Initial Case Reports of Cancer in Naked Mole-rats (Heterocephalus glaber).

Naked mole-rats (NMRs;Heterocephalus glaber) are highly adapted, eusocial rodents renowned for their extreme longevity and resistance to cancer. Because cancer has not been formally described in this species, NMRs have been increasingly utilized as an animal model in aging and cancer research. We previously reported the occurrence of several age-related diseases, including putative pre-neoplastic lesions, in zoo-housed NMR colonies. Here, we report for the first time 2 cases of cancer in zoo-housed NMRs. In Case No. 1, we observed a subcutaneous mass in the axillary region of a 22-year-old male NMR, with histologic, immunohistochemical (pancytokeratin positive, rare p63 immunolabeling, and smooth muscle actin negative), and ultrastructural characteristics of an adenocarcinoma possibly of mammary or salivary origin. In Case No. 2, we observed a densely cellular, poorly demarcated gastric mass of polygonal cells arranged in nests with positive immunolabeling for synaptophysin and chromogranin indicative of a neuroendocrine carcinoma in an approximately 20-year-old male NMR. We also include a brief discussion of other proliferative growths and pre-cancerous lesions diagnosed in 1 zoo colony. Although these case reports do not alter the longstanding observation of cancer resistance, they do raise questions about the scope of cancer resistance and the interpretation of biomedical studies in this model. These reports also highlight the benefit of long-term disease investigations in zoo-housed populations to better understand naturally occurring disease processes in species used as models in biomedical research.

Potential of information technology in dental education.

The use of information technology (IT) in dentistry is far ranging. In order to produce a working document for the dental educator, this paper focuses on those methods where IT can assist in the education and competence development of dental students and dentists (e.g. e-learning, distance learning, simulations and computer-based assessment). Web pages and other information-gathering devices have become an essential part of our daily life, as they provide extensive information on all aspects of our society. This is mirrored in dental education where there are many different tools available, as listed in this report. IT offers added value to traditional teaching methods and examples are provided. In spite of the continuing debate on the learning effectiveness of e-learning applications, students request such approaches as an adjunct to the traditional delivery of learning materials. Faculty require support to enable them to effectively use the technology to the benefit of their students. This support should be provided by the institution and it is suggested that, where possible, institutions should appoint an e-learning champion with good interpersonal skills to support and encourage faculty change. From a global prospective, all students and faculty should have access to e-learning tools. This report encourages open access to e-learning material, platforms and programs. The quality of such learning materials must have well defined learning objectives and involve peer review to ensure content validity, accuracy, currency, the use of evidence-based data and the use of best practices. To ensure that the developers' intellectual rights are protected, the original content needs to be secure from unauthorized changes. Strategies and recommendations on how to improve the quality of e-learning are outlined. In the area of assessment, traditional examination schemes can be enriched by IT, whilst the Internet can provide many innovative approaches. Future trends in IT will evolve around improved uptake and access facilitated by the technology (hardware and software). The use of Web 2.0 shows considerable promise and this may have implications on a global level. For example, the one-laptop-per-child project is the best example of what Web 2.0 can do: minimal use of hardware to maximize use of the Internet structure. In essence, simple technology can overcome many of the barriers to learning. IT will always remain exciting, as it is always changing and the users, whether dental students, educators or patients are like chameleons adapting to the ever-changing landscape.

An in-vitro and in-vivo methodology study of alveolar bone measurement using extra-oral radiographic alignment apparatus, Image Pro-Plus software and a subtraction programme.

