Cerebral Palsy

Numerous studies of the effects of estrogens for stroke prevention have yielded conflicting results in human and animal studies alike. We present a systematical analysis of study design and methodological differences between 66 studies where estrogens' impact on ischemic brain damage in rat models has been investigated, providing evidence that the differences in results may be explained by high estrogen doses produced by slow-release pellets. These pellets have been used in all studies showing increased neurologic damage because of estrogens. Our data indicate that the increased neurologic damage is related to the pellets' plasma concentration profile with an early, prolonged, supraphysiological peak. Neither the method of inducing the ischemic brain lesions, the choice of variables for measuring outcome, the measured plasma concentrations of estrogens at the time of ischemia nor rat population attributes (sex, strain, age, and diseases) are factors contributing to the discrepancies in results. This suggests that the effects of estrogens for stroke prevention are concentration related with a complex dose-response curve, and underscores the importance of carefully validating the experimental methods used. Future studies of hormone-replacement therapy in women may have to take dosage and administration regimens into account.Journal of Cerebral Blood Flow & Metabolism advance online publication, 20 May 2009; doi:10.1038/jcbfm.2009.66.

BACKGROUND: Cortical remapping after peripheral or central visual deafferentation alters visual perception, but it is unclear whether such a phenomenon impinges on areas remote from a scotoma. To investigate this question, we studied variations of perceptual spatial distortion in the visual field of patients with homonymous paracentral scotoma. METHODS: Two patients with right inferior homonymous paracentral scotoma were asked to describe their perception of a series of figures showing two isometric vertical lines symmetrically located on either side of a fixation point. In each figure, the fixation point varied by steps of 2 degrees along a hypothetical vertical line equidistant between the test lines. The lines subtended 20 degrees of visual angle, and the right line passed through the scotoma in both cases. Time for spatial distortion to manifest was recorded. RESULTS: Both subjects reported that the right line was perceived as shorter than the left one. The line shortening varied in magnitude with the distance of the fixation point from the end of the line and was more pronounced when the distance increased. Moreover, perceptual line shortening appeared 5-10 seconds after steady fixation, but values of shortening varied during the following 10 seconds. In addition, the right line appeared uninterrupted or slightly blurred in the scotoma region. CONCLUSIONS: These observations reflect long-range cortical reorganization after brain damage. Larger receptive fields in the periphery of the visual map could explain why perceptual shortening is more pronounced with increased eccentricity.

Premature infants now have an improved chance of survival, but the impact of respiratory therapies on the brain, particularly the cerebellum, remains unclear. We examined the effects of early nasal continuous positive airway pressure (EnCPAP) ventilation and delayed (Dn) CPAP on the development of the cerebellum in prematurely delivered baboons. The baboons were delivered at 125 +/- 2days of gestation and ventilated for 28 days with either EnCPAP commencing at 24 hours (n = 5) or DnCPAP commencing at 5 days (n = 5). Gestational controls (n = 4) were delivered at 153 days. Cerebella were assessed histologically, and an ontogeny study (90 days to term) was performed to establish values for key cerebellar developmental indicators. Cerebellar weight was reduced in DnCPAP but not EnCPAP animals versus controls; cerebellar/total brain weight ratio was increased in EnCPAP (p < 0.05) versus control and DnCPAP animals. There was no overt damage in the cerebella of any animals, but a microstructural alteration index based on morphological developmental parameters and microglial immunoreactivity was increased in both prematurely delivered cohorts versus controls (p < 0.001) and was higher in DnCPAP than EnCPAP animals (p < 0.05). These results indicate that respiratory regimens can influence cerebellar development and that early compared with delayed extubation to nCPAP seems to be beneficial.

Escherichia coli is the major Gram-negative bacterial pathogen in neonatal meningitis. Outer membrane protein A (OmpA) is a conserved major protein in the E. coli outer membrane and is involved in several host-cell interactions. To characterize the role of OmpA in the invasion of astrocytes by E. coli, we investigated OmpA-positive and OmpA-negative E. coli strains. Outer membrane protein A E44, E105, and E109 strains adhered to and invaded C6 glioma cells 10- to 15-fold more efficiently than OmpA-negative strains. Actin rearrangement, protein tyrosine kinase, and phosphoinositide 3-kinase activation were required for OmpA-mediated invasion by E. coli. In vitro infection of C6 cells and intracerebral injection into mice of the E44 strain induced expression of the astrocyte differentiation marker glial fibrillary acidic protein and the inflammatory mediators cyclooxygenase 2 and nitric oxide synthase 2. After intracerebral infection with E44, all C57BL/6 mice died within 36hours, whereas 80% of mice injected with E44 premixed with recombinant OmpA protein survived. Astrocyte activation and neutrophil infiltration were reduced in brain tissue sections in the mice given OmpA. Taken together, these data suggest that OmpA-mediated invasion plays an important role in the early stage of E.coli-induced brain damage, and that it may have therapeutic use in E. coli meningitis.

