the defect becomes evident. During development of the kidney Adamts-1 expression was specifically detected in the developing loops of Henle, as well as in the proximal and distal convoluted tubules. Expression was not detected in the ureter, ureteric bud or its derivatives as had been previously suggested. At 6 months and I year of age, the Adamts-1 null mice displayed interstitial fibrosis in the cortical and medullary regions of the kidney. At I year of age, the Adamts-1 null mice displayed mild interstitial matrix expansion associated with increased collagen type IV expression, without apparent tubular dilatation, compared to wild-type animals. Immunohistochemical analysis demonstrated TGF-beta protein localized to infiltrating macrophages and glomeruli of Adamts-1 null mice. Conclusions. Adamts-1 is required for the normal development of the kidney. The defect observed in its absence results from a dysgenic malformation affecting the medulla that becomes apparent at birth, once the kidneys start to function.