OBJECTIVES: (a) To validate a method for acquiring reproducible radiographic images and repeatable measurements of digital images. (b) To investigate the clinical and radiographic changes following periodontal surgery and in a periodontally healthy control group. METHODS: In-vitro study. Sixteen dried human skulls had replicate intra-oral radiographs taken using an extra-oral alignment apparatus under simulated clinical conditions, and measurements were made on the images using Image Pro-Plus analysis software. In-vivo study. Seven subjects, aged 38-63 years with chronic periodontitis, were treated using replaced flap surgery. Nine patients with healthy periodontal tissues were recruited as a control group. Clinical measurements and radiographs were taken pre-surgery and 6 months afterwards, and at the same interval for untreated healthy controls using the alignment apparatus. Radiographs were analysed using Image Pro-Plus and subtraction radiography. RESULTS: Radiographs had a high degree of reliability (ICC 0.98-0.99) for the in-vitro study and intra-operator repeatability of measurements was high (ICC 0.65-0.99) for the in-vivo study. Over this interval there were both significant clinical improvements and in bone gain within infra-bony defects on radiographs. Subtracted images showed that out of 17 surgically treated sites, 13 showed evidence of bone gain, one showed no change, two showed bone loss and one could not be interpreted due to poor alignment. Overall there were no significant clinical or radiographic changes in the control group. CONCLUSIONS: Radiographic images were highly reproducible. Measurements had a high degree of repeatability. The methods used allowed accurate quantitative and qualitative measurement of change in alveolar bone. This technique would allow accurate measurement of any changes in alveolar bone levels in patients with periodontal disease.

Quantification of dental plaque on lingual tooth surfaces using image analysis: reliability and validation.

AIM: The aim of this study was to increase the versatility and further validate the method reported by Smith et al. (2001) by testing the reliability of plaque measurement against two well-known dental plaque quantification methodologies using image analysis in a clinical trial. METHOD: The teeth of 40 subjects were disclosed before digital images of the labial and lingual surfaces of their upper and lower incisors were acquired. The amount of plaque present was quantified using a modification of the method described by Smith et al. (2001). The method was modified for obtaining images of the lingual surfaces by incorporating the use of orthodontic occlusal mirrors and 5-mm pieces of moistened blue articulating paper used to enable calibration. Plaque measurements were made from 320 upper and lower anterior teeth from the 40 subjects by two operators. Fliess' coefficient of reliability was used to assess intra- and inter-operator reliability and the independent sample t test was used to assess statistical significance between test and control groups after checking the data for normality. For validation, measurements were recorded using the Turesky et al. (1970) (modification of the Quigley & Hein (1962) plaque index and the Addy et al. (1983) plaque area index. The results were compared with the image analysis method using Pearson's correlation coefficient. RESULTS: The results for reliability were within Fliess' range of "excellent" for both intra-operator repeatability and inter-operator reproducibility. Pearson's correlation coefficients showed highly significant values indicating the close similarity between all three methods. CONCLUSIONS: This method for the measurement of dental plaque on lingual surfaces of anterior teeth proved reliable. The combined results from the labial and lingual surfaces of anterior teeth using image analysis produced trial conclusions comparable with the alternate plaque quantification methods used, with less clinician time and further producing a permanent database of images for future use.

Concordance between undergraduate dental students and their lecturers in their attitudes towards difficult patients.

The 'difficult' patient syndrome is caused by an imbalance in the dentist-patient relationship which may be influenced by human, cultural and psychosocial factors. The aim of this study was to compare the concordance between undergraduate dental students and lecturers in the degree of difficulty assigned to vignettes describing 'difficult' patients and to describe the extent to which ratings are influenced by gender, place of study and experience of specific 'difficult' patients. A questionnaire with 21 patient-stereotypes identified as difficult from the specialized literature was prepared. Both students and lecturers had to determine the degree of difficulty of each stereotype on a Likert-like scale. The students selected were in the final 2 years before graduation in Santiago de Compostela (Spain) and Porto (Portugal) Dental Schools. Lecturers were selected by simple random sampling method. Both lecturers and undergraduate students found more difficulty in those patients classified as aggressive, manipulative help-rejecters or patients with invasive companions. On the other hand, drug abusers and HIV-positive patients were ranked as presenting low levels of difficulty. Our results seem to point to the need of improving undergraduate teaching and learning of specific procedures for the management of aggressive or stubborn patients and those with invasive companions.

Effect of non-surgical periodontal treatment on clinical parameters and the numbers of Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemcomitans at adult periodontitis sites.

