Clinicopathological characteristics of histiocytic sarcoma affecting the central nervous system in dogs.

BackgroundHistiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic.ObjectiveTo characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS.AnimalsOne hundred two dogs with HS, 62 dogs with meningioma.MethodsRetrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data.ResultsPredisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P <.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P < .001), but overall prognosis was poor.Conclusions and clinical importanceClinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities

Velo-Cardio-Facial Syndrome

Purpose of review: Velo-cardio-facial syndrome has emerged from obscurity to become one of the most researched disorders this past decade. It is one of the most common genetic syndromes in humans, the most common contiguous gene syndrome in humans, the most common syndrome of cleft palate, and the most common syndrome of conotruncal heart malformations. Velo-cardio-facial syndrome has an expansive phenotype, a factor reflected in the wide range of studies that cover both clinical features and molecular genetics. In this review, we cover multiple areas of research during the past year, including psychiatric disorders, neuroimaging, and the delineation of clinical features. Recent findings: The identification of candidate genes for heart anomalies, mental illness, and other clinical phenotypes has been reported in the past year with a focus on TBX1 for cardiac and craniofacial phenotypes and COMT and PRODH for psychiatric disorders. The expansive phenotype of velo-cardio-facial syndrome continues to grow with new behavioral and structural anomalies reported. Treatment issues are beginning to draw attention, although most authors continue to focus on diagnostic issues. Summary: Its high population prevalence, estimated to be as common as 1:2000 has sparked a large amount of research, as has the model the syndrome serves for identifying the causes of mental illness and learning disabilities, but it is obvious that more information is needed. Intensive scrutiny of velo-cardio-facial syndrome will undoubtedly continue for many years to come with the hope that researchers will turn more of their attention to treatment and treatment outcomes

Cognitive and Psychiatric Predictors to Psychosis in Velocardiofacial Syndrome: A 3-Year Follow-Up Study

Objective: To predict prodromal psychosis in adolescents with velocardiofacial syndrome (VCFS). Method: 70 youth with VCFS, 27 siblings of youth with VCFS and 25 community controls were followed from childhood (Mean age = 11.8 years) into mid-adolescence (mean age 15.0 years). Psychological tests measuring intelligence, academic achievement, learning/memory, attention and executive functioning as well as measures of parent and clinician ratings of child psychiatric functioning were completed at both time point. Results: Major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder diagnoses increased in the VCFS sample. With very low false positive rates, the best predictor of adolescent prodromal psychotic symptoms was parent ratings of childhood odd/eccentric symptoms and child performance on a measure of executive functioning, the Wisconsin Card Sorting Test. Conclusions: Similar to the non-VCFS prodromal psychosis literature, a combination of cognitive and psychiatric variables appears to predict psychosis in adolescence. A child with VCFS who screens positive is noteworthy and demands clinical attention

miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production.

Interleukin (IL)-8 levels are higher than normal in cystic fibrosis (CF) airways, causing neutrophil infiltration and non-resolving inflammation. Overexpression of microRNAs that target IL-8 expression in airway epithelial cells may represent a therapeutic strategy for cystic fibrosis. IL-8 protein and mRNA were measured in cystic fibrosis and non-cystic fibrosis bronchoalveolar lavage fluid and bronchial brushings (n=20 per group). miRNAs decreased in the cystic fibrosis lung and predicted to target IL-8 mRNA were quantified in βENaC-transgenic, cystic fibrosis transmembrane conductance regulator (Cftr)-/- and wild-type mice, primary cystic fibrosis and non-cystic fibrosis bronchial epithelial cells and a range of cystic fibrosis versus non-cystic fibrosis airway epithelial cell lines or cells stimulated with lipopolysaccharide, Pseudomonas-conditioned medium or cystic fibrosis bronchoalveolar lavage fluid. The effect of miRNA overexpression on IL-8 protein production was measured. miR-17 regulates IL-8 and its expression was decreased in adult cystic fibrosis bronchial brushings, βENaC-transgenic mice and bronchial epithelial cells chronically stimulated with Pseudomonas-conditioned medium. Overexpression of miR-17 inhibited basal and agonist-induced IL-8 protein production in F508del-CFTR homozygous CFTE29o(-) tracheal, CFBE41o(-) and/or IB3 bronchial epithelial cells. These results implicate defective CFTR, inflammation, neutrophilia and mucus overproduction in regulation of miR-17. Modulating miR-17 expression in cystic fibrosis bronchial epithelial cells may be a novel anti-inflammatory strategy for cystic fibrosis and other chronic inflammatory airway diseases

22q11.2 Deletion Syndrome: Are Motor Deficits More Than Expected for IQ Level?

