Sclerostin and DKK1 Inhibition Preserves and Augments Alveolar Bone Volume and Architecture in Rats with Alveolar Bone Loss.

Alveolar bone is a mechanosensitive tissue that provides structural support for teeth. Alveolar bone loss is common with aging, menopause, tooth loss, and periodontitis and can lead to additional tooth loss, reduced denture fixation, and challenges in placing dental implants. The current studies suggest that sclerostin and DKK1, which are established osteocyte-derived inhibitors of bone formation, contribute to alveolar bone loss associated with estrogen ablation and edentulism in rats. Estrogen-deficient ovariectomized rats showed significant mandibular bone loss that was reversed by systemic administration of sclerostin antibody (SAB) alone and in combination with DKK1 antibody (DAB). Osteocytes in the dentate and edentulous rat maxilla expressed Sost (sclerostin) and Dkk1 (DKK1) mRNA, and molar extraction appeared to acutely increase DKK1 expression. In a chronic rat maxillary molar extraction model, systemic SAB administration augmented the volume and height of atrophic alveolar ridges, effects that were enhanced by coadministering DAB. SAB and SAB+DAB also fully reversed bone loss that developed in the opposing mandible as a result of hypo-occlusion. In both treatment studies, alveolar bone augmentation with SAB or SAB+DAB was accompanied by increased bone mass in the postcranial skeleton. Jaw bone biomechanics showed that intact sclerostin-deficient mice exhibited stronger and denser mandibles as compared with wild-type controls. These studies show that sclerostin inhibition, with and without DKK1 coinhibition, augmented alveolar bone volume and architecture in rats with alveolar bone loss. These noninvasive approaches may have utility for the conservative augmentation of alveolar bone.

Diabetic gastroparesis alters the biomagnetic signature of the gastric slow wave.

BACKGROUND: Gastroparesis is characterized by delayed gastric emptying without mechanical obstruction, but remains difficult to diagnose and distinguish from other gastrointestinal (GI) disorders. Gastroparesis affects the gastric slow wave, but non-invasive assessment has been limited to the electrogastrogram (EGG), which reliably characterizes temporal dynamics but does not provide spatial information. METHODS: We measured gastric slow wave parameters from the EGG and magnetogastrogram (MGG) in patients with gastroparesis and in healthy controls. In addition to dominant frequency (DF) and percentage power distribution (PPD), we measured the propagation velocity from MGG spatiotemporal patterns and the percentage of slow wave coupling (%SWC) from EGG. KEY RESULTS: No significant difference in DF was found between patients and controls. Gastroparesis patients had lower percentages of normogastric frequencies (60 ± 6% vs 78 ± 4%, p < 0.05), and higher brady (9 ± 2% vs 2 ± 1%, p < 0.05) and tachygastric (31 ± 2% vs 19 ± 1%, p < 0.05) frequency content postprandial, indicative of uncoupling. Propagation patterns were substantially different in patients and longitudinal propagation velocity was retrograde at 4.3 ± 2.9 mm/s vs anterograde at 7.4 ± 1.0 mm/s for controls (p < 0.01). No difference was found in %SWC from EGG. CONCLUSIONS & INFERENCES: Gastric slow wave parameters obtained from MGG recordings distinguish gastroparesis patients from controls. Assessment of slow wave propagation may prove critical to characterization of underlying disease processes. Future studies should determine pathologic indicators from MGG associated with other functional gastric disorders, and whether multichannel EGG with appropriate signal processing also reveals pathology.

Noninvasive biomagnetic detection of intestinal slow wave dysrhythmias in chronic mesenteric ischemia.