BACKGROUND, AIMS: The purpose of this study was to relate the numbers of Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemcomitans cells to clinical parameters at diseased and healthy periodontal sites before and after non-surgical periodontal therapy using a sensitive quantitative PCR method (Q-PCR). METHOD: The sensitivity of the Q-PCR was less than 10 cells for all three species. Subgingival plaque samples were collected from 541 sites in 50 adult periodontitis subjects pre-treatment, post-treatment and at a follow-up visit (3-6 months post-treatment). Pocket probing depth, attachment loss and bleeding on probing were recorded at each visit and both healthy and diseased sites in each subject were sampled. RESULTS: Quantification revealed that P. gingivalis counts were associated with pocket depth (p=0.006) and attachment loss (p=0.010); however, neither P. intermedia nor A. actinomycetemcomitans was associated with the clinical signs examined. Post-treatment, there was a significant decrease in the numbers of all three species in both the diseased and healthy sites (86-99%) but none were eradicated. Positive associations were found between any two of the three species studied both pre- and post-therapy. By the follow-up visit, there was a significant improvement in the probing depth of deep sites (p=0.001) but in no other clinical parameters. CONCLUSION: This study demonstrates the usefulness of Q-PCR for enumerating putative pathogens in clinical periodontal specimens and that the numbers of the three organisms in all sites decrease with non-surgical periodontal therapy.

A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.

Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis.

BACKGROUND: Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries. METHODS AND RESULTS: An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13). CONCLUSIONS: Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.

Interleukin-1 and IL-1 receptor antagonist in gingival crevicular fluid.

BACKGROUND/AIMS: This study aimed to investigate the cytokine IL-1beta and its receptor antagonist IL-1ra in gingival crevicular fluid (GCF), in patients with adult periodontitis. METHOD: A total of 40 GCF samples were harvested from 10 subjects with moderate to severe adult periodontitis and 10 healthy controls. Subjects were selected from both genders, with all the upper anterior teeth present, and with no relevant systemic illness, pregnancy or recent medication. All subjects were non-smokers and had not received any periodontal therapy within the preceding 3 months. Deep bleeding sites, deep non-bleeding sites and healthy sites were investigated in relation to upper anterior teeth. Clinical measurements were recorded for each site, after obtaining a GCF sample. IL-1beta and IL-1ra were quantified using new commercially available ELISA kits (Quantikine), and could be detected in all samples. RESULTS: The mean concentration for IL-1beta was 0.11 (SD 0.14) pg/microl for bleeding periodontitis sites, 0.04 (0.05) pg/microl for non-bleeding periodontitis sites, and 0.01 (0.03) pg/microl for healthy sites (p<0.001). In contrast, the mean concentration for IL-1ra was 6.99 (9.78) pg/microl for healthy sites, 0.59 (0.44) pg/microl for non-bleeding periodontitis sites, and 0.44 (0.36) pg/microl for bleeding periodontitis sites (p<0.001, except for comparisons between bleeding and non-bleeding periodontitis sites, p>0.05). For healthy sites, a strong inverse relationship was found between IL-1beta and IL-1ra levels in GCE. CONCLUSIONS: The results suggest a strong relationship between the severity of adult periodontitis and the increasing GCF levels of IL-1beta and decreasing levels of IL-1ra.

Quinolones as gonadotropin releasing hormone (GnRH) antagonists: simultaneous optimization of the C(3)-aryl and C(6)-substituents.

A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal.

Identification of Phe313 of the gonadotropin-releasing hormone (GnRH) receptor as a site critical for the binding of nonpeptide GnRH antagonists.

The dog GnRH receptor was cloned to facilitate the identification and characterization of selective nonpeptide GnRH antagonists. The dog receptor is 92% identical to the human GnRH receptor. Despite such high conservation, the quinolone-based nonpeptide GnRH antagonists were clearly differentiated by each receptor species. By contrast, peptide antagonist binding and functional activity were not differentiated by the two receptors. The basis of the differences was investigated by preparing chimeric receptors followed by site-directed mutagenesis. Remarkably, a single substitution of Phe313 to Leu313 in the dog receptor explained the major differences in binding affinities and functional activities. The single amino acid replacement of Phe313 of the human receptor with Leu313 resulted in a 160-fold decrease of binding affinity of the nonpeptide antagonist compound 1. Conversely, the replacement of Leu313 of the dog receptor with Phe313 resulted in a 360-fold increase of affinity for this compound. These results show that Phe313 of the GnRH receptor is critical for the binding of this structural class of GnRH antagonists and that the dog receptor can be "humanized" by substituting Leu for Phe. This study provides the first identification of a critical residue in the binding pocket occupied by nonpeptide GnRH antagonists and reinforces cautious extrapolation of ligand activity across highly conserved receptors.