Myocardial clefts are congenital abnormalities related to myocardial fiber or fascicle disarray that have been described in healthy volunteers as well as in the setting of hypertrophic cardiomyopathy. A cleft or crypt can be described as a discrete, approximately “V” shaped fissure extending into but confined by the myocardium, with a tendency to narrow or occlude in systole without local hypokinesia or dyskinesia. While little is known about the clinical significance of this entity, this report elaborates on the confounding terminology and differential diagnosis of this condition. Copyright (c) 2009 Wiley Periodicals, Inc.

OBJECTIVE: The aims of this study were to determine how frequently orofacial clefts were diagnosed prenatally and to investigate factors associated with prenatal diagnosis. METHODS: We included 2298 mothers from the National Birth Defects Prevention Study, each of whom gave birth to a child with an orofacial cleft, and assessed associated factors using logistic regression. RESULTS: The frequencies of prenatal diagnosis for cleft lip and palate, cleft lip only, and cleft palate only were 33.3%, 20.3%, and 0.3%, respectively. Among cases with cleft lip with or without cleft palate, cleft type, geographic location, maternal body mass index, household income, year of infant's birth, and presence of multiple birth defects were significantly associated with receiving a prenatal diagnosis. CONCLUSION: In the majority of infants with orofacial clefts, a prenatal diagnosis was not made. Receiving a prenatal diagnosis was significantly associated with several infant and maternal characteristics. Copyright (c) 2009 John Wiley & Sons, Ltd.

In developmental and reproductive toxicity studies, drinking water is a common means of delivering the test agent. Reduced consumption of toxicant-containing water raises questions about indirect effects of reduced maternal fluid consumption resulting from unpalatability, versus direct effects of the test compound. Issues to consider include: objective assessment of dehydration and thirst, the relative contributions of innate and learned behaviors to drinking behavior and flavor preference, and the objective assessment of physiologic stress. Not only do lab animals under ad lib conditions consume more water than the minimum required to maintain fluid balance, animals faced with water restriction have substantial physiologic capacity for protection of metabolic processes. Measures of blood biochemistry can provide quantifiable, objective indications of fluid balance, but changes in these parameters could result from other causes such as effects of a test toxicant. Consummatory behaviors in response to perceived need are highly influenced by learning. Hence, the drinking behavior, water intake, and flavor acceptance/preference of animals used in toxicology experiments could be subject to learning experiences with the test compound. Physiological symptoms of stress produced by water deprivation may be distinguishable from the symptoms associated with other generalized stressors, such as food deprivation, but doing so may be beyond the scope of most developmental or reproductive toxicity studies. Use of concurrent controls, paired to test groups for water consumption, could help distinguish between the direct effects of a test toxicant as opposed to effects of reduced water consumption alone. Birth Defects Res (Part B), 2009. (c)2009 Wiley-Liss, Inc.

Magnetic resonance imaging (MRI) to date remains the only imaging modality allowing direct visualization of the bone marrow compartment, in general having high sensitivity for bone marrow abnormalities. However, signal intensity changes in many different diseases presented with diffuse bone marrow infiltration show more overlap than difference, resulting in poor specificity. Therefore, MRI cannot be applied for initial diagnostic purposes in most diseases but should be reserved for staging, monitoring of therapy, and detection of disease recurrence after treatment. Diffuse infiltrative disease occurring at the hematopoietically active bone marrow, the vertebrae, pelvis, and femora should be areas included in imaging studies at a minimum if whole-body imaging cannot be applied. In this article, in-depth information is provided on selected topics, including Gaucher’s disease, Hodgkin’s disease and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and changes in bone marrow after different medication strategies, with overviews of the field provided by multiple recent papers in the literature.

Rituximab is a chimeric anti-CD20 monoclonal antibody widely used in the treatment of B-cell non-Hodgkin lymphomas (NHL). Most adverse effects are due to infusion-related reactions, and severe respiratory complications are rare. We retrospectively reviewed clinical data and serial imaging studies of five patients with NHL treated with rituximab-containing chemotherapy who developed new pulmonary abnormalities on routine follow-up FDG-PET/CT imaging. None of the patients had pulmonary lymphoma or other pulmonary disease before therapy and all remained asymptomatic during follow-up. New pulmonary interstitial FDG-uptake was detected on follow-up FDG-PET/CT between 1 and 3 months post-treatment, preceded computed tomography abnormalities in one case, and persisted for several months. FDG uptake was linear, subpleural with maximum Standardized uptake value (SUV) from 2.0 to 5.84. Rituximab-containing chemotherapy for NHL may be associated with asymptomatic late pulmonary toxicity characterised by a distinct FDG uptake pattern. Awareness of this finding is important and should not be confused with lymphoma.

The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD-95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD-95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage-dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease.