Cerebral Palsy

BACKGROUND:: Untreated, more than 95% of female SWR x NZB: F(1) (SNF(1)) mice spontaneously develop a fatal lupus-like glomerulonephritis by 8 months-of-age, while disease onset in males is much slower. METHODS:: Timed-pregnant SNF(1) mice (10 per treatment) were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestational day (GD) 12 by oral maternal gavage with 0, 40, or 80 mug/kg TCDD. RESULTS:: Offspring of the TCDD-exposed dams showed numerous alterations in T lineage cells at 24 weeks-of-age. Females but not males showed decreased CD4(+)8(+) and increased CD4(-)8(-) thymocytes. Females also showed increased autoreactive CD4(+)Vbeta17(a+) axillary and inguinal lymph node T cells. Concanavalin A-stimulated splenocytes from prenatal TCDD-treated mice produced decreased interleukin 17 (IL-17) in the females while males showed increased IL-2 and IFN-gamma, and diminished IL-4. Mitogen-stimulated pan-lymphoproliferative responses were significantly increased across sex by TCDD. Anti-IgG and anti-C3 immune complex deposition in kidneys was present in the males after TCDD, and visibly worsened in females. CONCLUSIONS:: Developmental TCDD exposure can permanently alter T lymphopoiesis in autoimmune-prone SNF1 mice. The alteration profile is beyond the classic immune suppression response, to also include exacerbation and induction of a lupuslike autoimmune disease. Birth Defects Research (Part A) 2009. (c) 2009 Wiley-Liss, Inc.

Congenital anomalies do not occur in all babies born after a teratogenic exposure. Whether a given exposure is teratogenic depends on the chemical nature and physical properties of the agent, the dose and route of exposure, when in pregnancy the exposure occurs, and genetic and other factors that affect susceptibility. Teratogenic birth defects are inherently multifactorial. Absolute risk, relative risk, and population attributable risk provide useful but different information regarding teratogenic effects. Statistical significance and clinical significance also are important considerations, but they may not be concordant. Demonstrating a teratogenic effect is easier if it is sought in a subgroup of patients in whom the effect is likely to be particularly prominent. The ability to detect a significant risk is, therefore, generally increased by subgroup analysis of epidemiology studies, but the greater the number of analyses performed, the higher the probability of finding associations that reach nominal statistical significance by chance alone. This problem is well recognized, but it is difficult to solve. The only compelling evidence for the reality of an association between maternal exposure to an agent during pregnancy and teratogenic effects in the children is replication of the findings in independent studies, but this is hard to obtain. As a consequence, there are very few exposures for which the available information is sufficient to make evidence-based recommendations regarding the clinical management of teratogenic risks. It is important to admit these limitations and to learn more about exposures that cause birth defects and how to prevent them. Birth Defects Research (Part A) 2009. (c) 2009 Wiley-Liss, Inc.

Routine anatomic ultrasound performed in the second trimester has a detection rate of approximately 70-90% for fetal congenital abnormalities (Nyberg and Souter, J Ultrasound Med 2001;6:655-674). The central nervous system abnormalities are one of the most common ones detected. Chiari malformation is among the CNS abnormalities diagnosed in the fetal period (Bianchi et al., Fetology – diagnosis and management of the fetal patient, McGraw-Hill, 2000). The Arnold-Chiari malformation was first described in 1883 by Cleland (Romero et al., Prenatal diagnosis of congenital anomalies, Appleton and Lange, 1988). It is characterised by the prolapse of the hindbrain structures below the level of the foramen magnum. It can be associated with skeletal abnormalities and neurological dysfunction. In type I, a lip of cerebellum is downwardly displaced with the tonsils, but the fourth ventricle remains in the posterior fossa. This condition may coexist with syringomyelia, which is a cyst formation on the cervical portion of the spinal cord (Creasy et al., Maternal fetal medicine principles and practice, 2004). We present a case where Chiari type 1 and syringomyelia detected at 18 weeks of gestation. The reason for referral to our center was an abnormal inward posturing of both upper and lower extremities (minimal gross movement and almost inexistent range of motion on fetal joints). On further fetal evaluation, an abnormal brain ultrasound was identified. Prenatal diagnosis of Chiari type 1 malformation and syringomyelia is almost nonexistent when reviewing the literature is the reason why this case is presented.

