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AIM: (1) To determine the plaque inhibition properties of two formulations of alcohol-free mouthwash [0.1% w/w cetylpyridinium chloride (CPC) (B) and 0.05% w/w CPC (A)] versus a placebo mouthwash (C). (2) To compare the plaque-inhibiting activity between these two new CPC mouthwashes. MATERIAL AND METHODS: A double-blind, crossover study with three 1-week periods was used. Subjects were randomly assigned to one of the following groups. Group 1 (n=10) received the mouthwashes A, C and B in the periods 1, 2 and 3, respectively, group 2 (n=11) received the mouthwashes in the order B, A, C, while group 3 (n=11) received the mouthwashes in the order C, B, A. Mean plaque areas and Quigley & Hein plaque index scores were analysed using anova (analysis of variance). Measurements were made at the start of each period (baseline) and at 16, 24 and 40 h. RESULTS: Mean plaque scores were similar across the groups at baseline. At all time points thereafter, volunteers using mouthwash A or B had significantly lower plaque areas and plaque index scores than those using mouthwash C (p<0.05), but there were no significant differences between the test formulations. At 16 h, the reduction in plaque area relative to mouthwash C was 22% for mouthwash A and 18% for mouthwash B; at 24 h, 11% for mouthwash A and 15% for mouthwash B; and at 40 h, 15% for mouthwash A and 16% for mouthwash B. CONCLUSIONS: The use of both CPC mouthwashes resulted in less plaque accumulation compared with the control. There was no statistically significant difference in plaque accumulation between the two CPC mouthwashes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: A female Rio Cauca caecilian Typhlonectes natans (estimated as between 10 and 18 years of age) housed at the Smithsonian National Zoological Park in Washington, D.C., developed progressive severe coelomic effusion over a 4-week period. The coelomic effusion was diagnosed via radiographs and ultrasound, and a sample of the fluid was obtained for analysis, which revealed a low-protein transudate suggestive of inflammation. As the coelomic effusion progressed, the caecilian became tachypneic, hyporexic, and lethargic. The caecilian was started on antibiotics and a diet trial, but signs continued despite therapy., Methods: An exploratory celiotomy was performed, which revealed adipose tissue torsion with local lymphangiectasia and a presumptive biliary cyst. Surgical correction was unable to be achieved due to concern for fatal hemorrhage, as the vasculature associated with the torsion was severely distended. Due to the severity of the torsion and associated risks, the caecilian was euthanized intraoperatively and subsequently necropsied for histologic evaluation., Result: After reviewing the caecilian's presentation and the progression of disease, it is suspected that the severe coelomic effusion was secondary to lymphangiectasia, which occurred subsequent to the adipose tissue torsion., Conclusion: This is the first reported case of adipose tissue torsion and associated clinical disease in an aquatic caecilian and should be a differential for progressive coelomic effusion in this species., (© 2024 American Fisheries Society.)

Objective: To determine the effectiveness of dry hydrogen peroxide (DHP) in reducing environmental bioburden in occupied areas., Design: Prospective environmental cohort study., Setting: The study was conducted in 2 tertiary-care hospitals and 1 free-standing emergency department., Intervention: Environmental air and surface sites were cultured before and after continuous deployment of DHP systems in targeted hospital areas., Methods: In total, 1,554 surface and 1,036 air samples were collected from 74 patient areas among the 3 facilities on 3 consecutive days before DHP deployment and on days 14, 30, 60, and 90 after deployment. At each sampling time, 2 air samples were collected at each facility from 1 room without DHP, along with 2 outdoor samples from each facility. The impact of negative-pressure usage on the efficacy of DHP was also evaluated, with 1 hospital continuously using negative pressure, another utilizing it only in patient isolation scenarios, and another without negative pressure., Results: In the 2 facilities without continuous negative pressure, exposure to DHP was associated with a significant reduction in surface bioburden, characterized as total colony-forming units ( P = .019; P = .002). Significant associations between DHP exposure and reductions in airborne bacterial load at the 2 hospitals were observed ( P ≤ .001; P = .041), and the free-standing emergency department experienced a reduction that did not achieve statistical significance ( P = .073)., Conclusions: Our findings confirm that DHP has the potential to reduce microbial air and surface bioburden in occupied patient rooms with standard ventilation parameters.

