Cerebral Palsy

Mucopolysaccharidosis (MPS) type IIIC or Sanfilippo syndrome type C is a rare autosomal recessive disorder caused by the deficiency of the lysosomal membrane enzyme, heparan sulfate acetyl-CoA (AcCoA): alpha-glucosaminide N-acetyltransferase (HGSNAT; EC 2.3.1.78), which catalyzes transmembrane acetylation of the terminal glucosamine residues of heparan sulfate prior to their hydrolysis by alpha-N-acetylglucosaminidase. Lysosomal storage of undegraded heparan sulfate in the cells of affected patients leads to neuronal death, causing neurodegeneration and severely impaired development accompanied by mild visceral and skeletal abnormalities, including mild dwarfism, coarse facies, and joint stiffness. To date, 50 HGSNAT mutations have been identified in MPS IIIC patients: 40 were previously published and 10 novel mutations are reported here. The mutations span the entire structure of the gene and include 13 splice-site mutations, 11 insertions and deletions, 8 nonsense mutations, and 18 missense mutations (http://chromium.liacs.nl/LOVD2/home.php?select_db=HGSNAT). In addition, four polymorphisms result in amino acid changes that do not affect activity of the enzyme. In this work we discuss the spectrum of MPS IIIC mutations, their clinical presentation and distribution within the patient population, and speculate how the mutations may affect the structure and function of HGSNAT. Hum Mutat 30, 918-925, 2009. (c) 2009 Wiley-Liss, Inc.

BACKGROUND: Following the investigation of a birth defects cluster involving migrant farmworkers employed in North Carolina and Florida, it became clear that greater efforts were needed to protect agricultural workers from pesticide exposure. METHODS: Documentation is drawn from peer-reviewed published articles, government reports and news accounts. RESULTS: The birth defects cluster was identified and investigated by state and federal pesticide poisoning surveillance system staff. Following the investigation, efforts were initiated to highlight pesticides as an important public health issue needing more attention. A series of subsequent events led to the creation and passage of important legislation recently enacted in North Carolina. The legislation resulted in funding to promote various activities to prevent harm from pesticides including strengthening surveillance, improving the quality of pesticide compliance inspections, and increasing and improving pesticide safety training. The legislation also broadened the coverage of anti-retaliation rules to include agricultural workers, and increased recordkeeping requirements pertaining to pesticide applications. CONCLUSION: The important and positive impacts that can occur through surveillance activities are highlighted. As such, it is important to continue to support and improve occupational illness and injury surveillance programs. Am. J. Ind. Med. 2009. Published 2009 Wiley-Liss, Inc.

OBJECTIVE: While estrogen treatment exacerbates disease in models of systemic lupus erythematosus (SLE), the effects of progesterone are unclear. This study was undertaken to assess the effects of continuous progesterone treatment on autoantibody production and spontaneous glomerulonephritis (GN) in a mouse model of SLE. METHODS: Female (NZB x NZW)F(1) (NZB/NZW) mice were treated with vehicle, 2 mg of depot medroxyprogesterone acetate (DMPA), or 10 mg of DMPA every 6 weeks. Survival, proteinuria, and serum anti-double-stranded DNA (anti-dsDNA) levels were monitored. At 39 weeks of age, kidneys were analyzed for abnormalities and glomerular accumulation of IgG subclasses and C3. Spleen leukocyte subsets were also analyzed. RESULTS: DMPA treatment reduced mortality in a dose-dependent manner in association with reduced proteinuria and glomerular damage. High-dose DMPA treatment resulted in a reduction of total serum IgG and IgG2a anti-dsDNA antibody levels, whereas IgG1 anti-dsDNA antibody levels were modestly increased. High-dose DMPA reduced glomerular accumulation of IgG1, IgG2a, IgG3, and complement, while low-dose DMPA decreased glomerular IgG2a and IgG3 levels compared with vehicle treatment. CONCLUSION: Our findings indicate that treatment of premorbid female NZB/NZW mice with DMPA reduces mortality and attenuates spontaneous GN, likely through multiple mechanisms, including altered ratios of protective Th2-related IgG antibodies versus nephritogenic Th1-related IgG autoantibodies. Thus, estrogen and progesterone may have disparate effects on lupus autoimmunity, lending new significance to observed hormonal imbalances in patients with SLE. These data also suggest that treatment of SLE patients with DMPA may have therapeutic benefit.

