Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility.

Resistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res 68:5318-5325, 2008) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

Inhibition of Aminoglycoside 6'-N-acetyltransferase Type Ib (AAC(6')-Ib): Structure-Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors.

The aminoglycoside 6'-N-acetyltransferase type Ib (AAC(6')-Ib) is a common cause of resistance to amikacin and other aminoglycosides in Gram-negatives. Utilization of mixture-based combinatorial libraries and application of the positional scanning strategy identified an inhibitor of AAC(6')-Ib. This inhibitor's chemical structure consists of a pyrrolidine pentamine scaffold substituted at four locations (R1, R3, R4, and R5). The substituents are two S-phenyl groups (R1 and R4), an S-hydroxymethyl group (R3), and a 3-phenylbutyl group (R5). Another location, R2, does not have a substitution, but it is named because its stereochemistry was modified in some compounds utilized in this study. Structure-activity relationship (SAR) analysis using derivatives with different functionalities, modified stereochemistry, and truncations was carried out by assessing the effect of the addition of each compound at 8 µM to 16 µg/mL amikacin-containing media and performing checkerboard assays varying the concentrations of the inhibitor analogs and the antibiotic. The results show that: (1) the aromatic functionalities at R1 and R4 are essential, but the stereochemistry is essential only at R4; (2) the stereochemical conformation at R2 is critical; (3) the hydroxyl moiety at R3 as well as stereoconformation are required for full inhibitory activity; (4) the phenyl functionality at R5 is not essential and can be replaced by aliphatic groups; (5) the location of the phenyl group on the butyl carbon chain at R5 is not essential; (6) the length of the aliphatic chain at R5 is not critical; and (7) all truncations of the scaffold resulted in inactive compounds. Molecular docking revealed that all compounds preferentially bind to the kanamycin C binding cavity, and binding affinity correlates with the experimental data for most of the compounds evaluated. The SAR results in this study will serve as the basis for the design of new analogs in an effort to improve their ability to induce phenotypic conversion to susceptibility in amikacin-resistant pathogens.

Equity, social determinants and public health programmes--the case of oral health.

The WHO Commission on Social Determinants of Health issued the 2008 report 'Closing the gap within a generation - health equity through action on the social determinants of health' in response to the widening gaps, within and between countries, in income levels, opportunities, life expectancy, health status, and access to health care. Most individuals and societies, irrespective of their philosophical and ideological stance, have limits as to how much unfairness is acceptable. In 2010, WHO published another important report on 'Equity, Social Determinants and Public Health Programmes', with the aim of translating knowledge into concrete, workable actions. Poor oral health was flagged as a severe public health problem. Oral disease and illness remain global problems and widening inequities in oral health status exist among different social groupings between and within countries. The good news is that means are available for breaking poverty and reduce if not eliminate social inequalities in oral health. Whether public health actions are initiated simply depends on the political will. The Ottawa Charter for Health Promotion (1986) and subsequent charters have emphasized the importance of policy for health, healthy environments, healthy lifestyles, and the need for orientation of health services towards health promotion and disease prevention. This report advocates that oral health for all can be promoted effectively by applying this philosophy and some major public health actions are outlined.

Effects of weight and syntactic priming on the production of cantonese verb-doubling.

Verb-doubling, where a copy of the main verb occurs both before and after the direct object, is a structure commonly used in Chinese in sentences containing a frequency or duration phrase. In Cantonese, verb-doubling is highly optional and therefore problematic for existing syntactic, semantic, and pragmatic accounts of its distribution in Mandarin. The current study investigates the role of grammatical weight and syntactic priming in the choice of verb-doubling in Cantonese. Following (Hawkins in Efficiency and complexity in grammars, Oxford University Press, Oxford, 2004) theory of efficiency and complexity in grammars, we hypothesized that speakers would choose verb-doubling over the canonical structure more often when the object NP was heavy, in order to minimize processing domains. In addition, we expected an effect of syntactic priming whereby the choice of structure is influenced by a previously encountered structure. The results of two elicited production experiments revealed no weight-based preference for verb-doubling, and only minor effects of grammatical weight, but clear effects of syntactic priming: (1) for both canonical primes and verb-doubling primes, speakers tended to repeat previously heard structures; (2) the priming effect was just as strong in the heavy NP condition, where speakers made more errors recalling the semantic content of the sentence, suggesting that semantic information is represented separately from syntactic information; (3) the priming effect was stronger for informationally accurate responses, suggesting that recently activated structures are easier to produce than other structures under conditions of increased cognitive load. We conclude that the choice between verb-doubling and canonical structure in Cantonese is easily influenced by the structure of recently encountered sentences, with weight effects, if any, being more difficult to detect.

Aspectual asymmetries in the mental representation of events: Role of lexical and grammatical aspect.