Between 1983 and 2012, six giant panda cubs ( Ailuropoda melanoleuca ) born at a zoological institution were stillborn or died between the ages of 3 and 200 h. Two of the six cubs had panhepatic centrilobular hepatic necrosis (CHN), granulocytic extramedullary hematopoiesis (GEM), positive liver culture for Staphylococcus species, and terminal liver failure. Another low-weight cub was administered oxygen therapy immediately after birth and developed hyaline membranes in air spaces and hepatic necrosis restricted to the hilar region. A retrospective analysis of liver and lung lesions, pulmonary microanatomy, blood-gas barrier ultrastructure, and hepatic myofibroblast proliferation was conducted on the six cubs. Neonates with CHN had concurrent severe periportal GEM accompanied by severe myofibroblast proliferation. The pulmonary blood-gas barrier was markedly increased in one cub with CHN. Developmentally, the lungs of all but one cub were at the late saccular stage, and the lowest-weight cub was in early saccular stage, consistent with immaturity, and had pneumonia comparable to neonatal respiratory distress syndrome (RDS). Stage of lung development was eliminated as the primary factor leading to CHN. The pathogenesis of CHN in these neonates is proposed to be transformation of hepatic stellate cells to myofibroblasts initiating blockage and microvascular constriction of hepatic sinusoids, resulting in insufficient perfusion and cellular hypoxia of hepatocytes surrounding central veins in acinar zone 3.

Natural and anthropogenic infrasound may travel vast distances, making it an invaluable resource for monitoring phenomena such as nuclear explosions, volcanic eruptions, severe storms, and many others. Typically, these waves are captured using pressure sensors, which cannot encode the direction of arrival-critical information when the source location is not known beforehand. Obtaining this information therefore requires arrays of sensors with apertures ranging from tens of meters to kilometers depending on the wavelengths of interest. This is often impractical in locations that lack the necessary real estate (urban areas, rugged regions, or remote islands); in any case, it requires multiple power, digitizer, and telemetry deployments. Here, the theoretical basis behind a compact infrasound direction of arrival sensor based on the acoustic metamaterials is presented. This sensor occupies a footprint that is orders of magnitude smaller than the span of a typical infrasound array. The diminutive size of the unit greatly expands the locations where it can be deployed. The sensor design is described, its ability to determine the direction of arrival is evaluated, and further avenues of study are suggested.

While elastic metasurfaces offer a remarkable and very effective approach to the subwavelength control of stress waves, their use in practical applications is severely hindered by intrinsically narrow band performance. In applications to electromagnetic and photonic metamaterials, some success in extending the operating dynamic range was obtained by using nonlocality. However, while electronic properties in natural materials can show significant nonlocal effects, even at the macroscales, in mechanics, nonlocality is a higher-order effect that becomes appreciable only at the microscales. This study introduces the concept of intentional nonlocality as a fundamental mechanism to design passive elastic metasurfaces capable of an exceptionally broadband operating range. The nonlocal behavior is achieved by exploiting nonlocal forces, conceptually akin to long-range interactions in nonlocal material microstructures, between subsets of resonant unit cells forming the metasurface. These long-range forces are obtained via carefully crafted flexible elements, whose specific geometry and local dynamics are designed to create remarkably complex transfer functions between multiple units. The resulting nonlocal coupling forces enable achieving phase-gradient profiles that are functions of the wavenumber of the incident wave. The identification of relevant design parameters and the assessment of their impact on performance are explored via a combination of semianalytical and numerical models. The nonlocal metasurface concept is tested, both numerically and experimentally, by embedding a total-internal-reflection design in a thin-plate waveguide. Results confirm the feasibility of the intentionally nonlocal design concept and its ability to achieve a fully passive and broadband wave control., Competing Interests: The authors declare no competing interest.

A chytridiomycosis outbreak from Batrachochytrium dendrobatidis ( Bd) in a mixed-species plethodontid salamander exhibit resulted in four green salamander ( Aneides aeneus) deaths. One green salamander died before treatment, and three died during treatment with daily 0.005% itraconazole baths. All salamanders had evidence of severe Bd infections via cytology, histopathology, and/or polymerase chain reaction (PCR) at the time of death. Ten long-tailed salamanders ( Eurycea longicauda) and one two-lined salamander ( Eurycea bislineata) that shared the enclosure were initially negative for Bd on quantitative PCR but were prophylactically treated with daily 0.01% itraconazole baths for 11 days. Posttreatment testing yielded eight long-tailed salamanders and one two-lined salamander positive for Bd with low gene equivalents. All salamanders were negative after two to three treatment courses, and there were no additional mortalities. The difference in mortality and fungal load suggested that genus Aneides salamanders may be more susceptible to Bd than genus Eurycea salamanders.

