Cerebral Palsy

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad-DeltaE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad-DeltaE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad-DeltaE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad-DeltaE1B19/55 compared with those treated with Ad-DeltaE1B55, indicating that the E1B 19 kDa present in Ad-DeltaE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad-DeltaE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad-DeltaE1B19/55 and radiation was more efficacious than the combination of Ad-DeltaE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.Gene Therapy advance online publication, 4 June 2009; doi:10.1038/gt.2009.72.

Nonpowder (ball-bearing and pellet) weapons derive their source of energy from compressed air or carbon dioxide. Such weapons are dangerous toys that cause serious injuries and even death to children and adolescents. A retrospective chart review study was undertaken to describe nonpowder gun injuries at a southwestern US urban level I adult and pediatric trauma center. Specific emphasis was placed on intracranial injuries. Over the past 6 years, a total of 29 pediatric and 7 adult patients were identified as having nonpowder firearm injuries. The patient population was overwhelmingly male (89.7%; mean age, 11 years). Overall, 17 out of 29 pediatric patients (56.8%) sustained serious injury. Nine patients (30.0%) required operation, 6 (20.7%) sustained significant morbidity, and there were 2 deaths (6.9%). Injuries to the brain, eye, head, and neck were the most common sites of injury (65.6%). Specific intracranial injuries in 3 pediatric patients are described that resulted in the death of 2 children. We suggest that age warning should be adjusted to 18 years or older for unsupervised use to be considered safe of these potentially lethal weapons. Copyright © 2009 S. Karger AG, Basel.

BACKGROUND: Although hematopoietic stem cell transplantation (HSCT) is offered as a curative therapy for pediatric myelodysplastic syndrome (MDS), it may cause severe complications and mortality. Several reports have shown the efficacy of immunosuppressive therapy (IST) in adult patients with refractory anemia (RA), but its safety and efficacy remains to be fully elucidated in childhood RA. PROCEDURE: Eleven children diagnosed with RA and enrolled on a prospective multicenter trial conducted by the Japanese Childhood MDS Study Group were eligible for analysis. If patients showed transfusion dependent or suffered from infection due to neutropenia, they received IST consisting of antithymocyte globulin (ATG), cyclosporine (CyA), and methylprednisolone (mPSL). RESULTS: Eight children received IST, 2 received only supportive therapy, and one underwent HSCT without IST. Five (63%) of eight children who received IST showed hematological response. Of note, one patient showed the disappearance of monosomy 7 after IST. Responders were significantly younger than non-responders (29 months vs. 140 months; P = 0.03). No severe adverse events related to IST were reported in this study. Of 6 children with chromosomal abnormalities who received IST, four showed hematological response. The probability of failure-free and overall survival at 5 years was 63 +/- 17% and 90 +/- 9% respectively. CONCLUSION: IST is likely to be a safe and effective modality for childhood RA. Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc.

Kostmann disease or severe congenital neutropenia (SCN) is an autosomal recessive disorder of neutrophil production. Homozygous HAX1 mutations were recently identified in SCN patients belonging to the original family in northern Sweden described by Kostmann. Moreover, recent studies have suggested an association between neurological dysfunction and HAX1 deficiency. Here we describe a patient with a compound heterozygous HAX1 mutation consisting of a nonsense mutation (c.568C > T, p.Glu190X) and a frame-shift mutation (c.91delG, p.Glu31LysfsX54) resulting in a premature stop codon. The patient has a history of neutropenia and a propensity for infections, but has shown no signs of neurodevelopmental abnormalities. Pediatr Blood Cancer. (c) 2009 Wiley-Liss, Inc.

BACKGROUND/AIM: Infants surviving congenital diaphragmatic hernia (CDH) suffer from anatomical and functional esophageal abnormalities. Previous work in the nitrofen animal model of CDH demonstrated malformations in neural crest-derived structures, including the vagus and recurrent laryngeal nerves. The aim of the present study was to assess whether the esophageal myenteric plexus is abnormal in rats with CDH. METHODS: We used the nitrofen-induced CDH fetal rat model. Two sections of the proximal, medium and distal esophagus from both groups were processed for immunohistochemical staining with anti-neuron specific enolase and anti-S-100 antibodies; the number of stained areas was recorded for each group. Whole-mount preparations of the entire esophagus of Control and CDH animals were histochemically stained for acetylcholinesterase; the density and area of the ganglia and the number of cells/ganglia were determined. Comparisons between groups were made by standard statistical methods. RESULTS: The number of immunohistochemically stained areas in transversal sections were decreased in CDH animals for anti-enolase (11.5+/-6.06 vs. 1.93+/-1.49, control vs. CDH, p<0.001) and anti S-100 antibodies (8.57+/-4.1 vs. 4.06+/-2.82, p<0.001). In whole-mount preparations the number of ganglia per high power field (35.16+/-6.57 vs. 29.29+/-10.26, p<0.05), the number of cells per ganglia (11.85+/-3.52 vs. 2.28+/-4.61, p<0.0001) and the relative area of the ganglia (0.35+/-0.32 vs. 0.18+/-0.42%, p<0.001), were also significantly decreased in CDH animals compared with Controls. CONCLUSIONS: Esophageal intrinsic innervation is defective in rat fetuses with CDH. If patients with CDH bear the same anomalies, this may explain some of their esophageal motility disorders. Finally, these findings support the concept of neural crest involvement in the pathogenic pathways of CDH.

