Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy.

OBJECTIVE: GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation. METHODS: Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline ß-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis. RESULTS: Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated. INTERPRETATION: The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.

A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna.

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

Dental professionals' experiences of managing children with carious lesions in their primary teeth - a qualitative study within the FiCTION randomised controlled trial.

BACKGROUND: The lack of evidence for the effective management of carious lesions in children's primary teeth has caused uncertainty for the dental profession and patients. Possible approaches include conventional and biological management alongside best practice prevention, and best practice prevention alone. The FiCTION trial assessed the effectiveness of these options, and included a qualitative study exploring dental professionals' (DPs) experiences of delivering the different treatment arms. This paper reports on how DPs managed children with carious lesions within FiCTION and how this related to their everyday experiences of doing dentistry. METHODS: Overall, 31 DPs from FiCTION-trained dental surgeries in four regions of the UK participated in semi-structured interviews about their experiences of the three treatment arms (conventional management of carious lesions and prevention (C + P), biological management of carious lesions and prevention (B + P) or prevention alone (PA)). A theoretical framework, drawing on social practice theory (SPT), was developed for analysis. RESULTS: Participants discussed perceived effectiveness of, and familiarity with, the three techniques. The C + P arm was familiar, but some participants questioned the effectiveness of conventional restorations. Attitudes towards the B + P arm varied in terms of familiarity, but once DPs were introduced to the techniques, this was seen as effective. While prevention was familiar, PA was described as ineffective. DPs manage children with carious lesions day-to-day, drawing on previous experience and knowledge of the child to provide what they view as the most appropriate treatment in the best interests of each child. Randomisation undermined these normal choices. Several DPs reported deviating from the trial arms in order to treat a patient in a particular way. Participants valued evidence-based dentistry, and expect to use the results of FiCTION to inform future practice. They anticipate continuing to use the full range of treatment options, and to personally select appropriate strategies for individual children. CONCLUSIONS: RCTs take place in the context of day-to-day practices of doing dentistry. DPs employ experiential and interpersonal knowledge to act in the best interests of their patients. Randomisation within a clinical trial can present a source of tension for DPs, which has implications for assuring individual equipoise in future trials.

Children and parents' perspectives on the acceptability of three management strategies for dental caries in primary teeth within the 'Filling Children's Teeth: Indicated or Not' (FiCTION) randomised controlled trial - a qualitative study.

BACKGROUND: The Filling Children's Teeth: Indicated Or Not? (FiCTION) randomised controlled trial (RCT) aimed to explore the clinical- and cost-effectiveness of managing dental caries in children's primary teeth. The trial compared three management strategies: conventional caries management with best practice prevention (C + P), biological management with best practice prevention (B + P) and best practice prevention alone (PA)-based approaches. Recently, the concept of treatment acceptability has gained attention and attempts have been made to provide a conceptual definition, however this has mainly focused on adults. Recognising the importance of evaluating the acceptability of interventions in addition to their effectiveness, particularly for multi-component complex interventions, the trial design included a qualitative component. The aim of this component was to explore the acceptability of the three strategies from the perspectives of the child participants and their parents. METHODS: Qualitative exploration, based on the concept of acceptability. Participants were children already taking part in the FiCTION trial and their parents. Children were identified through purposive maximum variation sampling. The sample included children from the three management strategy arms who had been treated and followed up; median (IQR) follow-up was at 33.8 (23.8, 36.7) months. Semi-structured interviews with thirteen child-parent dyads. Interviews were transcribed verbatim and analysed using a framework approach. RESULTS: Data saturation was reached after thirteen interviews. Each child-parent dyad took part in one interview together. The participants were eight girls and five boys aged 5-11 years and their parents. The children's distribution across the trial arms was: C + P n = 4; B + P n = 5; PA n = 4. Three key factors influenced the acceptability of caries management in primary teeth to children and parents: i) experiences of specific procedures within management strategies; ii) experiences of anticipatory dental anxiety and; iii) perceptions of effectiveness (particularly whether pain was reduced). These factors were underpinned by a fourth key factor: the notion of trust in the dental professionals - this was pervasive across all arms. CONCLUSIONS: Overall children and parents found each of the three strategies for the management of dental caries in primary teeth acceptable, with trust in the dental professional playing an important role.