Three juvenile, genetically related African lions (Panthera leo) were evaluated for discrete dome-shaped subcutaneous masses present over the proximal lateral metatarsal-tarsal area. The lesions measured 3-8 cm in diameter, were fluctuant to firm, nonulcerated, and attached to underlying structures. On radiographic evaluation, the lesions were characterized by well-circumscribed punctate mineralizations in the soft tissue surrounded by soft tissue swelling without evidence of adjacent bony involvement. On cut surface, the lesions were made of numerous loculi containing 2-5-mm round-to-ovoid, white-to-gray, firm structures interspersed with fibrous tissue and pockets of serosanguinous fluid. Hematology, serum biochemistry, serum thyroid screening (including total thyroxine, total triiodothyronine, free thyroxine, and free triiodothyronine), and serum vitamin D panels (including parathyroid hormone, ionized calcium, and 25-hydroxyvitamin D) were unremarkable. Histopathologic evaluation of the lesions was consistent with calcinosis circumscripta with fibroplasia, chronic inflammation, and seroma formation. An additional two genetically related lions were considered suspect for calcinosis circumscripta based on presentation, exam findings, and similarity to the confirmed cases. All masses self-regressed and were not associated with additional clinical signs other than initial lameness in two cases.

Gastric dilatation volvulus (GDV) was identified in six adult maned wolves ( Chrysocyon brachyurus ) housed at the Smithsonian Conservation Biology Institute in Front Royal, Virginia, and the Dickerson Park Zoo in Springfield, Missouri. Four individuals were found dead in their enclosures, and GDV was diagnosed postmortem based on radiographic and necropsy findings. Two individuals were diagnosed with GDV antemortem, with one wolf surviving following surgical intervention and supportive management. A concurrent splenic torsion was identified in three of six cases. Although GDV has been well documented in domestic dogs and is known to occur in maned wolves, objective, detailed case descriptions have been limited in this species. This report represents the first description of a surviving case of GDV in the maned wolf. Thorough species-specific documentation of any acutely fatal condition, such as GDV, is imperative for proper case recognition and medical management, with profound implications for species recovery efforts.

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

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., (© The Author(s) 2016.)

Acute gastric dilation resulting in death was identified in two adult black-footed ferrets (Mustela nigripes) housed at the Smithsonian Conservation Biology Institute in Front Royal, Virginia. Both individuals were adult males (3 and 5 yr) and previously clinically healthy prior to the event. The etiology of gastric dilation in both cases could not be definitively determined, and necropsy revealed severe cardiovascular compromise secondary to bloat. Limited literature is available regarding a syndrome of this type in adult black-footed ferrets. Differential diagnoses considered included gastric dilatation volvulus (GDV), severe gastric distention of unknown origin, and gastric outflow obstruction. Given the severity of this syndrome and the findings in these two cases, acute gastric dilation should be considered in black-footed ferrets presenting with acute abdominal distention, respiratory distress, and cardiovascular compromise.

A 20-y-old, male, ring-tailed lemur (Lemur catta) presented with a large, firm mass on the proximal caudolateral left femur. The animal displayed no clinical signs associated with the mass. Radiographs revealed a mineralized mass protruding from the femur, with an intact femoral cortex. Histopathology diagnosed osteochondroma in view of the presence of a peripheral layer of cartilage with progressive endochondral ossification and typical remodeling of bony trabeculae. The mass grew quickly after the initial biopsy, and a second surgery to debulk 95% of the tumor was performed. Histopathologic features of the larger samples were similar to those of the initial biopsies, with the cartilage layer being discontinuous and development of bone from some borders progressing directly from a periost-like layer. Nineteen months after the second surgery, the mass had regrown and extended further proximally on the femur toward the epiphysis, but the animal remained asymptomatic, and additional debulking was not attempted. This report is the first description of an osteochondroma in a prosimian and describes unique behavior of the tumor compared with osteochondromas found in humans, dogs, and cats.

