Cerebral Palsy

AIM: To investigate the transforming growth factor-? (TGF-?) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients.

METHODS: We examined TGF-?1, TGF-?2 and TGF-?3 (enzyme-linked immunosorbent assay), in 27 stage IV PBC patients (27 peripheral and 15 hepatic vein sera), 35 early (I-II) PBC and 60 healthy controls. As disease controls 28 hepatitis C virus (HCV) cirrhosis (28 peripheral and 17 hepatic vein serum), 44 chronic HCV hepatitis and 38 HCV-related hepatocellular carcinomas were included. We also tested liver tissue by immunohistochemistry to identify localization of TGF isoforms.

RESULTS: TGF-?1 was significantly decreased in all cirrhotics (PBC III-IV: median 13.4 ng/mL; range, 7.4-26.2, HCV cirrhosis: 11.6 ng/mL; range, 5.0-33.8), compared to controls (30.9 ng/mL; range, 20.9-37.8). TGF-?2 was increased in viral cirrhosis but not in PBC and chronic hepatitis. TGF-?3 (47.2 pg/mL; range, 27.0-79.7 in healthy controls) was increased in early and late PBC (I-II: 94.3 pg/mL; range, 41.5-358.6; III-IV: 152.8 pg/mL; range, 60.4-361.2; P < 0.001) and decreased in viral cirrhosis (37.4 pg/mL; range, 13.3-84.0; P < 0.05). Hepatic vein TGF-? levels were analogous to those in peripheral blood. Immunohistochemistry identified all isoforms in portal tract lymphocytes, sinusoidal cells and cholangiocytes. TGF-?3 was additionally overexpressed in hepatocytes in PBC patients.

CONCLUSION: The serum profile of TGF-? isoforms is different in cirrhotics. Increased TGF-?3 is characteristic of PBC. These findings may be related to the immunological abnormalities of PBC.

OBJECTIVE: Cortical malformations are important causes of neurological morbidity, but in many cases their etiology is poorly understood. Mice with Foxc1 mutations have cellular defects in meningeal development. We use hypomorphic and null alleles of Foxc1 to study the effect of meningeal defects on neocortical organization.

METHODS: Embryos with loss of Foxc1 activity were generated using the hypomorphic Foxc1(hith) allele and the null Foxc1(lacZ) allele. Immunohistologic analysis was used to assess cerebral basement membrane integrity, marginal zone heterotopia formation, neuronal overmigration, meningeal defects, and changes in basement membrane composition. Dysplasia severity was quantified using 2 measures.

RESULTS: Cortical dysplasia resembling cobblestone cortex, with basement membrane breakdown and lamination defects, is seen in Foxc1 mutants. As Foxc1 activity was reduced, abnormalities in basement membrane integrity, heterotopia formation, neuronal overmigration, and meningeal development appeared earlier in gestation and were more severe. Surprisingly, the basement membrane appeared intact at early stages of development in the face of severe deficits in meningeal development. Prominent defects in basement membrane integrity appeared as development proceeded. Molecular analysis of basement membrane laminin subunits demonstrated that loss of the meninges led to changes in basement membrane composition.

INTERPRETATION: Cortical dysplasia can be caused by cellular defects in the meninges. The meninges are not required for basement membrane establishment but are needed for remodeling as the brain expands. Specific changes in basement membrane composition may contribute to subsequent breakdown. Our study raises the possibility that primary meningeal defects may cortical dysplasia in some cases. Ann Neurol 2010;68:454-464.

The aim of this study was to test the hypothesis that patients with REM sleep behavior disorder, many of whom will develop Parkinson’s disease (PD) or a related synucleinopathy, will demonstrate decreased heart rate variability (HRV) compared with a group of age-matched controls as measured by an electrocardiogram during wakefulness. We compared HRV in 11 untreated idiopathic REM sleep behavior disorder patients (9 men and 2 women; mean age, 63.3 years; SD, 7.5 years) and 11 control subjects with idiopathic insomnia without REM sleep behavior disorder (7 men and 4 women; mean age, 59.5 years; SD, 8.7 years). Subjects with other causes of reduced HRV were excluded. HRV was determined from 5-minute presleep segments of a single channel electrocardiogram recorded during polysomnographic evaluations, using R-R intervals during wakefulness. Time domain, geometric measures, and spectral analysis of the R-R intervals were significantly different between cases and controls. A discriminant function analysis correctly classified 95.5% of subjects (overall model fit, P = 0.016). Leave-one-out cross-validation correctly classified 77.3% of subjects. HRV during wakefulness is significantly decreased in patients with idiopathic REM sleep behavior disorder compared with control subjects, suggesting abnormalities of both sympathetic and parasympathetic function. Patients with RBD may later develop motor and cognitive features of a Lewy body disorder, such as PD. Cardiac autonomic dysfunction is also impaired in PD, suggesting that impaired HRV may be an early sign of PD. HRV measured by routine electrocardiograms could be used to screen for Lewy body disorders such as PD. © 2010 Movement Disorder Society.

