A cross-sectional analysis of executive function in Down syndrome from 2 to 35 years.

BACKGROUND: Previous research has indicated a unique profile of executive function (EF) in children and adolescents with Down syndrome (DS). However, there is a paucity of research on EF in adults with DS. This study aimed to gain a broader understanding of strengths and weaknesses in EF in DS from 2 to 35 years. METHOD: Parents of 112 individuals with DS between 2 and 35 years participated in this study. Parents either completed the Behaviour Rating Inventory of Executive Function - for individuals 6+ years - or the Behaviour Rating Inventory of Executive Function Preschool Version - for children 2-5 years. RESULTS: Results suggest not only overall difficulties but also patterns of strength and weakness within EF for individuals with DS. For the 2 to 5-year-old group, emotional control and shift were relative strengths, planning/organisation and inhibit were intermediate skills, and working memory was a relative weakness. For the 6 to 18-year-old group, emotional control and organisation of materials were relative strengths, inhibit and initiate were intermediate skills, and working memory, monitor, planning/organisation, and shift were relative weaknesses. Most abilities were consistent from 2 to 18 years, except shift, which decreased in preadolescence before beginning to recover in adolescence. Across the full age range (2-35 years), composite scores indicated quadratic trends in inhibit, working memory, and planning/organisation, and a cubic trend in shift, with EF abilities generally declining in middle childhood before recovering in adulthood. CONCLUSIONS: This study extends previous research on EF in DS by providing an initial description of EF profiles across the lifespan. More longitudinal and behavioural research is needed to further characterise the development of EF in DS.

Post-tooth extraction sepsis without locoregional infection--a population-based study in Taiwan.

OBJECTIVE: To investigate the incidence and risk factors of post-tooth extraction sepsis in patients without locoregional infection. SUBJECTS AND METHODS: We assessed all claim records of the Taiwanese National Health Insurance program in 2005. Admissions for patients aged > or =16 years containing a discharge diagnosis of sepsis, and who received tooth extraction within 14 days before the admission were identified. Patient charts were reviewed to confirm the diagnosis of sepsis and rule out other infection sources. The relationship between postextraction sepsis (PES) and clinical parameters was analyzed. RESULTS: Thirty-three of the 2 223 971 extraction cases met the criteria of PES, an incidence of 1.48 per 100 000, and seven patients (21.2%) died of the disease. Aging significantly increased the risk of PES (P < 0.001). Pre-existing comorbidities were found in 20 of the 33 cases, with diabetes mellitus and hematologic diseases the most common. The method, number, and position of extraction had no influence on PES incidence. Blood cultures were positive in 25 patients (75.8%) and isolates included species of the Streptococcus, Actinomyces, Klebsiella, Bacteroides, Prevotella, and Enterococcus genera. CONCLUSION: Tooth extraction is associated with a low but significant risk of postoperative sepsis, especially in the elderly and patients with underlying diseases.

Cell-mediated immunity and head and neck cancer: with special emphasis on betel quid chewing habit.

Betel quid (BQ) chewing is popular in Taiwan, India, and many southeast-Asian countries. BQ chewing has strong association with the risk of oral leukoplakia (OL), oral submucous fibrosis (OSF), and oral cancer (OC). BQ components exhibit genotoxicity and may alter the structure of DNA, proteins and lipids, resulting in production of antigenicity. BQ ingredients are also shown to induce keratinocyte inflammation by stimulating the production of prostaglandins, TNF-alpha, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in keratinocytes. These events may provoke tissue inflammation, early cell-mediated immunity (CMI), and immune surveillance in BQ chewers. However, BQ components also directly affect the functional activities of immunocompotent cells, and moreover tumor cells may hypo-respond to the CMI via diverse mechanisms such as induction of apoptosis of lymphocytes, induction of production of suppressor T cells, downregulation of MHC molecules in tumor cells, etc. Clinically, an alteration in lymphocyte subsets, a decrease in total number of lymphocytes, and a reduction in functional activities of CMI have been observed in isolated peripheral blood mononuclear cells (PBMC) and tumor infiltrated lymphocytes (TIL) in patients with OSF, OL or OC. Adaptation of tumor cells to immune system may promote clonal selection of resistant tumor cells, leading to immune tolerance. Future studies on effects of BQ components on CMI and humoral immunity in vitro and in vivo can be helpful for chemoprevention of BQ-related oral mucosal diseases. To elucidate how virus infection, tobacco, alcohol and BQ consumption, and other environmental exposure affect the immune status of patients with oral premalignant lesions or OC will help us to understand the immunopathogenesis of OC and to develop immunotherapeutic strategies for OC.

Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells.

