Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels.

Pharmacological ascorbate (P-AscH-, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH- induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway. Both non-tumorigenic pancreatic ductal epithelial and PDAC cells display decreased clonogenic survival and increased doubling times after radiation treatment. In contrast, the addition of P-AscH- to radiation increases clonogenic survival and decreases the doubling time of non-tumorigenic epithelial cells but decreasing clonogenic survival and increasing the doubling time of PDAC cells. Results from the mitotic index and propidium iodide assays showed that while the P-AscH- treatments did not affect radiation-induced G2-checkpoint activation, it enhanced G2-accumulation. The addition of catalase reverses the increases in G2-accumulation, indicating a peroxide-mediated mechanism. In addition, P-AscH- treatment of PDAC cells suppresses radiation-induced accumulation of cyclin B1 protein levels. Both translational and post-translational pathways appear to regulate cyclin B1 protein levels after the combination treatment of PDAC cells with P-AscH- and radiation. The protein changes seen are reversed by the addition of catalase suggesting that hydrogen peroxide mediates P-AscH- induced radiation sensitization of PDAC cells by enhancing G2-accumulation and reducing cyclin B1 protein levels.

The role of mitochondria in pharmacological ascorbate-induced toxicity.

At pharmacological levels, ascorbate (P-AscH-) acts as a pro-oxidant by generating H2O2, depleting ATP in sensitive cells leading to cell death. The aim of this study was to determine the role of ATP production by oxidative phosphorylation or glycolysis in mechanisms of resistance to P-AscH-induced cell death. Pancreatic cancer cells were used to generate ρ0 cells by mitochondrial overexpression of the Y147A mutant uracil-N-glycosylase or Herpes Simplex Virus protein. The ρ0 phenotype was confirmed by probing for mitochondrial DNA, mitochondrial DNA-encoded cytochrome c oxidase subunit 2, and monitoring the rate of oxygen consumption. In ρ0 cells, glycolysis accounted for 100% of ATP production as there was no mitochondrial oxygen consumption. Even though the activities of H2O2-removing antioxidant enzymes were similar in both the parental and ρ0 clones, P-AscH- -induced clonogenic cell death in ρ0 cells showed more resistance than the parental cell line. In addition, P-AscH- induced more DNA damage and more consumption of NAD+ and greater decreases in the production of ATP in the parental cell line compared to the ρ0 cells. Thus, cancer cells that largely use oxidative phosphorylation to generate ATP may be more sensitive to P-AscH- compared with cells that are glycolysis-dependent.

Does Working Memory Impact Functional Outcomes in Individuals With ADHD: A Qualitative and Comprehensive Literature Review.

OBJECTIVE: Working Memory (WM) is a domain of executive functioning often impaired in individuals with ADHD. Although assumed to cause difficulties across functioning, the scope of impairments from WM deficits in ADHD has not been investigated. The aim of this study was to examine outcomes associated with WM deficits in ADHD. METHOD: We conducted a search of the scientific literature on WM deficits, and Freedom From Distractibility (FFD), in ADHD using PubMed and PsycInfo databases. RESULTS: The final sample included 11 controlled studies of WM/FFD deficits in ADHD with operationalized assessment of outcomes in academic, social, and emotional areas. WM assessment was divided into auditory-verbal memory (AVM) and spatial-visual memory (SWM). Seven studies examined WM deficits in academic functioning, eight studies assessed WM deficits in social functioning, and three assessed WM deficits in psychopathology. CONCLUSION: The majority of the literature suggests that WM deficits affect primarily academic functioning.

Esophageal IgG4: Clinical, Endoscopic, and Histologic Correlations in Eosinophilic Esophagitis.