The present study was the first report demonstrating that pulsed electromagnetic field (PEMF) could partially prevent bone strength and architecture deterioration and improve the impaired bone formation in streptozotocin-induced diabetic rats. The findings indicated that PEMF might become a potential additive method for inhibiting diabetic osteopenia or osteoporosis.

INTRODUCTION: Diabetes mellitus (DM) can cause various musculoskeletal abnormalities. Optimal therapeutic methods for diabetic bone complication are still lacking. It is essential to develop more effective and safe therapeutic methods for diabetic bone disorders. Pulsed electromagnetic field (PEMF) as an alternative noninvasive method has proven to be effective for treating fracture healing and osteoporosis in non-diabetic conditions. However, the issue about the therapeutic effects of PEMF on diabetic bone complication has not been previously investigated.

METHODS: We herein systematically evaluated the preventive effects of PEMF on diabetic bone loss in streptozotocin-treated rats. Two similar experiments were conducted. In each experiment, 16 diabetic and eight non-diabetic rats were equally assigned to the control, DM, and DM?+?PEMF group. DM?+?PEMF group was subjected to daily 8-h PEMF exposure for 8 weeks.

RESULTS: In experiment 1, three-point bending test suggested that PEMF improved the biomechanical quality of diabetic bone tissues, evidenced by increased maximum load, stiffness, and energy absorption. Microcomputed tomography analysis demonstrated that DM-induced bone architecture deterioration was partially reversed by PEMF, evidenced by increased Tb.N, Tb.Th, BV/TV, and Conn.D and reduced Tb.Sp and SMI. Serum OC analysis indicated that PEMF partially prevented DM-induced decrease in bone formation. In experiment 2, no significant difference in the bone resorption marker TRACP5b was observed. These biochemical findings were further supported by the dynamic bone histomorphometric parameters BFR/BS and Oc.N/BS.

CONCLUSIONS: The results demonstrated that PEMF could partially prevent DM-induced bone strength and architecture deterioration and improve the impaired bone formation. PEMF might become a potential additive method for inhibiting diabetic osteoporosis.

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1?) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1? mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1? and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild-type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.

BACKGROUND: Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). DGK? is widely distributed in the central nervous system, such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. Recent studies reported that the splice variant at the COOH-terminal of DGK? was related to bipolar disorder, but its detailed mechanism is still unknown.

METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we performed behavioral tests using DGK? knockout (KO) mice to investigate the effects of DGK? deficits on psychomotor behavior. DGK? KO mice exhibited some behavioral abnormalities, such as hyperactivity, reduced anxiety, and reduced depression. Additionally, hyperactivity and reduced anxiety were attenuated by the administration of the mood stabilizer, lithium, but not haloperidol, diazepam, or imipramine. Moreover, DGK? KO mice showed impairment in Akt-glycogen synthesis kinase (GSK) 3? signaling and cortical spine formation.

CONCLUSIONS/SIGNIFICANCE: These findings suggest that DGK? KO mice exhibit lithium-sensitive behavioral abnormalities that are, at least in part, due to the impairment of Akt-GSK3? signaling and cortical spine formation.

BACKGROUND: ADAM17/TACE activity is important during embryonic development. We wished to investigate possible roles of this metalloprotease, focusing on vascular development.

METHODOLOGY/PRINCIPAL FINDINGS: Mice mutant in the enzymatic activity of ADAM17 were examined at various stages of embryonic development for vascular pattern and integrity using markers for vessel wall cells. We observed hemorrhage and edema starting at embryonic day E14.5 and becoming more severe as development proceeded; prior to embryonic day E14.5, embryos appeared normal. Staining for PECAM-1/CD31 revealed abnormalities in the patterns of branching of the embryonic vasculature at E14.5.

CONCLUSIONS/SIGNIFICANCE: These abnormalities preceded association of pericytes or monocyte/macrophage cells with the affected vessels and, therefore, presumably arise from defects in endothelial function consequent upon failure of ADAM17 to cleave one or more substrates involved in vascular development, such as Notch, Delta, VEGFR2 or JAM-A. Our study demonstrates a role for ADAM17 in modulating embryonic vessel development and function.