Betel quid (BQ) chewing shows a strong correlation to the incidence of oral submucous fibrosis (OSF), leukoplakia and oral cancer. BQ contains mainly areca nut, lime, Piper betle leaf (PBL) and the inflorescence of P. betle (IPB). Hydroxychavicol (4-allyl-catechol, HC), as a major phenolic compound in PBL and IPB, is shown to induce oxidative stress, glutathione (GSH) depletion and cell cycle deregulation. Using bivariate BrdU/PI flow cytometry, KB cells in DNA synthesis (S phase) are shown to be sensitive to the toxic effect of HC and show cell cycle arrest and apoptosis following exposure to 0.1 and 0.3 mM HC. HC-induced apoptosis and cell cycle arrest are associated with mitochondrial membrane potential (delta Psim) depolarization as revealed by a decrease in rhodamine fluorescence. N-acetyl-L-cysteine (1 mM), superoxide dismutase (100 U/ml) and catalase (1000 U/ml) were effective in prevention of HC-induced GSH depletion (as indicated by chloromethylfluorescein fluorescence), reactive oxygen species (ROS) production (by dichlorofluorescein fluorescence), cell cycle arrest and apoptosis. However, dimethylthiourea (2 mM), neocuproine (1 mM), 1,10-phenanthroline (200 microM) and desferrioxamine (0.5 mM) showed little effect on HC-induced cell changes. HC elevated the cellular and mitochondrial GSH levels at moderate concentrations (0.05-0.1 mM), whereas at a concentration of 0.3 mM, inhibitory effects were noted. These results indicate that HC consumption may be associated with BQ-chewing-related oral mucosal diseases via GSH depletion, ROS production, mitochondrial dysfunction, cell cycle disturbance and the induction of apoptosis. These events are related to the production of superoxide radicals and hydrogen peroxide.

Prevention of the areca nut extract-induced unscheduled DNA synthesis of gingival keratinocytes by vitamin C and thiol compounds.

There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is the major risk factor of oral cancer in India, Taiwan, South Africa and numerous other countries. Areca nut (AN) extract, the main component of BQ, exerts cytotoxicity and genotoxicity to several types of cells. In the present study, AN extract induced the unscheduled DNA synthesis (UDS) of gingival keratinocytes (GK). Vitamin C, at concentration of 50 and 200 microg/ml prevented the AN-induced UDS by 41 and 56%, respectively. Glutathione (GSH, 1-3 mM) and N-acetyl-L-cysteine (NAC, 1-3 mM) also protected the AN-induced UDS by 89-100 and 76-90%. These preventive effects were not due to cytotoxicity as analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Deferoxamine (20 and 30 mM), an iron chelator and a free radical scavenger, also prevented AN extract induced UDS of GK by 30-55%. On the contrary, banthocuproine (50-200 microM, a copper chelator) and 1,10-phenanthroline (50, 100 microM, a lipid permeable iron chelator), lacked preventive effects. Specific reactive oxygen species scavengers such as dimethyl-sulfoxide (2%), mannitol (10-20 mM), dimethylthiourea (10-20 mM), pyruvate (10 mM), catalase (200 and 400 U/ml), and superoxide dismutase (50 and 200 U/ml) also lacked these preventive effects. Moreover, higher concentrations of H(2)O(2) (0.5-1 mM) inhibited the basal levels of UDS by 19-37%. Interestingly, NAC, GSH, Vitamin C and deferoxamine cannot prevent the AN-induced morphological changes of GK at similar concentrations. These results reveal that AN extract-induced UDS of GK is associated with free radical reactions. Possibly different ingredients of AN is responsible for genotoxicity and cytotoxicity. Vitamin C, GSH and NAC may be potentially used in the future for chemoprevention of BQ chewing related oral mucosal lesions.

Inducing the cell cycle arrest and apoptosis of oral KB carcinoma cells by hydroxychavicol: roles of glutathione and reactive oxygen species.

Hydroxychavicol (HC; 10 - 50 microM), a betel leaf component, was found to suppress the 2% H(2)O(2)-induced lucigenin chemiluminescence for 53 - 75%. HC (0.02 - 2 microM) was also able to trap superoxide radicals generated by a xanthine/xanthine oxidase system with 38 - 94% of inhibition. Hydroxyl radicals-induced PUC18 plasmid DNA breaks was prevented by HC (1.6 - 16 microM). A 24-h exposure of KB cells to HC (0.5, 1 mM) resulted in 54 - 74% cell death as analysed by a 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. HC (10, 50 microM) further suppressed the growth of KB cells (15 and 76%, respectively). Long-term colony formation of KB cells was inhibited by 51% with 10 microM HC. Pretreatment of KB cells with 100 microM HC inhibited the attachment of KB cells to type I collagen and fibronectin by 59 and 29%, respectively. Exposure of KB cells to 0.1 mM HC for 24 h resulted in cell cycle arrest at late S and G2/M phase. Increasing the HC concentration to 0.25 and 0.5 mM led to apoptosis as revealed by detection of sub-G(0)/G(1) peaks with a concomitant decrease in the number of cells residing in late S and G(2)/M phase. Inducing the apoptosis of KB cells by HC was accompanied by marked depletion in reduced form of GSH (>0.2 mM) and the increasing of reactive oxygen species production (>0.1 mM) as analysed by CMF- and DCF-single cell fluorescence flow cytometry. These results indicate that HC exerts antioxidant property at low concentration. HC also inhibits the growth, adhesion and cell cycle progression of KB cells, whereas its induction of KB cell apoptosis (HC>0.1 mM) was accompanied by cellular redox changes.

