Cerebral Palsy

Object Cerebral ischemia is the leading cause of preventable death in cases of major trauma with severe traumatic brain injury (TBI). Intracranial pressure (ICP) control and cerebral perfusion pressure (CPP) manipulation have significantly reduced the mortality but not the morbidity rate in these patients. In this study, the authors describe their 5-year experience with brain tissue oxygen (PbtO(2)) monitoring, and the effect of a brain tissue oxygen-directed critical care guide (PbtO(2)-CCG) on the 6-month clinical outcome (based on the 6-month Glasgow Outcome Scale score) in patients with TBIs. Methods One hundred thirty-nine patients admitted to Creighton University Medical Center with major traumatic injuries (Injury Severity Scale [ISS] scores >/= 16) and TBI underwent prospective evaluation. All patients were treated with a PbtO(2)-CCG to maintain a brain oxygen level > 20 mm Hg, and control ICP < 20 mm Hg. The role of demographic, clinical, and imaging parameters in the identification of patients at risk for cerebral hypooxygenation and the influence of hypooxygenation on clinical outcome were recorded. Outcomes were compared with those in a historical ICP/CPP patient cohort. Subgroup analysis of severe TBI was performed and compared to data reported in the Traumatic Coma Data Bank. Results The majority of injuries were sustained in motor vehicle crashes (63%), and diffuse brain injury was the most common abnormality (58%). Mechanism of injury, severity of TBI, pathological entity, neuroimaging results, and trauma indices were not predictive of ischemia. Factors affecting death included gunshot injury, poor trauma indices, subarachnoid hemorrhage, and coma. After standard resuscitation, 65% of patients had an initially low PbtO(2). Data are presented as means +/- SDs. Treatment with the PbtO(2)-CCG resulted in a 44% improvement in mean PbtO(2) (16.21 +/- 12.30 vs 23.65 +/- 14.40 mm Hg; p < 0.001), control of ICP (mean 12.76 +/- 6.42 mm Hg), and the maintenance of CPP (mean 76.13 +/- 15.37 mm Hg). Persistently low cerebral oxygenation was seen in 37% of patients at 2 hours, 31% at 24 hours, and 18% at 48 hours of treatment. Thus elevated ICP and a persistent low PbtO(2) after 2 hours represented increasing odds of death (OR 14.3 at 48 hours). Survivors and patients with good outcomes generally had significantly higher mean daily PbtO(2) and CPP values compared to nonsurvivors. Polytrauma, associated with higher ISS scores, presented an increased risk of vegetative outcome (OR 9.0). Compared to the ICP/CPP cohort, the mean Glasgow Outcome Scale score at 6 months in patients treated with PbtO(2)-CCG was higher (3.55 +/- 1.75 vs 2.71 +/- 1.65, p < 0.01; OR for good outcome 2.09, 95% CI 1.031-4.24) as was the reduction in mortality rate (25.9 vs 41.50%; relative risk reduction 37%), despite higher ISS scores in the PbtO(2) group (31.6 +/- 13.4 vs 27.1 +/- 8.9; p < 0.05). Subgroup analysis of severe closed TBI revealed a significant relative risk reduction in mortality rate of 37-51% compared with the Traumatic Coma Data Bank data, and an increased OR for good outcome especially in patients with diffuse brain injury without mass lesions (OR 4.9, 95% CI 2.9-8.4). Conclusions The prevention and aggressive treatment of cerebral hypooxygenation and control of ICP with a PbtO(2)-directed protocol reduced the mortality rate after TBI in major trauma, but more importantly, resulted in improved 6-month clinical outcomes over the standard ICP/CPP-directed therapy at the authors' institution.

Human leukocyte antigen (HLA) class I expression defects frequently occur in colorectal cancers bearing mismatch repair (MMR) deficiencies and are interpreted as immune evasion mechanisms to avoid cancer cell recognition and elimination by the immune system. MMR-deficient tumours are thought to be more prone to lose HLA class I expression, due to their frequent generation of aberrant peptides which can stimulate a cytotoxic T-cell-mediated response. MUTYH-associated polyposis (MAP) is a colorectal cancer syndrome caused by defects in the MUTYH DNA repair enzyme. Impairment of MUTYH activity could lead to a surplus of mutated peptides which would be presented to cytotoxic T-cells through the HLA class I molecules. We have studied the frequency of HLA class I expression defects in MAP carcinomas and have compared it to those observed in MMR-deficient and -proficient colorectal tumours. Immunohistochemical detection of the expression of HLA class I, beta2-microglobulin (beta2m), and antigen-processing machinery molecules was performed in 37 primary MAP carcinomas and nine metastases resected from 29 MAP patients. Furthermore, we sequenced the beta2m, TAP1, and TAP2 genes. Defects in HLA class I expression were detected in 65% of primary MAP carcinomas, affecting 72% of patients. HLA class I expression abnormalities were often concomitant with beta2m expression loss and mutations in the beta2m gene. Loss of HLA class I expression is thus a frequent event in MAP carcinomas, similarly to MMR-deficient colorectal tumours. The extensive mutagenic background of these tumours most likely triggers a strong selective pressure, exerted by the immune system on the tumour, which favours the outgrowth of tumour cell clones with an immune evasive phenotype. Our data provide additional evidence for a link between DNA repair deficiencies and altered HLA class I phenotypes in colorectal cancer. Copyright (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