Cost-effectiveness of child caries management: a randomised controlled trial (FiCTION trial).

BACKGROUND: A three-arm parallel group, randomised controlled trial set in general dental practices in England, Scotland, and Wales was undertaken to evaluate three strategies to manage dental caries in primary teeth. Children, with at least one primary molar with caries into dentine, were randomised to receive Conventional with best practice prevention (C + P), Biological with best practice prevention (B + P), or best practice Prevention Alone (PA). METHODS: Data on costs were collected via case report forms completed by clinical staff at every visit. The co-primary outcomes were incidence of, and number of episodes of, dental pain and/or infection avoided. The three strategies were ranked in order of mean cost and a more costly strategy was compared with a less costly strategy in terms of incremental cost-effectiveness. Costs and outcomes were discounted at 3.5%. RESULTS: A total of 1144 children were randomised with data on 1058 children (C + P n = 352, B + P n = 352, PA n = 354) used in the analysis. On average, it costs £230 to manage dental caries in primary teeth over a period of up to 36 months. Managing children in PA was, on average, £19 (97.5% CI: -£18 to £55) less costly than managing those in B + P. In terms of effectiveness, on average, there were fewer incidences of, (- 0.06; 97.5% CI: - 0.14 to 0.02) and fewer episodes of dental pain and/or infection (- 0.14; 97.5% CI: - 0.29 to 0.71) in B + P compared to PA. C + P was unlikely to be considered cost-effective, as it was more costly and less effective than B + P. CONCLUSIONS: The mean cost of a child avoiding any dental pain and/or infection (incidence) was £330 and the mean cost per episode of dental pain and/or infection avoided was £130. At these thresholds B + P has the highest probability of being considered cost-effective. Over the willingness to pay thresholds considered, the probability of B + P being considered cost-effective never exceeded 75%. TRIAL REGISTRATION: The trial was prospectively registered with the ISRCTN (reference number ISRCTN77044005) on the 26th January 2009 and East of Scotland Research Ethics Committee provided ethical approved (REC reference: 12/ES/0047).

Fluoride retention in infants living in fluoridated and non-fluoridated areas: effects of weaning.

Limited knowledge is available on total fluoride exposure, excretion and retention in infants, despite the first year of human life being the critical period for dental development and risk of dental fluorosis. This study investigated total daily fluoride intake (TDFI), excretion (TDFE) and retention (TDFR) in infants living in fluoridated and non-fluoridated water areas at pre- and post-weaning stages of development. Healthy infants, aged 0-12 months, were recruited and their TDFI (mg/kg body weight (BW) per d), from diet and toothpaste ingestion, was assessed over a 3-d period using a dietary diary and tooth-brushing questionnaire. TDFE (mg/kg BW per d) was estimated by collecting 48-h urine and faeces. TDFR (mg/kg BW per d) was estimated by subtracting TDFE from TDFI. A total of forty-seven infants completed the study: sixteen at pre-weaning and thirty-one at post-weaning stages, with a mean age of 3·4 and 10·0 months, respectively. TDFI was lower in the non-fluoridated area (P<0·001) and at the pre-weaning stage (P=0·002) but higher in formula-fed infants (P<0·001). TDFE was mainly affected by type of feeding, with higher excretion in formula-fed infants (P<0·001). TDFR was lower in the non-fluoridated area (P<0·001) and at the pre-weaning stage (P<0·001) but higher in formula-fed infants (P=0·001). In conclusion, a relatively large proportion of fluoride intake is retained in the body in weaned infants. This is an important consideration in fluoride-based prevention programmes, with goals to maximise caries prevention while minimising the risk of dental fluorosis.

A Comparison of Simple Analytical Methods for Determination of Fluoride in Microlitre-Volume Plasma Samples.