OBJECTIVE: To determine the cytotoxicity of natural killer (NK) cells and the level of differentiation of hematopoietic stem cells (HSCs) into NK cells in systemic lupus erythematosus (SLE). METHODS: Patients with SLE (n = 108), rheumatoid arthritis (RA; n = 90), Behçet’s disease (n = 39), or ankylosing spondylitis (n = 41) and healthy control subjects (n = 173) were enrolled in the study. NK cell levels, NK cell cytotoxicities, and lymphokine-activated killer (LAK) activities against K562 cells were measured by flow cytometry. Gene expression was assessed by reverse transcription-polymerase chain reaction. NK cells were differentiated from peripheral blood and bone marrow HSCs in vitro. RESULTS: Percentages and absolute numbers of NK cells, cytotoxicities, and LAK activities were significantly lower in the peripheral blood of SLE and RA patients than in that of healthy controls. In particular, this NK cell deficiency was more prominent in patients with lupus nephritis and those with thrombocytopenia. Notably, purified NK cells derived from SLE patients, but not RA patients, were found to have lower cytotoxicities and LAK activities than those from healthy controls. This defect of NK cells in SLE patients was found to be related to lower numbers of NK precursors and to the down-regulation of perforin and granzyme in NK cells. The proliferative capacity of HSCs, the percentages of NK cells differentiated from HSCs, and NK cell cytotoxicities were significantly lower in SLE patients. CONCLUSION: In SLE patients, circulating levels of NK cells were diminished and their cytotoxicities were impaired. Furthermore, the differentiation of HSCs into NK cells was found to be defective. These abnormalities possibly contribute to immune system dysregulation in SLE.

OBJECTIVES: To evaluate the potential value of early fetal echocardiography (EFE) by means of four-dimensional (4D) spatiotemporal image correlation (STIC) technology for either reassurance of normality or prenatal diagnosis of major congenital heart defects (CHDs). METHODS: Sixty-nine pregnant women from 11 to 15 weeks' gestation underwent EFE. 4D-STIC volumes were acquired by the transvaginal approach for later review by two different examiners. STIC evaluation was considered complete when the four-chamber view, and the origin and double-crossing of the great arteries were identified correctly. Color Doppler imaging was used to detect either septal shunts or transvalvular regurgitation/aliasing suggesting abnormalities. STIC diagnoses were compared with those of conventional EFE. Reliability was assessed by postnatal examination, or autopsy in cases of termination of pregnancy or perinatal death. RESULTS: The median gestational age at volume acquisition was 13 + 3 weeks. Eleven (15.9%) cases of CHD were diagnosed. A complete EFE was possible in 64 cases. We were able to provide reassurance of normality in 51 of the 53 confirmed normal hearts, with no false-positive results for major defects, although two minor defects (one ventricular septal defect (VSD) and one persistent left superior vena cava) were falsely suspected. The only false negative was a significant VSD at birth overlooked by both observers. Therefore, the total accuracy of STIC-EFE was 95.3% (61/64), with sensitivity, specificity, and positive and negative predictive values of 90.9%, 96.2%, 83.3% and 98.1%. The accuracy of conventional EFE (98.4%, 63/64) was slightly better than that of STIC, with no false-positive results recorded. CONCLUSIONS: Offline evaluation of 4D-STIC acquired volumes of the fetal heart in the first and early second trimester of pregnancy is reliable not only for early reassurance of normal cardiac anatomy but also to diagnose most major structural heart defects. Copyright (c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.

BACKGROUND: This laboratory has been investigating the utility of X-ray micro-computed tomography (micro-CT) to produce high-resolution, 3D images of skeletal structures in common laboratory species. The present investigation uses micro-CT evaluation of skeletons from rabbit fetuses exposed to the known teratogen, hydroxyurea. METHODS: Groups of 4-6 mated Dutch Belted female rabbits each were administered vehicle or hydroxyurea (62.5 to 500 mg/kg) once on GD 12. On GD 28, all live fetuses were weighed, euthanized, and viscera removed. Up to 7 fetuses per litter were placed into a custom-made polystyrene holder and scanned in the micro-CT imaging system. Raw projection data were acquired in approximately 15 seconds, and reconstructed images at 100-micron cubic voxel dimension could be viewed as early as 20 minutes later. Fetuses were subsequently stained with alizarin red, and findings recorded separately for each method without knowledge of treatment group. RESULTS: Except for a few isolated cases, micro-CT evaluation detected the same skeletal malformations, variations, and incomplete ossifications as seen by the staining method. Skeletal elements that are very small (e.g., caudal-most vertebrae, metacarpal no. 1) or those with a minimal degree of ossification were occasionally not observed with micro-CT. However, this difference did not impact the overall study conclusions. Femur length was easily measured by micro-CT. CONCLUSIONS: These results indicate that micro-CT imaging can effectively assess rabbit fetal skeletal structures, and for those laboratories with this resource, may be used to significantly reduce time prior to skeletal evaluation and hazardous wastes associated with staining. Birth Defects Res (Part B), 2009. (c) 2009 Wiley-Liss, Inc.