Hepatocellular carcinoma was diagnosed in five slender tailed meerkats (Suricata suricatta) housed at the Smithsonian Institution's National Zoological Park between 1980 and 2013. Animals included four females and one male, ranging from 7 to 15 yr of age. Common clinical signs included weight loss and lethargy. Three of the neoplasms originated from the right medial liver lobe and were located adjacent to or partially incorporated in the gall bladder. Three animals had solitary masses, and two animals had multiple hepatic masses; all were characterized by polygonal to round neoplastic hepatocytes arranged in a trabecular pattern with smaller regions of varied solid, adenoid, and rarely peliod cell patterns. Hemorrhage and necrosis often with cystic degeneration was noted in all five cases. There was no evidence of metastatic disease in any of the cases examined.

This paper presents the formulation and implementation of an Error in Constitutive Equations (ECE) method suitable for large-scale inverse identification of linear elastic material properties in the context of steady-state elastodynamics. In ECE-based methods, the inverse problem is postulated as an optimization problem in which the cost functional measures the discrepancy in the constitutive equations that connect kinematically admissible strains and dynamically admissible stresses. Furthermore, in a more recent modality of this methodology introduced by Feissel and Allix (2007), referred to as the Modified ECE (MECE), the measured data is incorporated into the formulation as a quadratic penalty term. We show that a simple and efficient continuation scheme for the penalty term, suggested by the theory of quadratic penalty methods, can significantly accelerate the convergence of the MECE algorithm. Furthermore, a (block) successive over-relaxation (SOR) technique is introduced, enabling the use of existing parallel finite element codes with minimal modification to solve the coupled system of equations that arises from the optimality conditions in MECE methods. Our numerical results demonstrate that the proposed methodology can successfully reconstruct the spatial distribution of elastic material parameters from partial and noisy measurements in as few as ten iterations in a 2D example and fifty in a 3D example. We show (through numerical experiments) that the proposed continuation scheme can improve the rate of convergence of MECE methods by at least an order of magnitude versus the alternative of using a fixed penalty parameter. Furthermore, the proposed block SOR strategy coupled with existing parallel solvers produces a computationally efficient MECE method that can be used for large scale materials identification problems, as demonstrated on a 3D example involving about 400,000 unknown moduli. Finally, our numerical results suggest that the proposed MECE approach can be significantly faster than the conventional approach of L(2) minimization using quasi-Newton methods.

Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R., (Copyright 2010 Elsevier Ltd. All rights reserved.)

MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.

Background: To determine if patients without dobutamine induced left ventricular wall motion abnormalities (WMA) but an increased LV end-diastolic wall thickness (EDWT) exhibit a favorable cardiac prognosis., Results: Between 1999 and 2001, 175 patients underwent a dobutamine stress cardiovascular magnetic resonance (DCMR) procedure utilizing gradient-echo cines. Participants had a LV ejection fraction >55% without evidence of an inducible WMA during peak dobutamine/atropine stress. After an average of 5.5 years, all participants were contacted and medical records were reviewed to determine the post-DCMR occurrence of cardiac death, myocardial infarction (MI), and unstable angina (USA) or congestive heart failure (CHF) warranting hospitalization.In a multivariate analysis, that took into account Framingham and other risk factors associated with cardiac events, a cine gradient-echo derived LV EDWT > or =12 mm was associated independently with an increase in cardiac death and MI (HR 6.0, p = 0.0016), and the combined end point of MI, cardiac death, and USA or CHF warranting hospitalization (HR 3.0, p = 0.0005)., Conclusion: Similar to echocardiography, CMR measures of increased LV wall thickness should be considered a risk factor for cardiac events in individuals receiving negative reports of inducible ischemia after dobutamine stress. Additional prognostic studies of the importance of LV wall thickness and mass measured with steady-state free precession techniques are warranted.