The aim was to compare potential methods for fluoride analysis in microlitre-volume plasma samples containing nano-gram amounts of fluoride. Methods: A group of 4 laboratories analysed a set of standardised biological samples as well as plasma to determine fluoride concentration using 3 methods. In Phase-1, fluoride analysis was carried out using the established hexamethyldisiloxane (HMDS)-diffusion method (1 mL-aliquot/analysis) to obtain preliminary measurement of agreement between the laboratories. In Phase-2, the laboratories analysed the same samples using a micro-diffusion method and known-addition technique with 200 µL-aliquot/analysis. Coefficients of Variation (CVs) and intra-class correlation coefficients (ICCs) were estimated using analysis of variance to evaluate the amount of variation within- and between-laboratories. Based on the results of the Phase-2 analysis, 20 human plasma samples were analysed and compared using the HMDS-diffusion method and known-addition technique in Phase-3. Results: Comparison of Phase-1 results showed no statistically significant difference among the laboratories for the overall data set. The mean between- and within-laboratory CVs and ICCs were < 0.13 and ≥0.99, respectively, indicating very low variability and excellent reliability. In Phase-2, the overall results for between-laboratory variability showed a poor CV (1.16) and ICC (0.44) for the micro-diffusion method, whereas with the known-addition technique the corresponding values were 0.49 and 0.83. Phase-3 results showed no statistically significant difference in fluoride concentrations of the plasma samples measured with HMDS-diffusion method and known- addition technique, with a mean (SE) difference of 0.002 (0.003) µg/mL. In conclusion, the known-addition technique could be a suitable alternative for the measurement of fluoride in plasma with microlitre-volume samples.

Comparison of total ionic strength adjustment buffers III and IV in the measurement of fluoride concentration of teas.

BACKGROUND: Tea is the second most consumed drink in the UK and a primary source of hydration; it is an important source of dietary fluoride (F) for consumers and also abundant in aluminium (Al). Varying ranges of F concentrations in teas have been reported worldwide which may be, in part, due to differences in analytical techniques used to measure this ion. AIM: The effect of using total ionic adjustment buffers (TISAB) III or IV when measuring F concentration of black teas available in the UK was investigated and compared. Based on this evaluation, the effects of three different infusion times, 1 min, 10 min and 1 h, caffeine content and tea form on the F contents of the tea samples were investigated. METHODS: The F concentrations of 47 tea samples were measured directly using a fluoride ion-selective electrode (F-ISE), TISAB III and IV and infusion times of 1 min, 10 min and 1 h. RESULTS: Mean (SD) F concentration of tea samples for all infusion times was statistically significantly higher ( p < 0.001) measured by TISAB IV (4.37 (2.16) mg/l) compared with TISAB III (3.54 (1.65) mg/l). A statistically significant positive correlation ( p < 0.001) was found between Al concentration (mg/l) and differences in F concentration (mg/l) measured using the two TISABs; the difference in F concentration measured by the two TISABs increased with the magnitude of Al concentration. CONCLUSION: Due to higher concentrations of F and Al in teas and their complexing potential, use of TISAB IV facilitates more accurate measurement of F concentration when using an F-ISE and a direct method.

Fluoride concentrations in a range of ready-to-drink beverages consumed in Heilongjiang Province, north-east China.

Consumption of ready-to-drink beverages, as a potential source of fluoride (F), has increased considerably in China over the last decade. To help inform the public and policy makers, this study aimed to measure F concentration of ready-to-drink beverages on sale in Heilongjiang province, north east China. Three batches of 106 drink products manufactured by 26 companies were purchased from the main national supermarkets in Harbin, Heilongjiang province, China. The F concentration of all samples was determined, in triplicate, using a fluoride ion-selective electrode in conjunction with a meter and a direct method of analysis. The products were categorised into 10 groups according to product type. F concentrations of the samples ranged from 0.012-1.625 mg/l with a mean of 0.189 mg/l and a median of 0.076 mg/l. More than half of the products (55%) had an F concentration of ≤0.1 mg/l, while <5% had a F concentration of >0.7 mg/l. The 'tea with milk' group contained the highest mean F concentration (1.350 mg/l), whereas the lowest mean F concentration (0.027 mg/l) was found for the 'fruit juice' group. For some products, such as tea, fruit juice and carbonated beverages, there were substantial variations in F concentration between batches, manufacturers and production sites. In conclusion, ready-to-drink products (apart from tea), sold in Heilongjiang province, China, when consumed in moderation are unlikely to constitute a substantial risk factor for the development of dental or skeletal fluorosis.