Chronic mesenteric ischemia (CMI) is a challenging clinical problem that is difficult to diagnose noninvasively. Diagnosis early in the disease process would enable life-saving early surgical intervention. Previous studies established that superconducting quantum interference device (SQUID) magnetometers detect the slow wave changes in the magnetoenterogram (MENG) noninvasively following induction of mesenteric ischemia in animal models. The purpose of this study was to assess functional physiological changes in the intestinal slow wave MENG of patients with chronic mesenteric ischemia. Pre- and postoperative studies were conducted on CMI patients using MENG and intraoperative recordings using invasive serosal electromyograms (EMG). Our preoperative MENG recordings showed that patients with CMI exhibited a significant decrease in intestinal slow wave frequency from 8.9 ± 0.3 cpm preprandial to 7.4 ± 0.1 cpm postprandial (P < 0.01) that was not observed in postoperative recordings (9.3 ± 0.2 cpm preprandial and 9.4 ± 0.4 cpm postprandial, P = 0.86). Intraoperative recording detected multiple frequencies from the ischemic portion of jejunum before revascularization, whereas normal serosal intestinal slow wave frequencies were observed after revascularization. The preoperative MENG data also showed signals with multiple frequencies suggestive of uncoupling and intestinal ischemia similar to intraoperative serosal EMG. Our results showed that multichannel MENG can identify intestinal slow wave dysrhythmias in CMI patients.

Mind the gap! A comparison of oral health knowledge between dental, healthcare professionals and the public.

INTRODUCTION: The importance of consistent, accurate and unambiguous messages are well documented in oral health promotion literature. Whether the reality of delivering messages in the field fulfils these principle is questionable. OBJECTIVE: This paper explores the perceptions of dental professionals, healthcare professionals and lay community members with regard to key oral health messages in order to highlight any inconsistencies and knowledge gaps between and within groups for disease risk factors. METHOD: A questionnaire was administered to individuals who belonged to three groups: dental professionals, healthcare professionals and lay community members. The questionnaire established knowledge regarding risk factors for caries, periodontal disease and erosion. RESULTS: Thirty-five (57.4%) of the dental group answered the whole questionnaire correctly, with 22 (27.8%) and 9 (5.1%) of the healthcare and lay community group answering the whole questionnaire correctly, respectively. The question of fluoride levels in children's toothpaste was the main reason for incorrect answers in the dental group. CONCLUSIONS: The results of this survey demonstrate a knowledge gradient from dental professionals through to healthcare professionals and then to lay members of the community. The knowledge base observed in the dental group is reflected in the other two groups as would be expected albeit with a significant gap between each group. As expected the dental professionals are generally well informed, but not as well informed as could be expected.

Effects of body mass index on gastric slow wave: a magnetogastrographic study.

We measured gastric slow wave activity simultaneously with magnetogastrogram (MGG), mucosal electromyogram (EMG) and electrogastrogram (EGG) in human subjects with varying body mass index (BMI) before and after a meal. In order to investigate the effect of BMI on gastric slow wave parameters, each subject's BMI was calculated and divided into two groups: subjects with BMI ≤ 27 and BMI > 27. Signals were processed with Fourier spectral analysis and second-order blind identification (SOBI) techniques. Our results showed that increased BMI does not affect signal characteristics such as frequency and amplitude of EMG and MGG. Comparison of the postprandial EGG power, on the other hand, showed a statistically significant reduction in subjects with BMI > 27 compared with BMI ≤ 27. In addition to the frequency and amplitude, the use of SOBI-computed propagation maps from MGG data allowed us to visualize the propagating slow wave and compute the propagation velocity in both BMI groups. No significant change in velocity with increasing BMI or meal was observed in our study. In conclusion, multichannel MGG provides an assessment of frequency, amplitude and propagation velocity of the slow wave in subjects with differing BMI categories and was observed to be independent of BMI.

Evaluating oral health promotion activity within a general dental practice.

The prevention of the common dental diseases is fundamental to modern day general dental practice. Oral health promotion (OHP) is therefore key to facilitating health outcomes within organisations. The literature surrounding OHP stresses the importance of evaluation in order to assess the effectiveness of OHP activities. This paper describes the evaluation of OHP within a general dental practice setting. Early attendance, the use of adult toothpastes during childhood and consequential fluorosis are investigated. A small service evaluation study of 100 consecutive patients was undertaken. The results support the ongoing promotion of early attendance and the use of toothpastes with adequate fluoride levels. There was no evidence of unsightly fluorosis in the sample studied.

Biomagnetic and bioelectric detection of gastric slow wave activity in normal human subjects--a correlation study.