Effects of evidence-based treatment and consent on professional autonomy.

Recent high profile cases like Wisheart (Bristol babies) has placed healthcare professional autonomy under both ethical and legal scrutiny, reflected by the growing number of civil cases brought by the public. The aim of this paper is to investigate the effect of evidence-based treatment on the legal requirements of consent, when the treatment transcends the therapeutic boundary. The potential effect on the autonomy of healthcare professionals is also discussed. The study revealed that although consent remains the cornerstone of defence in many areas of therapeutic treatment, it is open to significant legal challenge in the grey area between therapeutic evidence-based treatment and non-evidenced-based procedures. Consent remains the cornerstone of defence for therapeutic procedures. However, it is less certain with innovative treatment or procedures that transcend the therapeutic boundaries and are shown to be non-evidence-based.

Potent antagonists of gonadotropin releasing hormone receptors derived from quinolone-6-carboxamides.

SAR studies which focused upon the C-6 position of a recently described series of quinolone gonadotropin releasing hormone antagonists are reported. Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines. Amides related to 9y were especially potent, functional antagonists of rat and human GnRH receptors.

A retrospective study of shared learning on the BMedSci Dental Technology course at The University of Sheffield.

The aim of this study was to identify the level of shared learning on a Bachelor of Medical Science in Dental Technology (BMedSci) course at the University of Sheffield, School of Clinical Dentistry. A summative evaluation of the course was carried out, using semi-structured nominal group interviews. BMedSci students, BDS students and recent graduates were questioned and their answers analysed to identify shared learning activities. The results revealed that different levels of shared learning opportunities occurred within the different departments which delivered the course modules. Shared learning was viewed favourably by the students. It has the potential to maximise the use of resources and offers the opportunity for developing an integrated dental team.

Characterization of endothelin receptors in the anesthetized ferret: a novel model for investigating the functional ET(B) receptor subtypes.

The pharmacology of endothelin (ET)-1, big ET-1, ET-3, and S6c were characterized in the anesthetized ferret to assess whether this species would provide a new and suitable nonrodent model to be used in characterization of endothelin antagonists. Unlike other species such as dog, rabbit, and rat, the ferret exhibited a dose-dependent pressor response to both ET-1 and big ET-1 with no preceding vasodilatory response. The median effective concentration (ED50) values were 0.047+/-0.009 and 0.469+/-0.003 nmol/kg for ET-1 and big ET-1, respectively. ET-3 and S6c, however, were found to elicit a transient vasodilatory response preceding the pressor response, with ED50 values of 0.23+/-0.09 and 0.18+/-0.03 nmol/kg, respectively. The rank potency of the agonists for the pressor response was found to be ET-1 > S6c > big ET-1 > ET-3. The ET(A)-specific antagonist BQ-123 was shown to block only partially the ET-1 and big ET-1 pressor response with median antagonistic dose (AD50) of 0.24+/-0.11 and 0.015+/-0.005 mg/kg, i.v., respectively, and blockade of the ET(A) receptor did not uncover an ET(B)-induced vasodilation. The dual ET(A/B) antagonist L-754,142 completely antagonized the ET-1 and big ET-1 pressor responses with AD50 values of 0.195+/-0.063 and 0.019+/-0.006 mg/kg, respectively. The ET(B) antagonist BQ-788 blocked the depressor response of S6c entirely but was unable to antagonize the pressor response completely. BQ-123 was shown to antagonize the S6c pressor response partially, suggesting a possible interaction between the ET(A) and ET(B) receptors in the ferret. The unexpected absence of an ET-1-mediated depressor response but the presence of ET-3 and S6c vasodilation in this species supports the theory that there may be subtypes of the ET(B) receptor. These studies demonstrate that the anesthetized ferret provides a suitable model for assessing the physiological potencies of the endothelins and may provide a tool for further understanding of the diversity of the ET(B) receptor.

Gingival crevicular fluid osteocalcin in adult periodontitis.