Development of a Database of the Fluoride Content of Selected Drinks and Foods in the UK.

It is important to monitor systemic fluoride (F) intake from foods, drinks and inadvertent toothpaste ingestion in order to minimise the risk of dental fluorosis while maximising caries prevention. In the UK, an F database containing the F content of commercially available foods and drinks was compiled from 518 products analysed using an acid-diffusion method and F-ion-selective electrode. The individual products analysed ranged from <0.01 µg F/100 g for butter/margarine (miscellaneous foods group) to 1,054.20 µg F/100 g for canned sardines (fish group). These findings, along with the wide range of F contents found within the food groups, highlight the need for comprehensive F content labelling of food and drink products.

Total daily fluoride intake and the relative contributions of foods, drinks and toothpaste by 3- to 4-year-old children in the Gaza Strip - Palestine.

BACKGROUND: Children in Gaza Strip suffer from a high prevalence of dental fluorosis. AIMS: To estimate and compare total daily fluoride (F) intake (TDFI) and investigate the relative contributions of different sources of F to TDFI, in 3- to 4-year-old children in Gaza Strip, exposed to low (<0.7 mg/litre), moderate (0.7-1.2 mg/litre) or high (>1.2 mg/litre) F concentrations in tap water. DESIGN: A 3-day food diary and samples of tap water, drinks, foods, toothpastes and toothbrushing expectorate were collected from 216 children receiving low (n = 81), moderate (n = 72) or high (n = 63) F concentrations in tap water. F concentration of samples was analysed using an F-ion-selective electrode. TDFI from all sources was estimated. Data were analysed by anova and Tukey's test. RESULTS: The mean (±SD) F concentration in low, moderate and high F tap waters was 0.21(±0.15), 0.91(±0.13) and 1.71(±0.35) mg/litre, respectively. Mean (±SD) TDFI was 0.02(±0.01), 0.04(±0.01) and 0.05(±0.03) mg/kg bw/day, respectively (P < 0.0001). Foods made the largest contribution (63.9%) to TDFI. CONCLUSION: Total daily fluoride (F) intake increased as F concentration in tap water increased. Foods were the primary source of F. Programmes for monitoring fluoride expose should consider the fluoride concentration of water used for food preparation and local dietary behaviours.

Nutrient intake and dietary patterns of relevance to dental health of 12-year-old Libyan children.

OBJECTIVE: There are few data on the dietary intake of children in Libya, and none on free sugars intake. The present study aimed to report the intake of macronutrients and eating habits of relevance to dental health in a group of Libyan schoolchildren and to investigate any gender differences for these variables. DESIGN: Dietary information was obtained from a randomly selected sample using an estimated 3 d food diary. Dietary data were coded using food composition tables and entered into a Microsoft® Access database. Intakes of energy, macronutrients, sugars and the amount of acidic items consumed were determined using purpose-written programs. SETTING: Benghazi, Libya. SUBJECTS: Schoolchildren aged 12 years. RESULTS: One hundred and eighty children (ninety-two boys and eighty-eight girls) completed the study. Their mean age was 12·3 (sd 0·29) years. The average daily energy intake was 7·01 (sd 1·54) MJ/d. The percentage contributions to energy intake from protein, fat and carbohydrate were 16 %, 30 % and 54 %, respectively. Total sugars contributed 20·4 % of the daily energy intake, and free sugars 12·6 %. The median daily intake of acidic items was 203 g/d, and of acidic drinks was 146 g/d. There were no statistically significant differences in nutrient intakes between genders. Intake of acidic items was higher in girls (P < 0·001). CONCLUSIONS: The contribution to energy intake from macronutrients was in accordance with global nutrition guidelines. The acidic drinks intake was low compared with other populations, while free sugars intake was above the recommended threshold of 10 % of energy intake.

ADA clinical recommendations on topical fluoride for caries prevention.