The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

Objectives: The purpose of this study was to determine the prognostic utility of dobutamine cardiac magnetic resonance (DCMR) stress test results in women., Background: To date, the preponderance of studies reporting the utility of DCMR stress results for predicting cardiac prognosis have been performed in men. We sought to determine the utility of DCMR results for predicting cardiac prognosis in women., Methods: Two hundred sixty-six consecutively referred women underwent DCMR in which left ventricular wall motion (LVWM) was assessed at rest and after intravenous dobutamine and atropine. Inducible LVWM abnormalities were identified during testing. Women were contacted to determine the post-DCMR occurrence of a cardiac event. All events were substantiated according to defined criteria and then were verified after a thorough medical record review by individuals blinded to testing data., Results: Women were contacted an average of 6.2 +/- 1.6 (median 6.2, range 0.8 to 10.4) years after DCMR; 27% of the women experienced an inducible LVWM abnormality during testing. In those with and without inducible LVWM abnormalities, the proportion of women with cardiac events were 63% versus 30%, respectively, (hazard ratio [HR]: 2.7; 95% confidence interval [CI]: 1.8 to 4.3 for the presence of inducible LVWM abnormalities p < 0.0001). The proportion of women with myocardial infarction (MI) and cardiac death were 33.3% and 7.5%, respectively. This resulted in a HR for MI and cardiac death of 4.1 (95% CI: 2.2 to 9.4) for those with versus those without inducible LVWM abnormalities; p < 0.0001. A subgroup analysis was performed in women without a history of coronary artery disease and in those with LVWM abnormalities, DCMR remained an adverse predictor of cardiac events (HR: 4.0, 95% CI: 1.8 to 9.0, p = 0.003)., Conclusions: Inducible LVWM abnormalities during DCMR predict cardiac death and MI in women. Similar to men, these results indicate that DCMR is a valuable noninvasive stress imaging modality for identifying cardiac risk in women with known or suspected ischemic heart disease.

Background and Aims: Whole grain food sources have been associated with lowered risk of cardiovascular disease (CVD). Studies in recent years have strengthened this observation and elucidated potential mechanisms for this association. This study sought to quantitate the available observational evidence on whole grain intake and clinical cardiovascular events., Methods and Results: Seven prospective cohort studies with quantitative measures of dietary whole grains and clinical cardiovascular outcomes were identified from MEDLINE searches and a review of the literature. Based on event estimates adjusted for cardiovascular risk factors, greater whole grain intake (pooled average 2.5 servings/d vs. 0.2 servings/d) was associated with a 21% lower risk of CVD events [OR 0.79 (95% CI: 0.73-0.85)]. Similar estimates were noted for different CVD outcomes (heart disease, stroke, fatal CVD) and in sex-specific analyses. Conversely, refined grain intake was not associated with incident CVD events [1.07 (0.94-1.22)]., Conclusions: There is a consistent, inverse association between dietary whole grains and incident cardiovascular disease in epidemiological cohort studies. In light of this evidence, policy-makers, scientists, and clinicians should redouble efforts to incorporate clear messages on the beneficial effects of whole grains into public health and clinical practice endeavors.

LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [3H]CP55940 to cloned human and rat CB1 receptors with IC50 values of 631+/-98 nM, and 690+/-41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB1 receptor and does not act on the CB1 receptor to inhibit food intake in mice.

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.

The high spatial and temporal resolution of cardiovascular magnetic resonance (CMR) images makes it well-suited for use in the assessment of right ventricular and left ventricular function in patients who have cardiovascular disorders. This article reviews CMR methods used to assess regional and global ventricular function.

Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.

The purpose of this study was to present and evaluate a blended-learning course developed for undergraduate (B.D.S.), postgraduate, and diploma (hygiene and therapy) students at the University of Sheffield School of Clinical Dentistry. Blended learning is the integration of classroom face-to-face learning with online learning. The overall methodology used for this study was action research. The data were collected using three processes: questionnaires to collect contextual data from the students taking the course; a student-led, nominal group technique to collect group data from the participants; and a non-participant observer technique to record the context in which certain group and individual behaviors occurred. The online component of the course was accepted as a valuable resource by 65 percent of those responding. While online information-sharing occurred (31 percent of the students posted in forums), there was no evidence of online collaboration, with only 8 percent replying to forum postings. Accessibility of the online environment was one of the main concerns of the students at the nominal group sessions. Differences regarding overall engagement with the course between the student groups (years) were observed during the sessions. The majority of the students were satisfied with the Information and Communication Technologies (ICT) course. No statistically significant differences between males and females were found, but there were differences between different student cohorts (year groups).