Oxidative stress and TGFbeta-induced disturbance of cells and tissues are implicated in initiation and progression of pathophysiology of cells/tissues. Using primary human Trabecular Meshwork (TM) cells from normal and glaucomatous subjects, this study demonstrated that peroxiredoxin (PRDX) 6, an antioxidant, offsets the deleterious effects of oxidative stress on TM cells by optimizing ROS and TGFbeta levels. An analysis of glaucomatous TM cells revealed a reduced expression of PRDX6 mRNA and protein. Biochemical assays disclosed enhanced levels of ROS, as well as high levels of TGFbetas and these cells expressed elevated extracellular matrix (ECM) and Tsp1 proteins with reduced MMP2; conditions implicated in the pathophysiology of glaucoma. Non-glaucomatous TM cells exposed to TGFbetas/ROS showed similar features as in glaucomatous cells. The abnormalities induced were reversed by delivery of PRDX6. The data provide evidence that oxidative stress-induced abnormality in TM may be related to reduced PRDX6 expression and provide a foundation for antioxidant-based therapeutics for treating glaucoma.

RATIONALE: The antipsychotic drug, olanzapine, often induces weight gain and glucose metabolism disturbances, which may result from feeding pattern abnormalities. OBJECTIVES: The objectives of the study were to examine the effects of a chronic olanzapine treatment on feeding patterns in the rat and to investigate a potential time-related association between feeding patterns and the appearance of glucose metabolism abnormalities and adiposity. METHODS: Male rats were treated with olanzapine (2 mg/kg/day), haloperidol (1 mg/kg/day) or a control solution (drugs mixed with the food). In experiment 1, treatments lasted 26 days and feeding patterns were measured on day 21. In experiment 2, treatments lasted for 46 days, and an oral glucose tolerance test (OGTT) was realised on day 31. At the end of both experiments, plasma parameters and body composition were analysed. RESULTS: In experiment 1, olanzapine-treated animals showed increased meal number, decreased ingestion rate, meal size and inter-meal interval, and no change in total food intake. Plasma glucose, OGTT and body composition were not altered. In experiment 2, after 31 days of treatment, fasting blood glucose was increased and OGTT indicated an insulin resistance. After 46 days of treatment, hyperglycaemia was aggravated (compared to 31 days), and adiposity was increased in olanzapine-treated animals. In both experiments, the haloperidol-treated rats did not differ from the control ones. CONCLUSION: Chronic olanzapine treatment produces changes in feeding patterns, in a way consistent with an increased incentive drive to eat. As a whole, the results raise the hypothesis that long-term alteration of feeding pattern by olanzapine may predispose to disturbances in the regulation of energy metabolism.

BACKGROUND: We evaluated the relationship between computed tomography angiography (CTA) and SPECT, and assessed to determine the clinical usefulness of the fusion image using CTA and myocardial perfusion imaging (MPI). METHODS: Forty-one consecutive patients [after coronary artery bypass operation (n = 13) and suspected stenosis (n = 28)] underwent MPI and CTA. SPECT/CTA fused images were generated. RESULTS: In total, 687 segments including bypass graft in 164 coronary arteries were analyzed. Myocardial ischemia on MPI was observed in 11 patients among 28 with CTA abnormalities, one had both ischemia and infarction, and 7 had only infarction. Segment-based analysis showed that ischemia was found in 14 segments (24%) among 59 stenoses on CTA. Forty stenotic segments (69%) were not associated with perfusion abnormality. The rest 5 stenotic segments were considered equivocal (8%). A fusion image made it possible to associate perfusion defects with its corresponding coronary artery in 4 out of 5 equivocal lesions on side-by-side analysis. Patients with incremental diagnostic information on SPECT/CTA fusion (n = 4) had significant smaller coronary diameter than that of not-improved coronary vessels (2.0 +/- 0.4 vs. 3.9 +/- 0.4 mm, p = 0.001). CONCLUSION: Cardiac fusion imaging accurately diagnosed functionally relevant coronary stenosis. SPECT/CTA fusion images in coronary artery disease may provide added diagnostic information on functional relevance of coronary artery disease.