SCOPE AND PURPOSE: This guideline is intended to assist practitioners with decision making about the use of topical fluoride caries-preventive agents. It presents evidence-based clinical recommendations on professionally applied and prescription strength, home-use topical fluoride agents for caries prevention. Three clinical questions on the use of topical fluoride caries-preventive agents are addressed: In primary and permanent teeth, does the use of a topical fluoride compared to no topical fluoride reduce the incidence of new lesions, or arrest or reverse existing coronal and/or root caries? For primary and permanent teeth, is one topical fluoride agent more effective than another in reducing the incidence of, or arresting or reversing coronal and/or root caries?Does the use of prophylaxis before application of topical fluoride reduce the incidence of caries to a greater extent than topical fluoride application without prophylaxis? Sodium, stannous and acidulated phosphate fluoride for professional and prescription home use, including varnishes, gels, foams, rinses and prophylaxis pastes were evaluated. METHODOLOGY: The previous version of this review (2006 ADA policy) was based on assimilation of evidence from systematic reviews. However, this update synthesises primary evidence collected through systematic review and appraisal of the literature.The Cochrane Library and Medline (via PubMed) were searched. Relevant systematic reviews and other selected articles were hand-searched.Two reviewers independently screened titles and abstracts, with one reviewer assessing all manuscripts in full for meeting the inclusion criteria. Two different members of the expert panel then approved the exclusion list. Discrepancies were resolved through discussion with the Chair of the workgroup. The USPSTF grading system was used. REVIEW AND UPDATING: Five-year interval update in line with the ADA policy. RECOMMENDATIONS: For individuals at risk of dental caries: 2.26% fluoride varnish or 1.23% fluoride (APF) gel, or prescription strength, home-use 0.5% fluoride gel or paste, or 0.09% fluoride mouth rinse for children who are aged six or over.The panel judged that the benefits outweighed the potential for harm for all professionally applied and prescription strength, home-use topical fluoride agents and age groups except for children aged under six years. Only 2.26% fluoride varnish was recommended for children less than six years old, as the panel considered the risk of adverse events (particularly nausea and vomiting) associated with swallowing all other professionally applied topical fluoride agents outweighed the potential benefits.There was insufficient data to answer the question on arresting and reversing coronal and/or root caries, so these outcomes were not addressed in the clinical recommendations. RESEARCH RECOMMENDATIONS: These focused on development of standard methodologies for well-designed trials with standardised reporting and trial registration. Specific areas for research included: investigation of mechanisms of fluoride action and effects against a background fluoride exposure; investigation of specific sub-groups such as high-risk elderly; research on specific products; measure and outcome development for arrested caries; economics and dissemination/implementation to realise guideline use.

Prevalence and aetiology of juvenile skeletal fluorosis in the south-west of the Hai district, Tanzania--a community-based prevalence and case-control study.

INTRODUCTION: Fluorosis is endemic throughout the East African Rift valley, including parts of Tanzania. The aim of the study was to identify all cases of deforming juvenile skeletal fluorosis (JSF) in a northern Tanzanian village and to document the extent of dental fluorosis (DF). METHODS: Door-to-door prevalence survey of all residents of the village. Residents were assessed for the presence of DF and JSF. Those with JSF and randomly selected controls from the same age range were further assessed for possible JSF risk factors. RESULTS: The village had a population of 1435. DF was endemic within the population, being present in 911 (75.5%; 95% CI, 73.0-77.9) of dentate individuals who were examined (n = 1207). JSF was present in 56 of 1263 people examined, giving a prevalence of 4.4% (95% CI, 3.3-5.6) and was more common in males. Low body mass index, drinking predominantly well water 3 years previously, not being weaned on bananas, the use of fluoride salts in cooking during childhood and drinking more cups of tea per day were independent predictors of JSF. CONCLUSIONS: Juvenile skeletal fluorosis is a common and preventable public health problem. Providing clean, low-fluoride, piped water to affected communities is of obvious health benefit.

The FiCTION dental trial protocol - filling children's teeth: indicated or not?