BACKGROUND: Assessment of developmental toxicity has historically included assessment of fetal skeletal morphology after alizarin red staining. X-ray micro-computed tomography (micro-CT) produces high-resolution images of skeletal structures and was investigated as an alternative method. METHODS: Groups of 5 mated Crl:CD (SD) female rats each were administered vehicle or boric acid (40 to 500 mg/kg/day) from GD 6 through 11. On GD 21, all live fetuses were weighed, euthanized, and viscera removed. Each litter was placed into a custom-made polystyrene holder and scanned in the micro-CT imaging system. Raw projection data were acquired in approximately 15 sec ( approximately 20 litters per hour) and reconstructed images at 100-micron cubic voxel dimension could be viewed as early as 20 min later. Fetuses were subsequently stained with alizarin red, and findings recorded separately for each method without knowledge of treatment group. RESULTS: Micro-CT evaluation of fetal rat skeletons detected essentially the same skeletal malformations, variations, and incomplete ossifications as seen by the staining method. The specific skeletal abnormalities that did not match exactly involved the smallest skeletal elements with minimal degrees of ossification (i.e., cervical ribs, hypoplastic 13(th) ribs, supernumerary ribs, the 5(th) sternebra, and numbers of caudal vertebrae), but the differences did not impact the overall conclusions. Additional measures such as femur length were easily measured by micro-CT. CONCLUSIONS: These results indicate that micro-CT imaging can effectively assess rat fetal skeletal structures, and for those laboratories with this resource, it may be used to significantly reduce time prior to skeletal evaluation and hazardous wastes associated with staining. Birth Defects Res (Part B), 2009. (c) 2009 Wiley-Liss, Inc.

During verbal-fluency tasks, impairments in performance and functional abnormalities in the inferior frontal cortex have been observed in both schizophrenia patients and their unaffected relatives. We sought to examine whether such functional abnormalities are a specific marker of genetic vulnerability to schizophrenia. We studied a sample of 132 subjects, comprising 39 patients with schizophrenia, 10 unaffected monozygotic (MZ) cotwins of schizophrenia probands, 28 patients with bipolar disorder, 7 unaffected MZ cotwins of bipolar disorder probands and 48 healthy controls. Blood oxygen level-dependent response was measured using functional magnetic resonance imaging during the performance of an overt verbal-fluency task with two levels of task difficulty, in a cytoarchitectonic region of interest encompassing Brodmann areas 44 and 45 bilaterally. Patients with schizophrenia and the unaffected MZ cotwins of schizophrenia probands showed increased activation in the inferior frontal cortex relative to healthy controls and bipolar patients. Increased engagement of the inferior frontal cortex during verbal-fluency may thus be a marker of genetic vulnerability to schizophrenia. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc.

Objective. Hypothesising that metabolic syndrome may be associated with or useful in the prediction of pre-eclampsia, we investigated the association between all components of metabolic syndrome and C-reactive protein (CRP) in women with and without pre-eclampsia. Methods. A case-control study was performed. Cases had gestational hypertension or pre-eclampsia and controls were term deliveries. Clinical data and maternal serum was collected. The presence of metabolic syndrome (3/5 variables present) and a metabolic score (continuous 0-5) were investigated. Significant associations were evaluated using t-tests, and Pearson chi-square tests of association. Multivariable logistic regression was used to control for confounders. Results. One-hundred and one cases and 267 controls were evaluated. We observed a higher odds of pre-eclampsia when metabolic syndrome was present (AOR = 2.71 [1.1-6.67], p = 0.03). For every one-unit increase in metabolic score, there was a 39% increased odds of pre-eclampsia (AOR = 1.39 [1.06-1.82], p = 0.017). The odds of pre-eclampsia were nearly four times higher when hs- CRP was >8 (AOR = 3.61 [2.14-6.12], p < 0.001). Conclusions. Metabolic syndrome and hs-CRP are associated with pre-eclampsia. Investigation is crucial to determine if these abnormal lipid and inflammatory pathways observed in women with pre-eclampsia are present pre-pregnancy or develop as a result of the disease process of pre-eclampsia. Further investigation is also warranted to determine whether these abnormalities persist post-pregnancy and if so, their contribution to long-term cardiovascular disease.

Aims. To assess the association of electrocardiographic repolarization and depolarization patterns to vulnerability to ventricular tachyarrhythmias. Methods. In the present case-control study, a 12-lead ECG, signal-averaged ECG (SAECG), T-wave and QRS morphology, and T-wave alternans (TWA) were analyzed in post-MI patients with and without documented sustained ventricular tachycardia (VT) or fibrillation (VF) (VT/VF group, n = 40, Non-VT/VF group, n = 37, respectively) and healthy subjects (n = 41). Results. The QRS complex duration, measured from standard ECG (128+/-32 ms vs. 102+/-21 ms, p < 0.001) or SAECG (125+/-25 ms vs. 99+/-20 ms, p < 0.001), was significantly longer in the VT/VF than Non-VT/VF group. Several T-wave morphology variables, e.g., the total cosine of the angle between the main vectors of T-wave and QRS loops (TCRT), were different in the VT/VF (-0.13+/-0.58) and Non-VT/VF group (-0.11+/-0.48) compared to the healthy controls (0.47+/-0.50, p < 0.001). However, there were no significant differences in any of the T-wave morphology variables including TWA between the two post-MI groups. Conclusion. Abnormalities in ventricular depolarization are more common among post-MI patients with prior VT/VF than in those without documented ventricular tachyarrhythmias. Abnormal T-wave morphology and TWA seem to reflect the heart disease rather than specifically vulnerability to VT/VF.