Temporal information is important in the construction of situation models, and many languages make use of perfective and imperfective aspect markers to distinguish between completed situations (e.g., He made a cake) and ongoing situations (e.g., He is making a cake). Previous studies in which the effect of grammatical aspect has been examined have shown that perfective sentences are often processed more quickly than imperfective ones (e.g., Chan, Yap, Shirai, & Matthews, 2004; Madden & Zwaan, 2003; Yap et al., 2004; Yap et al., 2006). However, these studies used only accomplishment verbs (i.e., verbs with an inherent endpoint, such as bake a cake). The present study on the processing of Cantonese includes activity verbs (i.e., durative verbs with no inherent endpoint, such as play the piano), and the results indicate a strong interaction between lexical aspect (i.e., verb type) and grammatical aspect. That is, perfective sentences were processed more quickly with accomplishment verbs, consistent with previous findings, but imperfective sentences were processed more quickly with activity verbs. We suggest that these different aspectual asymmetries emerge as a result of the inherent associations between accomplishment verbs and the bounded features of perfective aspect and between activity verbs and the unbounded features of imperfective aspect. The sentence stimuli from this study may be downloaded from mc.psychonomic-journals.org/content/supplemental.

Interventions for replacing missing teeth: bone augmentation techniques for dental implant treatment.

BACKGROUND: Dental implants require sufficient bone to be adequately stabilised. For some patients implant treatment would not be an option without bone augmentation. A variety of materials and surgical techniques are available for bone augmentation. OBJECTIVES: General objectives: To test the null hypothesis of no difference in the success, function, morbidity and patient satisfaction between different bone augmentation techniques for dental implant treatment. SPECIFIC OBJECTIVES: (A) to test whether and when augmentation procedures are necessary; (B) to test which is the most effective augmentation technique for specific clinical indications. Trials were divided into three broad categories according to different indications for the bone augmentation techniques: (1) major vertical or horizontal bone augmentation or both; (2) implants placed in extraction sockets; (3) fenestrated implants. SEARCH STRATEGY: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Several dental journals were handsearched. The bibliographies of review articles were checked, and personal references were searched. More than 55 implant manufacturing companies were also contacted. Last electronic search was conducted on 9th January 2008. SELECTION CRITERIA: Randomised controlled trials (RCTs) of different techniques and materials for augmenting bone for implant treatment reporting the outcome of implant therapy at least to abutment connection. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted independently and in duplicate. Authors were contacted for any missing information. Results were expressed as random-effects models using mean differences for continuous outcomes and odd ratios for dichotomous outcomes with 95% confidence intervals. The statistical unit of the analysis was the patient. MAIN RESULTS: Seventeen RCTs out of 40 potentially eligible trials reporting the outcome of 455 patients were suitable for inclusion. Since different techniques were evaluated in different trials, no meta-analysis could be performed. Ten trials evaluated different techniques for vertical or horizontal bone augmentation or both. Four trials evaluated different techniques of bone grafting for implants placed in extraction sockets and three trials evaluated different techniques to treat bone dehiscence or fenestrations around implants. AUTHORS' CONCLUSIONS: Major bone grafting procedures of resorbed mandibles may not be justified. Bone substitutes (Bio-Oss or Cerasorb) may replace autogenous bone for sinus lift procedures of atrophic maxillary sinuses. Various techniques can augment bone horizontally and vertically, but it is unclear which is the most efficient. It is unclear whether augmentation procedures at immediate single implants placed in fresh extraction sockets are needed, and which is the most effective augmentation procedure, however, sites treated with barrier plus Bio-Oss showed a higher position of the gingival margin when compared to sites treated with barriers alone. Non-resorbable barriers at fenestrated implants regenerated more bone than no barriers, however it remains unclear whether such bone is of benefit to the patient. It is unclear which is the most effective technique for augmenting bone around fenestrated implants. Bone morphogenetic proteins may enhance bone formation around implants grafted with Bio-Oss. Titanium may be preferable to resorbable screws to fixate onlay bone grafts. The use of particulate autogenous bone from intraoral locations, also taken with dedicated aspirators, might be associated with an increased risk of infective complications. These findings are based on few trials including few patients, sometimes having short follow up, and often being judged to be at high risk of bias.

The hierarchical cluster analysis of oral health attitudes and behaviour using the Hiroshima University--Dental Behavioural Inventory (HU-DBI) among final year dental students in 17 countries.

OBJECTIVE: To explore and describe international oral health attitudes/ behaviours among final year dental students. METHODS: Validated translated versions of the Hiroshima University-Dental Behavioural Inventory (HU-DBI) questionnaire were administered to 1,096 final-year dental students in 17 countries. Hierarchical cluster analysis was conducted within the data to detect patterns and groupings. RESULTS: The overall response rate was 72%. The cluster analysis identified two main groups among the countries. Group 1 consisted of twelve countries: one Oceanic (Australia), one Middle-Eastern (Israel), seven European (Northern Ireland, England, Finland, Greece, Germany, Italy, and France) and three Asian (Korea, Thailand and Malaysia) countries. Group 2 consisted of five countries: one South American (Brazil), one European (Belgium) and three Asian (China, Indonesia and Japan) countries. The percentages of 'agree' responses in three HU-DBI questionnaire items were significantly higher in Group 2 than in Group 1. They include: "I worry about the colour of my teeth."; "I have noticed some white sticky deposits on my teeth."; and "I am bothered by the colour of my gums." CONCLUSION: Grouping the countries into international clusters yielded useful information for dentistry and dental education.