Background: The similarity between gingival squamous cell carcinoma (GSCC) and more common periodontal lesions may lead to a delay in diagnosis or misdiagnosis. Neoplastic lesions of gingival tissues are frequently diagnosed at an advanced stage., Methods: To assess the relative time from when patients first become aware of the problem to histopathologic diagnosis (total diagnostic time), 59 consecutive oral cancer cases were examined in this study. The following variables were considered: age, gender, smoking habits, tumor stage at diagnosis, and total diagnostic time. The median of the patients' total diagnostic time (1.5 months) was used as a cutoff point to distinguish between delayed and non-delayed cases. Analysis of the variables was undertaken using the Student t test and chi2 test, with a 95% confidence interval (CI)., Results: The total diagnostic time was <1.5 months for 75% of gingival carcinomas, 50% of tongue carcinomas, and 78% of floor-of-the-mouth carcinomas. It was >1.5 months for 25% of gingival carcinomas, 50% of tongue carcinomas, and 21% of floor-of-the-mouth carcinomas. No significant differences in time before diagnosis were found when gingival cancers were compared to other oral tumors (chi2=0.21; 95% CI=-0.40 to 0.26). However, by the time of diagnosis, gingival cancers had invaded adjacent structures more frequently than other oral cancers (chi2=13.51; 95% CI=0.18 to 0.85)., Conclusions: The gingival location of oral squamous cell carcinoma (OSCC) was associated with advanced stages at the time of diagnosis, due to early invasion of contiguous bone tissue (T4-primary tumor). This would indicate that even earlier referral and diagnosis are necessary.

Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.

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.

Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.

Objectives: This study aimed to evaluate the stain removing/controlling properties of a whitening dentifrice and a stain controlling system, in a parallel group, multiple use study., Methods: Subjects (63), were stratified according to baseline stain scores and randomly allocated to a group, A (standard dentifrice), B (whitening/stain removing dentifrice) or C (whitening/stain removing dentifrice, tooth polish, tooth polisher and whitening/stain removing mouthwash). At each attendance, extrinsic stain was scored blind by a trained and calibrated examiner using the Shaw and Murray Stain Index, under constant lighting conditions. In addition, whiteness was measured using a colorimeter., Results: The toothpaste regimens were well balanced at baseline (p=0.811). At 4 weeks, Regimens B and C had significantly less stain than A (p<0.05). Lower stain values were maintained/reduced for regimens B and C by week 6, with changes from baseline significantly greater than for Regimen A. When lightness was assessed by colorimeter, Regimen C was also found to be significantly whiter than Regimen A (p<0.05)., Conclusions: It was concluded that both whitening regimens had a significant effect on reducing tooth staining and improving whiteness over the 6 week time period.

Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.

The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed.