Background: borderline personality disorder (BPD) is a psychiatric diagnosis characterized by high exposure, reactivity, and vulnerability to stress. Given these abnormalities in stress reactivity in BPD, there is a question of whether the hypothalamic-pituitary-adrenal (HPA) axis functions normally in BPD, since the activation of the HPA axis normally occurs to coordinate both behavioral and physiologic responses to stress. Several studies have investigated the functioning of the HPA axis in BPD and have shown varied results. This review seeks to summarize and interpret the findings of this growing literature. Methods: Pubmed search for English language articles on borderline personality disorder and hypothalamic-pituitary-adrenal axis. Results: findings are mixed but suggest that important variables relevant to between-group differences include comorbid depression, comorbid posttraumatic stress disorder, dissociative symptoms, and history of childhood abuse. Discussion: comorbid diagnoses and clinical features such as trauma history and symptom severity may have variable, interacting influences on the psychoneuroendocrine profile in BPD. Also explored here are the implications of these findings for developing possible models of HPA-axis dysfunction in BPD, for identifying potential targets for treatment, and for improving the methodology of future studies.

The purpose of this study was to determine the discrepancy rates of radiology residents interpreting emergent neck and Circle of Willis magnetic resonance angiography (MRA) studies and to detect any adverse clinical outcomes. Three hundred seventeen MRA studies given preliminary reading by radiology residents were retrospectively reviewed over a 2-year period. Discrepancies were classified as either false negatives (failure to diagnose abnormalities) or false positives (misinterpreting normal scans as abnormal). The overall discrepancy rate was 12.1% for Circle of Willis MRA and 7.9% for neck MRA. Fourth-year residents had the lowest discrepancy rates (7.7%), but this was not statistically significant. The most common misses were stenosis greater than 70% (n = 9) and aneurysm (n = 12). No adverse clinical outcome was detected mainly due to rapid turnaround time for final reporting.

The valsalva manoeuvre (VM), used as an autonomic function test, can detect sympathetic and/or parasympathetic autonomic dysfunction. This study investigated the value of VM in patients with different Parkinsonian syndromes (PS). We continuously recorded blood pressure, ECG and respiration among 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson’s disease (PD) and in 27 healthy subjects matched in age and sex (Con). VM was performed in addition to metronomic breathing and tilt-table testing. VM could not be analysed in 26% of the ES patients. Valsalva ratio (VR), as a parameter of cardiovagal function, was pathologically decreased in all patient groups. Valsalva ratio (VR) was not able to discriminate parasympathetic dysfunction between patients and controls as well as E/I ratio of metronomic breathing. As a parameter of sympathetic dysfunction during VM, the physiological increase of blood pressure was more often missing during phase IV than phase II especially in PD and MSA patients. Correlation with orthostatic hypotension during tilt-table testing was only moderate. Although VM can demonstrate sympathetic and parasympathetic autonomic dysfunction, we cannot recommend VM as a first line autonomic test in PS patients. Metronomic breathing and tilt-table test seem more capable as parasympathetic resp. and sympathetic function tests to identify cardiovascular abnormalities in PS patients.

Schizophrenia is a severe brain disease that affects approximately 1% of the world’s population. Extensive study into the indication of and causes of this disease has been ongoing for decades. Historical review of research into associated abnormalities and markers common in schizophrenic patients has demonstrated a correlation with potential microbial origins in the development of the disease. While infectious etiologies could be responsible for some cases of schizophrenia, no consistent use of antiinfective agents has been developed for its prevention or treatment. Elucidation of the mechanisms for infectious roots of schizophrenia may open new avenues for effective treatment. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Strategies aimed at primary prevention provide an outstanding opportunity for reducing the onset and burden of cardiovascular (CV) disease. Lipid abnormalities, including high levels of low-density lipoprotein cholesterol (LDL-C), elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C), are associated with an increased risk of CV events, thereby serving as contributors to this process. By consensus, lowering LDL-C, generally with statin therapy, is the primary target of lipid-lowering therapy. However, statin therapy may be insufficient for patients with mixed dyslipidemia, especially those with insulin resistance syndromes. While the addition of niacin, fibrate or omega-3 fatty acids may be useful in this setting, outcomes data are lacking. Therefore, data from ongoing prospective studies will hopefully resolve this issue and facilitate identification of optimal strategies to augment CV risk reduction.