This study aimed to detect the levels of osteocalcin in gingival crevicular fluid (GCF) from healthy (< or =3 mm sulcus depth and non-bleeding) and diseased sites (> or =6 mm probing depth and bleeding) in subjects with adult periodontitis, in order to further investigate its potential as a possible marker of the disease process. Periodontal probing depths, attachment levels and gingival indices were recorded from one healthy and one diseased site in each of 20 subjects with adult periodontitis. Both GCF accumulated in the periodontal pocket or sulci and GCF flowing into the periodontal pocket or sulci over a three-minute interval were sampled. The amounts of osteocalcin in each GCF sample was determined using immunoassays. A mean of 2.34 ng/site (2.7 microg/ml) osteocalcin was found at diseased sites and a mean of 2.47 ng/site (5.47 microg/ml) was found at healthy sites for the accumulated GCF collection method. A mean of 0.17 ng/ site (2.17 microg/ml) osteocalcin was found at diseased sites and a mean of 0.14 ng/ site (1.85 microg/ml) at healthy sites for the flow method of GCF collection. There were no statistically significant differences between osteocalcin levels in diseased and healthy sites in subjects with adult periodontitis.

Periodontal probing depth and subgingival temperature in smokers and non-smokers.

The aim of this study was to investigate the difference in subgingival temperature between smokers and non-smokers at different probing depths, and the effect of probing depth on subgingival temperature for smokers and non-smokers. 20 smokers and 20 non-smokers, with adult periodontitis, and retained upper anterior teeth were included. Initially sublingual temperatures were recorded, followed by subgingival temperature, pocket probing depth, and bleeding upon probing measurements at 3 buccal points at probing depths of 2, 3, 4, 5, and 6 mm for each of the anterior teeth. Sublingual temperatures were consistently higher than subgingival temperatures. The subgingival temperature measurements of pockets which bled upon probing, were subtracted from the sublingual temperature to produce temperature differentials (delta T), independent of individual body temperature, that were compared between smokers and non-smokers. The relationship between probing depth and delta T was examined in, and between, smokers and non-smokers for bleeding sites. delta T was found to decrease linearly with the increase of probing depth, suggesting a subsequent increase of subgingival temperature. Smokers were found to have significantly increased delta T(suggesting lower subgingival temperatures) compared to non-smokers, at probing depths of 2, 3, 4, and 5 mm. The differences in delta T for sites 6 mm in depth were not statistically significant between the 2 groups. It is concluded that for maxillary buccal anterior sites, there is a decrease of temperature differentials with an increase of probing depth at bleeding sites for both smokers and non-smokers. Smokers had higher temperature differentials compared to non-smokers, at probing depths of 2, 3, 4 and 5 mm.

Gender and age-related differences in the pattern of complete denture referrals from general dental practitioners.

This study was designed to identify gender and age-related differences among complete denture referrals from general dental practice to a dental teaching hospital over a 4 year period. Referral rates were calculated according to male/female ratios in the edentulous population. Although more women than men were referred overall, the proportion of males to females referred was similar to that in the edentulous population. Significant gender-related differences in referral patterns were identified, suggesting that edentulous males with complete denture problems, and aged 69 or less, made proportionately less use of hospital services, and proportionately more when aged 70 or over.

Phylloquinone in gingival crevicular fluid in adult periodontitis.

Phylloquinone is a lipid soluble vitamin which is an absolute growth requirement for black-pigmented anaerobes, many of which are implicated in the aetiology of periodontal diseases. This cross-sectional study aimed to detect the levels of phylloquinone in GCF from healthy and diseased sites in subjects with adult periodontitis, in order to investigate further its potential role in the disease process. The sample consisted of eighteen patients with adult periodontitis. Periodontal probing depths, attachment levels and gingival indices were recorded from one healthy and one diseased site in each subject. GCF was sampled and the amount of phylloquinone in each sample was determined using reverse-phase high performance liquid chromatography coupled to electrochemical detection. The mean amount of phylloquinone in accumulated GCF from diseased sites was 406 pg/site and 80 pg/site from healthy sites (p=0.013). When the amounts of phylloquinone in GCF were expressed as concentrations the values were 228 ng/ml and 3350 ng/ml for diseased and healthy sites respectively (p=0.084). These findings suggest the levels of phylloquinone in GCF differs in periodontal health and disease in subjects with adult periodontitis. The total phylloquinone at diseased sites may provide the nutritional requirements favouring the growth of black-pigmented anaerobes.