Background/aims: This study aimed to investigate the concentration of the cytokine interleukin (IL)-1beta and its receptor antagonist IL-1ra in gingival crevicular fluid (GCF) in patients with adult periodontitis who were heavy smokers compared with non-smokers., Method: GCF samples were collected from two groups of subjects: smokers and non-smokers. Thirty-nine GCF samples were harvested from 13 subjects with moderate to severe adult periodontitis who were heavy smokers. A further 30 GCF samples were harvested from 10 subjects with moderate to severe adult periodontitis who were non-smokers. Subjects were selected from both genders and none had any relevant systemic illness, were pregnant, had recent medication or had received any periodontal therapy in the preceding 3 months. One deep bleeding site, one deep non-bleeding site and one healthy site were investigated in each subject. Clinical measurements were recorded for each site, after obtaining a GCF sample using a Periopaper strip. IL-1beta and IL-1ra were quantified using new commercially available ELISA kits (Quantikine), and could be detected in all samples., Results: For smokers, the mean concentrations for IL-1beta were 2714.5 (SD 4416.2) pg/ micro L for healthy sites, 37.0 (SD 57.2) pg/ micro L for non-bleeding periodontitis sites and 24.5 (SD 29.2) pg/ micro L for bleeding periodontitis sites. The concentrations of IL-1beta for non-smokers for the same category of sites were 393.8 (SD 867.1), 74.2 (SD 107.0) and 73.1 (SD 61.0) pg/ micro L, respectively. The mean concentrations of IL-1ra for smokers were 5.8 x 10(5) (SD 9.7) pg/ micro L for healthy sites, 2.2 x 10(5) (SD 0.15) pg/ micro L for deep non-bleeding sites and 0.19 x 10(5) (SD 0.07) pg/ micro L for deep bleeding sites. The concentrations for non-smokers were: 4.1 x 10(10) (SD 3.8), 18.1 x 10(5) (SD 20.4) and 3.2 x 10(5) (SD 2.3) pg/ micro L, respectively. Significance levels of P < 0.05 were found for comparisons of healthy vs. deep bleeding and deep non-bleeding sites for IL-1beta and IL-1ra in smokers, before adjustments for multiple testing. However, none of these comparisons reached statistical significance following adjustments for multiple testing. P < 0.05 for the correlation between IL-1beta and IL-1ra at healthy sites in smokers only. Differences in GCF concentrations for IL-1beta in smokers vs. non-smokers were significant for deep bleeding sites only (P < 0.05), the mean concentration of IL-1beta being lower in GCF from smokers vs. non-smokers. All differences in GCF concentrations of IL-1ra reached statistical significance for smokers vs. non-smokers. The mean concentrations of IL-1ra in GCF were lower in smokers compared with non-smokers for all categories of sites., Conclusions: A decreased concentration of IL-1beta and also IL-1ra was found in GCF from periodontitis sites compared to healthy sites in smokers and in non-smokers, although this did not reach statistical significance following adjustments for multiple testing. For comparisons between heavy smokers and non-smokers, statistically significant differences were found in the GCF concentrations of IL-1beta from deep bleeding sites only. Statistically significant differences were found in the IL-1ra concentrations for smokers vs. non-smokers for all categories of sites.

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.

A 2.5-year-old captive female mandrill (Papio sphinx) died following a protracted course of intermittent abdominal bloat, diarrhea, and severe weight loss. Necropsy revealed emaciation and marked gastrointestinal distention with gas and ingesta. Histologic evaluation revealed severe diffuse granulomatous enterocolitis and mesenteric lymphadenitis with massive numbers of 1-2-microm acid-fast bacilli within macrophages. Additionally, there was moderate to severe multifocal myocardial and vascular amyloidosis, moderate multifocal pyogranulomatous interstitial pneumonia with no acid-fast bacteria, and moderate multifocal glossal candidiasis. Samples of feces, ileum, and colon were positive for Mycobacterium avium subsp. paratuberculosis by radiometric culture and a polymerase chain reaction-amplified DNA probe specific for the insertion sequence IS900 of this organism.

Natural teeth with a healthy periodontal support exhibit stress transfer when functional forces are applied to them. These stress patterns show considerable variations during differing treatment modalities, which may influence both the tooth and supporting alveolar bone. The purpose of this study was to evaluate variations in the stress transfer under functional loads on first molars with periodontal furcation involvement, which were treated either with by root resection or root separation. This study used a two dimensional mathematical model of a mandibular first molar that was subjected to either a root separation or a root resection procedure. An evenly distributed dynamic load (600 N) was applied on two buccal cusps and distal fossae of the molar in centric occlusion. The analysis was performed using an IBM-compatible computer running standard analysis software. It was found that in the root resection model the stress values were maximum on the centre of rotation, and compressive stresses increased towards the middle of the cervical line. For the root separation model, the maximum shear stress values were observed in the distal portion, and a uniform stress distribution was observed in the mesial portion. Shear stress values for bone increased towards the centre in the bifurcation area. The outcomes of this study may be useful as a guide in clinical restorative procedures.

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.

A clinical record should include the personal demographic details of the patient, health status, diagnostic information and management/treatment options. However, clinical records are of little use without effective filing and retrieving systems. Coding is therefore necessary to deal with large amounts of differing data and a global coding system could be effectively developed through the use of information technology. The aim of this section was to review the main existing vocabularies and coding systems and to examine ways of improving their global application. It was concluded that global diagnostic codes would be beneficial to the patient, to the profession and to those responsible for strategic decisions concerning the delivery of health care. Extant dental clinical codes are not accepted widely or applied universally. There is an urgent need to identify existing coding systems and to assess their utility and potential for global application. Every effort should be made to include existing codes in the development of a global coding system on which all specialist areas would need to agree. This would require the provision of an overarching interdisciplinary focus and funding should be made available for this development and its implementation.

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.

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.

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.