Health-promoting schools: an opportunity for oral health promotion.

Schools provide an important setting for promoting health, as they reach over 1 billion children worldwide and, through them, the school staff, families and the community as a whole. Health promotion messages can be reinforced throughout the most influential stages of children's lives, enabling them to develop lifelong sustainable attitudes and skills. Poor oral health can have a detrimental effect on children's quality of life, their performance at school and their success in later life. This paper examines the global need for promoting oral health through schools. The WHO Global School Health Initiative and the potential for setting up oral health programmes in schools using the health-promoting school framework are discussed. The challenges faced in promoting oral health in schools in both developed and developing countries are highlighted. The importance of using a validated framework and appropriate methodologies for the evaluation of school oral health projects is emphasized.

A comparative study of oral health attitudes and behaviour using the Hiroshima University - Dental Behavioural Inventory (HU-DBI) between dental students in Britain and China.

The aim of this study was to compare oral health attitudes and behaviour between British and Chinese dental students. A cross-national survey using the Hiroshima University - Dental Behavioural Inventory (HU-DBI) was completed at the University of Leeds in Britain and West China University of Medical Sciences in China. In Britain and China, 192 of 266 and 180 of 303 dental students answered English and Chinese versions of the HU-DBI questionnaire, respectively. Data were statistically analyzed by logistic regression and the following results were obtained: 1) Self-reported gingival bleeding was more prevalent in Chinese students than in British students, although the number of students who had professional oral hygiene instruction was higher in China than in Britain; 2) 29% of Chinese students believed wearing dentures in old age was inevitable, whereas 7% of British students believed so; 3) Chinese students were substantially more concerned about the appearance of their teeth, gums and halitosis; and 4) 54% of Chinese students seek dental care only when symptoms arise, as compared to 13% of British students. In conclusion, bilateral comparison of countries using HU-DBI revealed interesting differences in oral health attitudes and behaviour, while the logistic regression model made it possible to differentiate British from Chinese students with a probability of nearly 95%.

Evaluation of community-based oral health promotion and oral disease prevention--WHO recommendations for improved evidence in public health practice.

Systematic evaluation is an integral part of the organisation and delivery of community oral health care programmes, ensuring the effectiveness of these community-based interventions. As for general health promotion programmes the common problems from effectiveness reviews of oral health interventions relate to the quality and validity of programme evaluations. Problems identified mostly refer to the quality of outcome measures, short-term timescales to assess change, inadequate evaluation methodologies and inappropriate evaluation of programme implementation and processes. It remains a challenge to oral health professionals to integrate community oral health programmes into a wider health agenda. Public health research focusing on the development of evaluation methodologies has identified a variety of issues including the importance of using pluralistic evaluation approaches (quantitative and/or qualitative), limitations of the randomised controlled trial (RCT) design for evaluation of public health interventions, the need to match evaluation methods with the nature of intervention, development of outcome measures appropriate for the nature of intervention, importance of developing workforce capacity in evaluation techniques, and the need for development of partnerships between health practitioners and academics in conducting evaluations. In June 2003, the WHO Oral Health Programme at Headquarters organised a two-day workshop to take forward the development and documentation of the evaluation of oral health promotion and oral disease prevention programmes. The aims of the workshop were to: (1) identify common problems and challenges in evaluating community-based oral health interventions; (2) explore developments in the evaluation approaches in public health; (3) share experiences in evaluating oral health intervention programmes implemented at national or community levels in developing and developed countries and (4) develop guidelines for quality evaluation of national and community oral health programmes. Twenty-two invitees from 15 countries attended in addition to WHO staff. The first day was devoted to presentations of oral health promotion and oral disease prevention programmes from around the world. During the second day, WHO staff at Headquarters in Geneva discussed aspects of evaluation of public health programmes. Two working groups were formed to discuss agreed topics, and the reports from their deliberations, together with the general discussion, resulted in the presentation of emerging key issues and recommendations. In summary, it was agreed that evaluation of oral health promotion and disease prevention programmes should integrate, whenever possible, with general health programmes. While the design and advantages of RCTs in clinical evaluations are well documented, the relevance of this design in evaluation of community oral disease preventive programmes and oral health promotion programmes are much less clearly defined. Subsequently, the conduct of such programmes may be inappropriately evaluated in systematic reviews. There is a need for more research into appropriate immediate, interim and ultimate outcome measures, as well as process evaluation, an assessment that is poorly understood and practised less often than outcome evaluation. Guidance on potential design, conduct, and especially the evaluation, of community oral disease prevention programmes and oral health promotion programmes should be developed and updated regularly. WHO Collaborating Centres could have a role in promoting good practice, training and collaboration between teams throughout the world. Centres undertaking systematic reviews should consider the guidelines given in the proposed WHO document when defining their evaluation criteria.