BACKGROUND: There is a lack of evidence for effective management of dental caries (decay) in children's primary (baby) teeth and an apparent failure of conventional dental restorations (fillings) to prevent dental pain and infection for UK children in Primary Care. UK dental schools' teaching has been based on British Society of Paediatric Dentistry guidance which recommends that caries in primary teeth should be removed and a restoration placed. However, the evidence base for this is limited in volume and quality, and comes from studies conducted in either secondary care or specialist practices. Restorations provided in specialist environments can be effective but the generalisability of this evidence to Primary Care has been questioned. The FiCTION trial addresses the Health Technology Assessment (HTA) Programme's commissioning brief and research question "What is the clinical and cost effectiveness of restoration caries in primary teeth, compared to no treatment?" It compares conventional restorations with an intermediate treatment strategy based on the biological (sealing-in) management of caries and with no restorations. METHODS/DESIGN: This is a Primary Care-based multi-centre, three-arm, parallel group, patient-randomised controlled trial. Practitioners are recruiting 1461 children, (3-7 years) with at least one primary molar tooth where caries extends into dentine. Children are randomized and treated according to one of three treatment approaches; conventional caries management with best practice prevention, biological management of caries with best practice prevention or best practice prevention alone. Baseline measures and outcome data (at review/treatment during three year follow-up) are assessed through direct reporting, clinical examination including blinded radiograph assessment, and child/parent questionnaires. The primary outcome measure is the incidence of either pain or infection related to dental caries. Secondary outcomes are; incidence of caries in primary and permanent teeth, patient quality of life, cost-effectiveness, acceptability of treatment strategies to patients and parents and their experiences, and dentists' preferences. DISCUSSION: FiCTION will provide evidence for the most clinically-effective and cost-effective approach to managing caries in children's primary teeth in Primary Care. This will support general dental practitioners in treatment decision making for child patients to minimize pain and infection in primary teeth. The trial is currently recruiting patients. TRIAL REGISTRATION: Protocol ID: NCTU: ISRCTN77044005.

ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function.

Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.

Fluoridated toothpaste: usage and ingestion of fluoride by 4- to 6-yr-old children in England.

Fluoridated toothpaste is effective for dental caries control, yet may be a risk factor for dental fluorosis. This study aimed to quantify fluoride ingestion from toothpaste by children and to investigate the effects of age, gender, and social class on the amount of fluoride ingested per toothbrushing session. Sixty-one children, 4-6 yr of age, were recruited: 38 were from low socio-economic (LSE) areas of Newcastle, UK, and 23 were from high socio-economic (HSE) areas of Newcastle, UK. All expectorated saliva, rinse water (if used), and residual toothpaste were collected after brushing at home and were analysed for fluoride. Of the children, 74% and 69% from HSE and LSE areas, respectively, claimed that they brushed twice per day. The mean (SD) weight of toothpaste dispensed was 0.67 (0.36) g. The mean (SD) amount of fluoride ingested per toothbrushing session and per day was 17.0 (14.7) and 29.3 (32.8) µg kg(-1) of body weight, respectively. Daily fluoride intake per kilogram of body weight did not differ significantly between children from LSE and HSE areas. Fluoride intake per toothbrushing session was significantly influenced by weight of toothpaste, its fluoride concentration, and the child's age. Whilst the average amount of toothpaste used per toothbrushing session was more than twice the recommended amount (of 0.25 g), only one child had a daily fluoride intake that exceeded the tolerable upper intake level of 0.1 mg kg(-1) of body weight for this age group.

The association between social deprivation and the prevalence and severity of dental caries and fluorosis in populations with and without water fluoridation.