Repair of oroantral communications in the third molar region by random palatal flap.

Various palatal flap procedures based on the greater palatine vessels have been advocated for the repair of oroantral communications (OACs). However, when the defect is located in the third molar region, difficulty is encountered in using the palatal flap because rotation is hindered by the vascular pedicle. In this study, we used random palatal flaps to repair OACs in the third molar area in 21 patients. The vascular pedicles were ligated and severed in all cases in order to evaluate whether it was necessary to preserve the greater palatine vessels when using the palatal rotation flap (PRF). The repair was successful in 16 cases (76.2%). The length/width ratio of the flap was the most important factor determining the outcome. The ratios were 2.23 +/- 0.12 and 2.40 +/- 0.14 in the success and failure groups, respectively and their difference was statistically significant (P<0.05). Other clinical parameters such as age, gender, antral infection, tooth displacement into the sinus and duration of the communication had no influence on the outcome (P>0.05). The study showed that the PRF with the appropriate length/width ratio can safely be used in a random fashion. This provided another option in the repair of oroantral communications of difficult locations such as in the tuberosity area.

Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glutathione, reactive oxygen species and mitochondrial membrane potential.

There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 microg/ml) and arecoline (20-120 microM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (> 0.2 mM) for 24 h induced G(2)/M cell cycle arrest of OMF and KB cells. Areca nut extract (> 400 microg/ml) also induced G(2)/M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G(0)/G(1) peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Deltabetam) and H(2)O(2) production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 microg/ml) induced decreasing and increasing H(2)O(2) production (by 2',7'-dichloro- fluorescein fluorescence), respectively. Hyperpolarization of Deltabetam (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml). AN extract (100- 1200 microg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Deltabetam, GSH level and intracellular H(2)O(2) production, these events being not coupled with cellular apoptosis.

Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives.

Betel quid (BQ)-chewing is a popular oral habit with potential links to the occurrence of oral cancer. Many of the literature-based studies reveal that areca nut (AN) extract may demonstrate mutagenic and genotoxic effects, in addition to inducing preneoplastic as well as neoplastic lesions in experimental animals. Areca nut should, thus, be highly suspected as a human carcinogen. Toxicity studies relating to AN-contained polyphenols and tannins are not conclusive, with both carcinogenic and anti-carcinogenic effects being reported. The mutagenicity and genotoxicity of areca alkaloids has been detected by many short-term assays. However, their genotoxicity to oral fibroblasts and keratinocytes, the target cells of BQ, has not been identified. It would thus appear that AN toxicity is not completely due to its polyphenol, tannin and alkaloid content. The single agent which is responsible for AN carcinogenicity awaits further clarification. Reactive oxygen species produced during auto-oxidation of AN polyphenols in the BQ-chewer's saliva, are crucial in the initiation and promotion of oral cancer. Nitrosation of areca alkaloids also produces AN-specific nitrosamines, that have been demonstrated to be mutagenic, genotoxic and are capable of inducing tumors in experimental animals. Arecaidine and AN extract are further suggested to be tumor promoters. Antioxidants such as glutathione and N-acetyl-L-cysteine can potentially prevent such AN-elicited cytotoxicity. Further studies are needed to delineate the metabolism of AN ingredient and their roles in the multi-step chemical carcinogenesis, in order to enhance the success of the future chemoprevention of oral cancer and oral submucous fibrosis.

Association between genetic polymorphism of tumor necrosis factor-alpha and risk of oral submucous fibrosis, a pre-cancerous condition of oral cancer.

Many cytokines have been thought to play important roles in the pathogenesis of oral submucous fibrosis (OSF), an areca nut chewing-specific pre-cancerous condition characterized by the deposition of collagen in oral submucosa. Tumor necrosis factor-alpha (TNF-alpha), situated in the class III region of human leukocyte antigen (HLA), is a mediator with multiple functions, including the regulation of inflammatory reaction and transcriptions of collagen and collagenase. In total, 809 male subjects were recruited for assessment of the association of OSF with a bi-allelic promoter-region (-308) polymorphism on the TNFA gene. The high production allele, TNF2, was significantly lower among OSF subjects (n = 166) than in areca-chewing controls (n = 284). This association was independent of oral cancer status. The multivariate-adjusted odds ratio for the TNFA 11 genotype was 2.6 (95% confidence interval = 1.4-4.9; p = 0.004). The finding may imply a multifunctional etiological factor of TNF-alpha in OSF pathogenesis.