This report discusses the principles of developmental and reproductive toxicity (DART) testing for biopharmaceuticals. Biopharmaceuticals are large-molecular-weight proteins or peptides produced by modern biotechnology techniques incorporating genetic engineering and hybridoma technologies. The principles of DART testing for biopharmaceuticals are similar to those for small-molecule pharmaceuticals and in general follow the regulatory guidance outlined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document S5(R2). However, because many biopharmaceuticals are species-specific, alternate approaches may be needed to evaluate DART potential as outlined in ICH S6. For molecules that show species-specific cross-reactivity restricted to non-human primates (NHP), some aspects of DART may require NHP testing. For biopharmaceuticals that are uniquely specific and only active on intended human targets or human and chimpanzee targets, surrogate molecules that cross-react with the more traditional rodent species may need to be developed and used for DART testing. Alternatively, genetically modified transgenic animals may also need to be considered. Surrogate molecules and transgenic animals may also be considered for DART testing even if the biopharmaceutical is active in NHPs in order to reduce the use of NHPs. Because of the unique properties of biopharmaceuticals, a case-by-case approach is needed for DART and general toxicity evaluation, which requires consideration of specific product attributes including biochemical and biophysical characteristics, pharmacological activity, and intended clinical indication. Birth Defects Res (Part B), 2009. (c) 2009 Wiley-Liss, Inc.

Mannosidosis is an extremely rare genetic disease occurring due to deficiency of the lysosomal enzyme, alpha-mannosidase. Patients with this disorder often suffer from musculoskeletal abnormalities and muscular weakness leading to joint destruction and severe morbidity along with other major systems involvement. We present here such a case of a 27-year-old male that highlights the challenges in management of hip joint destruction secondary to Mannosidosis.

Background. Cholesterol is an essential component of cell membrane constituting the neuronal cells and mediates multiple functions affecting neuronal transmission in the central nervous system. Abnormalities in serum lipid fractions have been reported in depression, but the clinical and biological significance of such findings are yet to be elucidated. Aims and objective. To study the abnormalities of lipid fractions in subjects with unipolar depression. Methodology. Thirty patients with unipolar depression and normal controls were recruited in this study. Serum total cholesterol, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, and triglycerides were studied. Data analysis was performed by using an analysis of covariance (ANCOVA) controlling for age, sex, body mass index, lifestyle, and dietary habits. Results. The data showed significant elevation of serum total cholesterol in depressed patients compared with normal controls. Identical results were obtained after controlling for the effects of confounders. Conclusion. Results of this study point to particular subgroup of subjects who have elevated cholesterol among the depressed cohort. This may have significant implications in risk assessment for cardiovascular disorders and planning preventive strategies.

Background aims Mesenchymal stromal cells (MSC) exhibit non-specific hematopoietic cell and/or stromal cell markers (e.g. CD73, CD105 and CD166) that have been used to identify MSC by flow cytometry. Because a neural glial antigen, NG2 (a progenitor cell marker in the central nervous system), is expressed by several tissue cells originating in the mesenchyme but not hematopoietic cells, it might be useful for isolating and identifying MSC. We investigated NG2 expression on culture-expanded MSC by flow cytometry. Methods Human bone marrow (BM) samples taken from 12 donors were cultured for MSC to be used in up to nine serial passages. Using flow cytometry, the neural glial antigen NG2 and commonly used MSC markers CD73, CD105 and CD166, were analyzed on the surface of culture-expanded MSC. The multipotential differentiation of the MSC was examined by adipogenic and osteogenic induction. Results The percentage of cells positive for NG2 was similar to the percentages of cells positive for CD73, CD105 and CD166 in all passages of BM samples. The mean fluorescent intensities of NG2 did not change with culture passage. The MSC was successfully differentiated into adipogenic and osteogenic lines. The cells showed no karyotypic abnormalities. Conclusions NG2 seems to be a promising marker for investigating the biology of MSC.