OBJECTIVE: Recent studies show increased serum and esophageal IgG4 in patients with eosinophilic esophagitis (EoE), suggesting a possible IgG4-involved process. The role of IgG4 in pediatric EoE has not been extensively investigated. Our aim was to analyze IgG4 in esophageal tissue in children in parallel to that in adults with EoE. METHODS: In a retrospective institutional review board-approved study, we performed immunohistochemical staining of IgG4 in esophageal biopsy specimens from 39 subjects: children with EoE (n = 16), adults with EoE (n = 15), children with reflux esophagitis (n = 4), and pediatric controls (n = 4). We assessed the relationships between IgG4 staining and clinical, endoscopic, and histopathologic characteristics. RESULTS: Patients with EoE were significantly more likely to stain positively for IgG4 than children with reflux esophagitis or controls (P = 0.015). Fifteen of 31 (48%) EoE cases stained positively for IgG4. None of the reflux esophagitis or control cases stained positively. IgG4 staining had 48% sensitivity and 100% specificity for EoE. There was a trend toward IgG4 staining being associated with foreign body/food impaction (P = 0.153). There was a strong association between distal IgG4 staining and basal zone hyperplasia (P = 0.003). CONCLUSIONS: Our study suggests IgG4 is not a consistent finding of EoE at disease diagnosis. Although IgG4 staining was specific for EoE, it had a poor sensitivity with positive staining in only 48% of EoE patients. Further studies are warranted to fully elucidate the role of IgG4 in EoE.

Abnormal fear circuitry in Attention Deficit Hyperactivity Disorder: A controlled magnetic resonance imaging study.

We examined whether non-traumatized subjects with Attention Deficit Hyperactivity Disorder (ADHD) have dysfunctional activation in brain structures mediating fear extinction, possibly explaining the statistical association between ADHD and other disorders characterized by aberrant fear processing such as PTSD. Medication naïve, non-traumatized young adult subjects with (N=27) and without (N=20) ADHD underwent a 2-day fear conditioning and extinction protocol in a 3T functional magnetic resonance imaging (fMRI) scanner. Skin conductance response (SCR) was recorded as a measure of conditioned response. Compared to healthy controls, ADHD subjects had significantly greater insular cortex activation during early extinction, lesser dorsal anterior cingulate cortex (dACC) activation during late extinction, lesser ventromedial prefrontal cortex (vmPFC) activation during late extinction learning and extinction recall, and greater hippocampal activation during extinction recall. Hippocampal and vmPFC deficits were similar to those documented in PTSD subjects compared to traumatized controls without PTSD. Non-traumatized, medication naive adults with ADHD had abnormalities in fear circuits during extinction learning and extinction recall, and some findings were consistent with those previously documented in subjects with PTSD compared to traumatized controls without PTSD. These findings could explain the significant association between ADHD and PTSD as well as impaired emotion regulation in ADHD.

Memantine in the Treatment of Executive Function Deficits in Adults With ADHD.

OBJECTIVE: To evaluate the efficacy and safety of memantine hydrochloride as an adjunct to stimulant pharmacotherapy for treating executive function deficits (EFDs) in adults with ADHD. METHOD: This was a 12-week, double-blind, placebo-controlled, randomized clinical trial of memantine added to open-label treatment with stimulant medication. Because of the small sample size, we considered a standardized mean difference (equivalent to effect size) of ≥0.5 and odds ratios ≥2 as indicators of trend improvements. RESULTS: Twelve participants received memantine and 14 received a placebo. Trend improvements favoring memantine were observed on Behavior Rating Inventory of Executive Functions-Adult Inhibition and Self-Monitor subscales when compared with Placebo. No significant changes were noted on the Cambridge Neuropsychological Test Automated Battery. CONCLUSION: Among adults with ADHD and EFDs, adjunct treatment with memantine to osmotic release oral system-methylphenidate (OROS-MPH) was associated with improvements in selective areas of executive functioning, supporting the need for further research.

A study of the neuropsychological correlates in adults with high functioning autism spectrum disorders.

OBJECTIVE: To examine the unique neuropsychological presentation in adults with high functioning autism spectrum disorders (HF-ASD) by comparison with adults with attention deficit hyperactivity disorder (ADHD). METHODS: Adults with ASD referred to a specialty clinic (n=26) were compared to two non-ASD groups with (n=52) and without (n=52) ADHD of similar age and sex. RESULTS: No differences in IQ were found. Subjects with HF-ASD were significantly more impaired than both comparison groups in processing speed, cognitive flexibility and sight words. Subjects with HF-ASD were more impaired than controls in working memory, but not the ADHD group. CONCLUSION: These findings suggest that there may be specific neuropsychological correlates of HF-ASD differing from ADHD that could have significant implications for identifying individuals at risk for ASD.