PURPOSE: Agents specifically targeting the vasculature as a mode of therapy are finding increasing use in the clinic, primarily in the treatment of colon cancer (Avastin) and age-related macular degeneration (Lucentis). We have previously shown that maternal administration of angiogenic inhibitors (TNP-470 [O-[chloroacetyl-carbamoyl]fumagillol, initially called AGM-1470], the first angiogenic inhibitor to undergo clinical trials, and Angiostatin(4.5), currently in phase I-III clinical trials) cause fetal growth restriction and/or placental abnormalities. During a rapid growth phase of ocular development in the mouse (embryonic days 12 to 19 [E12-E19]), the placenta mediates the metabolic requirements of the fetus and consequently may impact upon the growth of the highly oxygen sensitive fetal eye. METHODS: We injected pregnant dams (between E10.5 – E18.5) with anti-angiogenic agents, which caused either a placental insufficiency type of IUGR (intrauterine growth restriction; i.e., TNP-470) or frank placental pathology (Angiostatin(4.5) [AS(4.5)]), and assessed changes in absolute ocular dimensions, tissue types, and vascular profiles using stereological techniques. RESULTS: The experiments showed that ocular volumes were significantly reduced in fetal mice where dams were treated with either TNP-470 or AS(4.5). Furthermore, TNP-470 specifically caused a reduction in hyaloid blood vessel length and volume, the only intraocular vascular circulation in fetal mice. CONCLUSIONS: These experiments support the hypothesis that the angiogenic inhibitors (specifically TNP-470 and AS(4.5)) induce microphthalmia either indirectly by their known effects on placental morphology (and/or function) or directly via altering microvascular growth in the fetus. These results also warrant further investigation of a new experimental paradigm linking placental pathology-related fetal growth restriction and microphthalmia.

Active compounds in cannabis such as tetrahydrocannabinol (THC) interact with the inhibitory neurotransmitter delta-aminobutyric acid (GABA) but little is known about the functional effects of cannabis on human cortical brain processes. Therefore, the aim of the study was to investigate whether patients with chronic cannabis use demonstrate abnormalities in cortical inhibition or excitability. In all, 42 chronic cannabis using subjects (divided into heavy and light using subjects) and 19 controls were included in the study. Single and paired pulse transcranial magnetic stimulation were used to assess a number of parameters of cortical inhibition and cortical excitability. In addition, psychomotor function and THC plasma levels were measured. Both cannabis using groups (heavy and light use) demonstrated a reduction in short interval cortical inhibition compared with healthy controls, but there was no difference in other measures of cortical inhibition or cortical excitability. There was also no difference between the two groups on measures of psychomotor performance. Chronic cannabis use is associated with a reduction in cortical inhibition potentially related to activity at the GABA(A) receptors. Further research is required to explore whether this results from chronic cannabis use or reflects an underlying predisposition to developing chronic substance use problems.Neuropsychopharmacology advance online publication, 1 July 2009; doi:10.1038/npp.2009.71.

PURPOSE OF REVIEW: Diffusion tensor imaging (DTI) has a unique capability to delineate axonal tracts within the white matter, which has not been possible with previous noninvasive imaging techniques. In the past 10 years, we have witnessed a large increase in the use of DTI-based studies and a score of new anatomical knowledge and image analysis tools have been introduced in recent years. This review will provide an overview of the recent advancements in DTI-based studies and new image analysis tools. RECENT FINDINGS: DTI provided new dimensions for the characterization of white matter anatomy. This characterization of the white matter can be roughly divided into two categories. First, the white matter can be parcellated into constituent white matter tracts, based on pixel-by-pixel orientation and anisotropy information. Second, the DTI information can be extrapolated to obtain three-dimensional connectivity information. Based on these capabilities of DTI, many new image analysis tools are being developed to investigate the status of the white matter. SUMMARY: In the past, the white matter has often been treated as one compartment. With DTI and recently developed analysis tools, we can investigate the status of intra-white matter structures and deepen our understanding of white matter structures and their abnormalities under pathological conditions.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to be related to neuroprotection in cell culture and animal studies. Our aim was to verify the changes in human plasma BDNF and NGF concentrations induced by chronic alcohol use. Forty-one male patients with alcohol dependence were sampled the next morning of admission and compared with 41 healthy male subjects. Plasma BDNF and NGF were assayed using an enzyme-linked immunosorbent assay (ELISA). Mean plasma BDNF level was significantly higher in the patients with alcohol dependence (3502.21+/-1726.9 pg/mL) compared with the healthy subjects (861.75+/-478.9 pg/mL) (P=.000). Mean plasma NGF level was also significantly higher in patients with alcohol dependence (137.64+/-32.7 pg/mL) than in healthy subjects (112.61+/-90.2 pg/mL) (P=.012). Plasma BDNF and NGF levels showed significant negative correlation in alcohol dependence group (r=-0.388, P=.012). Increased plasma BDNF and NGF with negative correlation in alcohol-dependent patients may have some role in the regeneration of damage done by chronic alcohol use.