To examine motor function in children with 22q11.2 deletion syndrome (22q11.2) and a Full Scale IQ (FSIQ) comparable control group. This study was part of a prospective study of neuropsychological function in children 9 to 15 years of age with 22q11.2 and community control subjects and included children from these two populations with comparable FSIQs. Verbal IQs on the WISC-R for 40 children with 22q11.2 (88.4) and 24 community control subjects (87.2) were not different (P=.563). However, the performance IQs were (22q11.2; 81.1 vs community controls; 89.3;

The Neural Correlates of Non-Spatial Working Memory in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome)

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as the VCFS youths). Task performance of siblings tended to be more accurate than children with VCFS, who did not differ from community controls. All three-study groups recruited parietal regions that were equivalent in location and magnitude. Whereas the sibling group also recruited the dorsolateral prefrontal cortex (DLPFC), Broca\u27s area, and anterior cingulate, DLPFC activation was absent in the whole brain analyses of children with VCFS and controls. Moreover, the magnitude of frontal activation in VCFS participants was restricted relative to both siblings and controls. These findings suggest that VCFS participants exhibit frontal hypoactivation that is not attributable to performance. In addition, VCFS children and controls (many with idiopathic learning disabilities) appear to rely on phonological rehearsal to hold information on line instead of the DLPFC. Despite previous anatomic MRI reports of preserved frontal lobe volumes in VCFS therefore, these fMRI findings suggest that the frontal component of the distributed network subserving executive function and working memory may be disrupted in youth with this disorder

The Longitudinal Course of Attention Deficit/Hyperactivity Disorder in Velo-Cardio-Facial Syndrome

OBJECTIVE: To evaluate predictors of persistence of attention deficit/hyperactivity disorder (ADHD) in a large sample of children with velo-cardio-facial syndrome (VCFS) with and without ADHD followed prospectively into adolescence. STUDY DESIGN: Children with VCFS with (n = 37) and without (n = 35) ADHD who were on average 11 years old at the baseline assessment and 15 years old at the follow-up assessment were comprehensively assessed with structured diagnostic interviews and assessments of behavioral, cognitive, social, school, and family functioning. Control participants both with and without ADHD were also followed prospectively. RESULTS: In adolescence, 65% of children with VCFS continued to have findings consistent with ADHD. Childhood predictors of persistence were higher rates of familial ADHD, having childhood depression, having higher levels of hyperactivity, and a larger number of intrusion errors on a verbal list learning test at baseline. Approximately 15% of children with VCFS who did not have ADHD at Time 1 met diagnostic criteria for ADHD at Time 2. All of these children had subthreshold ADHD symptoms at Time 1. CONCLUSIONS: These findings prospectively confirm that persistence of ADHD into adolescence in VCFS is predicted by childhood variables that have been previously documented in the non-VCFS ADHD literature

Cortical Gyrification in Velo-Cardio-Facial (22q11.2 Deletion) Syndrome: A Longitudinal Study

Introduction: Velo-cardio-facial syndrome (VCFS) has been identified as an important risk factor for psychoses, with up to 32% of individuals with VCFS developing a psychotic illness. Individuals with VCFS thus form a unique group to identify and explore early symptoms and biological correlates of psychosis. In this study, we examined if cortical gyrification pattern, i.e. gyrification index (GI) can be a potential neurobiological marker for psychosis. Method: GIs of 91 individuals with VCFS were compared with 29 siblings and 54 controls. Further, 58 participants with VCFS, 21 siblings and 18 normal controls were followed up after 3 years and longitudinal changes in GI were compared. Additionally, we also correlated longitudinal changes in GI in individuals with VCFS with prodromal symptoms of psychosis on the Scale of Prodromal Symptoms (SOPS). Result: Individuals with VCFS had significantly lower GIs as compared to their siblings and normal controls. Longitudinal examination of GI did not reveal any significant group–time interactions between the three groups. Further, longitudinal change in GI scores in the VCFS group was negatively correlated with positive prodromal symptoms, with the left occipital region reaching statistical significance. Conclusion: The study confirms previous reports that individuals with VCFS have reduced cortical folding as compared to normal controls. However over a period of three years, there is no difference in the rate of change of GI among both individuals with VCFS and normal controls. Finally, our results suggest that neuroanatomical alterations in areas underlying visual processing may be an early marker for psychosis

Manic Symptoms and Behavioral Dysregulation in Youth with Velocardiofacial Syndrome (22q11.2 Deletion Syndrome).

Mania and bipolar disorder have been reported in adolescents and adults with velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Children with VCFS have a high prevalence of attention-deficit/hyperactivity disorder (ADHD), which may constitute a risk factor for the eventual development of bipolar disorder in this population. Therefore, we sought to determine whether children with VCFS exhibit more manic symptoms than community controls that also may have learning disorders and ADHD. The study population consisted of 86 children with VCFS and 36 community controls from ages 9 to 15 years, using measures of Young Mania Rating Scale-Parent Version, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), Child Behavior Checklist (CBCL), and Wechsler Intelligence Scale for Children-3rd edition (WISC-III). The results indicate that manic symptoms were not more prevalent in VCFS than in a community sample of children with learning disorders and ADHD. However, after accounting for symptoms of depression and ADHD, we found that manic symptoms in VCFS predicted uniquely to scores on four Child Behavior Checklist (CBCL) subscales, including anxiety, somatization, thought, and conduct problems. In contrast, manic symptoms in controls predicted uniquely to conduct problems only. Accordingly, our findings of severe behavioral impairment in youth with VCFS and manic symptoms suggest that these children may warrant more intensive monitoring and treatment relative to youth with VCFS and ADHD only