Clinical correlates of working memory deficits in youth with and without ADHD: A controlled study.

OBJECTIVE: Both working memory (WM; a brain system that provides temporary storage and manipulation of the information) and attention-deficit/hyperactivity disorder (ADHD) have been associated with educational deficits. Since WM deficits are prevalent in children with ADHD, the main aim of the present study was to examine whether educational deficits are driven by working memory deficits or driven by the effect of ADHD itself. METHOD: Participants were referred youth with (N = 276) and without (N = 241) ADHD ascertained from pediatric and psychiatric sources. Assessment included measures of psychiatric, psychosocial, educational, and cognitive functioning. Education deficits were defined as grade retention or placement in special classes and were assessed using interviews and written rating scales. Working memory was assessed using the Wechsler Intelligence Scale for Children-Revised (WISC-R) Freedom from Distractibility (FFD) factor based on Digit Span, Arithmetic, and Coding. RESULTS: Significantly more youth with ADHD had WM deficits than controls (31.9% vs. 13.7%, p < .05). In ADHD children, WM deficits were significantly (p < .01) associated with an increased risk for grade retention and placement in special classes as well as lower scores on reading and math achievement tests than for ADHD children without WM deficits. In contrast, no other differences were noted in other areas of functioning. Although WM deficits also had some adverse impact on educational and cognitive correlates in non-ADHD controls, these differences failed to attain statistical significance. CONCLUSION: WM deficits significantly and selectively increase the risk for academic deficits and cognitive dysfunction in children with ADHD beyond those conferred by ADHD. Screening for WM deficits may help identify children with ADHD at high risk for academic and cognitive dysfunction.

Examining the association between posttraumatic stress disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis examining the relationship between attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD). DATA SOURCES: We reviewed literature through PubMed and PsycINFO without a specified date range, utilizing the search (posttraumatic stress disorder OR PTSD) AND (ADHD OR attention deficit hyperactivity disorder OR ADD OR attention deficit disorder OR hyperkinetic syndrome OR minimal brain dysfunction). References from relevant articles were reviewed. STUDY SELECTION: We identified 402 articles; 28 met criteria. We included original human research in English that operationalized diagnoses of ADHD and PTSD, evaluated the relationship between the disorders, and included controls. We excluded articles that failed to differentiate ADHD or PTSD from nonspecific or subsyndromal deficits or failed to compare their relationship. DATA EXTRACTION: We extracted sample size, age, diagnostic methods, design, referral status, control type, and number of subjects with and without ADHD and PTSD alone and combined. We computed meta-analyses for 22 studies examining ADHD in PTSD and PTSD in ADHD using a random effects model and meta-analytic regression. We assessed for heterogeneity and publication bias and adjusted for intrastudy clustering. RESULTS: The relative risk (RR) for PTSD in ADHD was 2.9 (P < .0005); in samples using healthy controls, the RR was 3.7 (P = .001); and in samples using traumatized controls, the RR was 1.6 (P = .003). The RR for ADHD in PTSD was 1.7 (P < .0005); in samples using traumatized controls, the RR was 2.1 (P < .0005). The association was not significant in samples using psychiatric controls. CONCLUSIONS: Results indicate a bidirectional association between ADHD and PTSD, suggesting clinical implications and highlighting the need for neurobiological research that examines the mechanisms underlying this connection.

FGFR3 expression in Xenopus laevis.

We studied the expression of FGF receptor 3 (FGFR3) mRNA throughout early development of Xenopus laevis by RT-PCR and in situ hybridization. RT-PCR shows that FGFR3 mRNA is localized within the gastrula; regionalized staining is detected by the neural plate stage and continues throughout embryonic development. Strong expression is seen in developing neural structures, especially in the forebrain and hindbrain, including the developing eyes, and in lateral mesoderm. Comparison of these data with previous reports of FGF expression in this species suggests possible FGF-FGFR3 interactions. The pattern of FGFR3 expression appears to be strongly conserved among vertebrate embryos.