The aim of this study is to describe by video-nailfold capillaroscopy the microvascular involvement and capillary changes in children with Henoch-Schönlein purpura (HSp) and to establish a possible correlation with clinical outcome. Thirty-one patients underwent capillaroscopic evaluation through a videomicroscope during the acute phase and after 6 months. Twenty sex/age-matched controls were also examined. All capillaroscopic variables were statistically examined in combination with laboratoristic/clinical data. Architectural and morphological changes recorded during the acute phase were statistically significant in comparison to the controls (p < 0.01). At the follow-up, oedema was still observed in all patients, whereas, morphological changes only in two. There was a no significant correlation between capillaroscopy changes, laboratoristic/clinical data, and outcome. Video-nailfold capillaroscopy can be a simple tool to evaluate microvascular abnormalities in the acute phase of HSp, and the persistence of oedema could suggest an incomplete disease resolution at a microvascular level.

PurposeJoubert syndrome (JS) is an autosomal-recessive inherited complex malformation of the midbrain-hindbrain. It has been associated with ocular and oculomotor abnormalities. The aim of our study was to extend the ophthalmic knowledge in JS and to add new findings.MethodsIn a retrospective study, 10 consecutive patients, who met the revised diagnostic criteria of JS were included. Mutation analysis was carried out in all the cases. Each patient underwent a comprehensive neuro-ophthalmological examination.ResultsBilateral drusen of the optic disc were found in two patients. Four patients showed bilateral morphological and functional signs of retinal dystrophy (CEP290mutation in two cases and AHI1mutation in one case). In nine patients performance during smooth pursuit, saccades, and vestibulo-ocular reflex (VOR) cancellation was poor.ConclusionsTo the best of our knowledge, the association of optic disc drusen with JS has not yet been described. In support of the earlier findings, decreased smooth pursuit and VOR cancellation, as well as partial-to-complete oculomotor apraxia seem to be the key oculomotor features of JS. Genotype-phenotype correlations showed the predictive value of CEP290and AHI1mutations for retinal involvement.Eye advance online publication, 22 May 2009; doi:10.1038/eye.2009.116.

Objective:Although survivors of congenital diaphragmatic hernia (CDH) are at high risk for brain injury, little is known about their neurodevelopment. Studies exploring short-term outcomes in children who received extracorporeal membrane oxygenation (ECMO) therapy suggest an increased risk for abnormalities in tone and/or motor development. This study provides the first detailed examination of visual and fine-motor outcomes in adolescent survivors of high-risk CDH (manifesting within the first 24 h) who did not receive ECMO.Study Design:A total of 13 CDH survivors (mean age 12.9 years) and 11 typically developing controls, matched to the CDH sample in terms of age at test, intelligence quotient and socioeconomic status (SES), completed a battery of visual and motor tests.Results:CDH survivors performed normally on motor-free tests of visual-perceptual function and on tests requiring visual discrimination and scanning, but were impaired on tests requiring visual-motor integration and oral-motor programming.Conclusion:Survivors of high-risk CDH who did not receive ECMO treatment are at risk for long-term problems with oral motor and visuomotor control.Journal of Perinatology advance online publication, 21 May 2009; doi:10.1038/jp.2009.61.

PURPOSE OF REVIEW: Significant changes in concepts of managing Barrett’s esophagus have led to change in the recommendations concerning screening, surveillance, biomarkers, and therapies in this condition over the past several years. We summarize the important changes in this regard. RECENT FINDINGS: Narrow band imaging and esophageal capsule endoscopy are alternative methods to screen for Barrett’s esophagus. Narrow band imaging provides clear visualization of the mucosal pit patterns and vascular patterns, which improve the diagnostic value for specialized intestinal mataplasia. Esophageal capsule endoscopy is a new potential tool that allows a direct noninvasive visualization of esophagus. Research efforts are currently directed towards risk stratification of patients and biomarkers have been developed to predict development of esophageal adenocarcinoma. Recent studies have reported that frequent loss of heterozygosity (LOH) as well as allelic imbalances in chromosomes in esophageal adenocarcinoma. Fluorescent in-situ hybridization technique, which uses fluorescently labeled DNA probes to detect chromosomal alterations in cells, obtained from cytology specimens has been developed. It showed more sensitive and specific for abnormalities than PCR based techniques. Currently, many studies support the concept of endoscopic elimination of dysplastic lesions in the esophagus by a mucosal ablation therapy. Photodynamic therapy and radiofrequency ablation are recently developed, emerging techniques. SUMMARY: Recent advances in screening; prognostication and therapy for esophageal adenocarcinoma in Barrett’s esophagus have brought a significant new insight in clinical practices and will eventually ensure better patients outcomes.