BACKGROUND: To determine the association between social deprivation and the prevalence of caries (including caries lesions restricted to enamel) and enamel fluorosis in areas that are served by either fluoridated or non-fluoridated drinking water using clinical scoring, remote blinded, photographic scoring for caries and fluorosis. The study also aimed to explore the use of remote, blinded methodologies to minimize the effect of examiner bias. METHODS: Subjects were male and female lifetime residents aged 11-13 years. Clinical assessments of caries and fluorosis were performed on permanent teeth using ICDAS and blind scoring of standardized photographs of maxillary central incisors using TF Index (with cases for fluorosis defined as TF > 0). RESULTS: Data from 1783 subjects were available (910 Newcastle, 873 Manchester). Levels of material deprivation (Index of Multiple Deprivation) were comparable for both populations (Newcastle mean 35.22, range 2.77-78.85; Manchester mean 37.04, range 1.84-84.02). Subjects in the fluoridated population had significantly less caries experience than the non-fluoridated population when assessed by clinical scores or photographic scores across all quintiles of deprivation for white spot lesions: Newcastle mean DMFT 2.94 (clinical); 2.51 (photo), Manchester mean DMFT 4.48 (clinical); 3.44 (photo) and caries into dentine (Newcastle Mean DMFT 0.65 (clinical); 0.58 (photo), Manchester mean DMFT 1.07 (clinical); 0.98 (photo). The only exception being for the least deprived quintile for caries into dentine where there were no significant differences between the cities: Newcastle mean DMFT 0.38 (clinical); 0.36 (photo), Manchester mean DMFT 0.45 (clinical); 0.39 (photo). The odds ratio for white spot caries experience (or worse) in Manchester was 1.9 relative to Newcastle. The odds ratio for caries into dentine in Manchester was 1.8 relative to Newcastle. The odds ratio for developing fluorosis in Newcastle was 3.3 relative to Manchester. CONCLUSIONS: Water fluoridation appears to reduce the social class gradient between deprivation and caries experience when considering caries into dentine. However, this was associated with an increased risk of developing mild fluorosis. The use of intra-oral cameras and remote scoring of photographs for caries demonstrated good potential for blinded scoring.

Dental caries and its association with diet and dental erosion in Libyan schoolchildren.

BACKGROUND. The change towards a more Westernised diet in Libya may increase the risk of caries and erosion in children. AIMS. To investigate any association between dental caries, dental erosion, and potential dietary risk factors in Libyan schoolchildren. METHODS. A random sample of 791 schoolchildren aged 12 years underwent dental examination for caries and erosion and completed a questionnaire to provide dietary data. Dental caries was assessed using the WHO (Oral Health Surveys: Basic Methods, 1997) criteria. Erosion was assessed using UK National Diet and Nutrition Survey (NDNS, Young People Aged 4-18 years. Volume 2: Report of the Oral Health Survey, 2000) criteria. Associations between caries and dietary variables were investigated through bivariate and multivariate analyses. RESULTS. Of the 791 12-year olds, 57.8% (457) had caries experience and 40.8% (323) had experience of erosion. One hundred and ninety-two subjects (42%) of the subjects with caries experience also had erosion, whilst 131 subjects (39.2%) of the 334 without caries had clinical signs of erosion (P = 0.464; OR, 1.123; 95% CI, 0.842, 1.497). There was no statistically significantly relationship between dental caries and dental erosion. Frequency of consumption of fruit-based sugared drinks was statistically significantly positively associated with experience of caries (P = 0.002). CONCLUSIONS. Dental caries experience was associated with frequency of consumption of sugared dietary items but not with dental erosion.

Evaluating the use of fluorescent imaging for the quantification of dental fluorosis.

BACKGROUND: The quantification of fluorosis using fluorescence imaging (QLF) hardware and stain analysis software has been demonstrated in selected populations with good correlation between fluorescent image metrics and TF Index scores from photographs. The aim of this study was to evaluate the ability of QLF to quantify fluorosis in a population of subjects (aged 11-13) participating in an epidemiological caries and fluorosis survey in fluoridated and non-fluoridated communities in Northern England. METHODS: Fluorescent images of the maxillary incisors were captured together with standardized photographs were scored blind for fluorosis using the TF Index. Subjects were excluded from the analysis if there were restorations or caries on the maxillary central incisors. RESULTS: Data were available for 1774 subjects (n=905 Newcastle, n=869 Manchester). The data from the fluorescence method demonstrated a significant correlation with TF Index scores from photographs (Kendall's tau = 0.332 p<0.0001). However, a number of additional confounding factors such as the presence of extrinsic stain or increased enamel translucency on some subjects without fluorosis or at low levels of fluorosis severity had an adverse impact on tooth fluorescence and hence the outcome variable. This in conjunction with an uneven distribution of subjects across the range of fluorosis presentations may have resulted in the lower than anticipated correlations between the fluorescent imaging metrics and the photographic fluorosis scores. Nevertheless, the fluorescence imaging technique was able to discriminate between a fluoridated and non-fluoridated population (p<0.001). CONCLUSIONS: Despite confounding factors the fluorescence imaging system may provide a useful objective, blinded system for the assessment of enamel fluorosis when used adjunctively with photographic scoring.