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.

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.

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.

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.

Shared determinants of receptor binding for subtype selective, and dual endothelin-angiotensin antagonists on the AT1 angiotensin II receptor.

Site-directed interspecies amino acid exchange was used to compare the binding determinants of a novel dual endothelial-angiotensin receptor ligand, L-746,072, with type-1 angiotensin receptor (AT1) selective antagonists on AT receptors expressed in COS cells. These studies suggest that residues on AT receptors which are non-conserved between amphibian and mammalian species play a greater role in subtype selective ligand recognition than for dual receptor ligands. These data also support the hypothesis that a common non-peptide binding site exists within transmembrane domains on peptidergic receptors.

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.

Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist.

L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.

A comparison of postsurgical healing following debridement by ultrasonic or hand instruments.

Subjects for the study were 15 patients requiring periodontal surgery in the maxillary posterior quadrants. A split mouth technique with assignment of quadrants by random alternation was used. Assessments were carried out at given time intervals using the Gingival Index, crevicular fluid measurement, Plaque Index and Retention Index. Pain experience following surgery was also noted. Approximately 8 weeks after the initial assessment, periodontal flap surgery was carried out. On the one side debridement was carried out using an ultrasonic scaler, on the other side, hand instrumentation only was used. On the side receiving ultrasonic debridement during surgery, there was an increased rate of healing as measured by the Gingival Index and crevicular fluid. There was no difference in postoperative pain experience, Plaque Index or Retention Index.

The effect of a single application of subgingival antimicrobial or mechanical therapy on the clinical parameters of juvenile periodontitis.

Twenty-six (26) patients, 18 female and 7 male, aged 16 to 25 years (mean age 19.03 +/- 2.2 years) previously diagnosed as suffering from localized juvenile periodontitis were randomly assigned to one of the following treatment groups: 9 patients acted as controls; 8 received subgingival chlorexidine gel; and 9 had subgingival tetracycline paste application. All treatment modalities resulted in a pronounced improvement in PI, GI, and GI-S by 12 weeks (P < 0.001). The mean probing depths also decreased, but there were no significant differences found between the three groups. However, when the interproximal sites of the 3 groups were examined separately from the buccal and lingual sites, it was found that there was a significant (P < 0.05) difference between the probing depths, with the control group showing the greatest reduction of 2.58 mm and the chlorhexidine group showing the least reduction of 1.37 mm. It was concluded that a single application of topical subgingival tetracycline did not result in any short-term improvement over that achieved by standard non-surgical therapy in the clinical parameters of these localized juvenile periodontitis patients.

Evaluation of replica techniques for the surface ultrastructure of rodent and human palatal mucosa.

Two replicating techniques currently used for scanning electron microscopy were investigated qualitatively and quantitatively. The most accurate and reliable replicating material was an epoxy resin; this was superior to copper plating as the model material, despite some dimensional inaccuracies. The selected method was then used to obtain accurate elastomeric replicas of rodent and human palatal mucosa. Salivary-duct openings, epithelial cell boundaries, desquamating cells and cell-surface micropits were identified. In some areas, coccal organisms could be seen colonizing the epithelial surface.

Relative effectiveness of a rotary and conventional toothbrush in plaque removal.

The ability of a powered rotary toothbrush to remove 3- and 4-day-old microbial plaque deposits was evaluated in 10 young adults with healthy gingivae. Using a split mouth technique and a cross-over experimental design, the powered brush was compared with a conventional hand brush over a 14-day period. Statistical analysis of the results showed no significant differences between either method of brushing when the whole mouth, maxillary or mandibular arches were compared. Further analysis of the proximal scores again showed no significant differences between the powered brush or handbrush. The majority of the subjects preferred the conventional handbrush to the powered brush.

Ethanol and pH levels of proprietary mouthrinses.

This study measured the pH and alcohol (ethanol) content of a number of proprietary mouthrinses available for purchase by the general public, as well as assessing the influence of the alcohol content on police exhaled air analysis (breathalysing) procedures. The majority of the mouthrinses were acidic, some with a pH as low as 3.40. Only one was found to be alkaline and one near neutral in pH. The ethanol content varied from 0 to 27 per cent. The effect of the alcohol content on the results of the exhaled air analysis were transient and would be unlikely to influence any legal proceedings.

Rationale and techniques of non-surgical pocket management in periodontal therapy.

Traditional views on pocket instrumentation in periodontal therapy have centred upon the thorough scaling and planing of root surfaces, which aim to remove all calculus and substantial amounts of 'necrotic' and 'contaminated' cementum. The lack of scientific evidence for removing calculus in periodontal therapy, was highlighted by Frandsen and recent studies have also questioned the need for extensive root planing to remove 'substantial' amounts of cementum. The need for some degree of pocket instrumentation during periodontal therapy however, is beyond doubt, as clinical studies on the efficacy of nonsurgical periodontal treatment published during the last decade have clearly shown. A review of this important topic is therefore timely and this paper aims to elucidate some of the concepts which are currently the subject of debate. A resume of the formation and characteristics of the subgingival environment is a necessary starting point.

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.

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.

Mouthrinses as adjuncts in periodontal therapy.

Periodontal diseases are a group of related inflammatory disorders, initiated by dental plaque and causing destruction of the supporting structures of the teeth. Although the inflammatory response is a fundamental defence mechanism against bacterial infection, its persistence over a long period of time may extensively damage the periodontal tissues: cementum, alveolar bone, periodontal ligament and dentogingival tissues. These disorders, despite recent improvements in oral health are still a major cause of tooth loss in patients over 35 years of age.

Pulsed oral irrigation in the management of inflammatory periodontal diseases.

While subgingival scaling and root planing are effective at removing plaque, the use of periodic subgingival irrigation with a antimicrobial solution could be a useful adjunct. This paper initially discusses the management of inflammatory periodontal diseases in general, covering current mechanical therapy and chemical antimicrobials, before describing pulsed oral irrigation in more detail.