We measured gastric slow wave activity simultaneously with a Superconducting Quantum Interference Device (SQUID) magnetometer, mucosal electrodes and cutaneous electrodes in 18 normal human subjects (11 women and 7 men). We processed signals with Fourier spectral analysis and SOBI blind-source separation techniques. We observed a high waveform correlation between the mucosal electromyogram (EMG) and multichannel SQUID magnetogastrogram (MGG). There was a lower waveform correlation between the mucosal EMG and cutaneous electrogastrogram (EGG), but the correlation improved with the application of SOBI. There was also a high correlation between the frequency of the electrical activity recorded in the MGG and in mucosal electrodes (r = 0.97). We concluded that SQUID magnetometers noninvasively record gastric slow wave activity that is highly correlated with the activity recorded by invasive mucosal electrodes.

Overlap between Atlantic bluefin tuna spawning grounds and observed Deepwater Horizon surface oil in the northern Gulf of Mexico.

The 2010 Deepwater Horizon oil spill impacted the northern Gulf of Mexico (GOM) during the spring spawning season of Atlantic bluefin tuna (BFT). Overlap between BFT spawning habitat and surface oil in the northern GOM was examined using satellite-derived estimates of oil coverage, and spawning habitat models. Results suggested that although eggs and larvae were likely impacted by oil-contaminated waters in the eastern GOM, high abundances of larvae were located elsewhere, especially in the western GOM. Overall, less than 10% of BFT spawning habitat was predicted to have been covered by surface oil, and less than 12% of larval BFT were predicted to have been located within contaminated waters in the northern GOM, on a weekly basis. Our results provide preliminary but important initial estimates of the effects of the spill on larval BFT mortality, as concern continues over the appropriate management responses to impacts of the spill.

An effective oral health promoting message?

This paper questions the effectiveness of current oral health promoting activities in reducing social inequalities in oral health. An attempt is made to address the needs of dental professionals and nutritionists in communicating an understanding of biological aspects of the aetiology of caries and erosion. With a clear understanding of the disease process oral health promoters can possibly reduce social inequalities in oral health. A clear common message which satisfies both dental and nutritional professionals is presented. The issues of commonality and ambiguity are fundamental to effective behavioural/teaching practice. Currently the evidence base suggests that dietary messages are inconsistent and ambiguous. Therefore, a clear common and unambiguous dietary message, based on science, could go some way to improving oral health inequalities.

Improving the accuracy of ultrafast ligand-based screening: incorporating lipophilicity into ElectroShape as an extra dimension.

In a previous paper, we presented the ElectroShape method, which we used to achieve successful ligand-based virtual screening. It extended classical shape-based methods by applying them to the four-dimensional shape of the molecule where partial charge was used as the fourth dimension to capture electrostatic information. This paper extends the approach by using atomic lipophilicity (alogP) as an additional molecular property and validates it using the improved release 2 of the Directory of Useful Decoys (DUD). When alogP replaced partial charge, the enrichment results were slightly below those of ElectroShape, though still far better than purely shape-based methods. However, when alogP was added as a complement to partial charge, the resulting five-dimensional enrichments shows a clear improvement in performance. This demonstrates the utility of extending the ElectroShape virtual screening method by adding other atom-based descriptors.

Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization.

Elevated serum levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) are found in patients with phosphate wasting diseases and chronic kidney disease-mineral and bone disorder (CKD-MBD). These diseases are associated with rickets and renal osteodystrophy, respectively. FGF23 is secreted from osteoblastic cells and signals through FGFRs, membrane coreceptor alpha-Klotho (Klotho), and, possibly, a circulating form of Klotho. Despite the absence of detectable Klotho on osteoblastic cells, studies have suggested that forced FGF23 expression in osteoblasts inhibited mineralization. Thus, we examined the effects of exogenously applied FGF23 on osteoblastic MC3T3.E1 cell proliferation and differentiation, with and without soluble Klotho. MC3T3.E1 cells were cultured in osteoblast differentiation medium, supplemented with FGF23 (0.1-1,000 ng/mL), Klotho (50 ng/mL), the combination FGF23 + Klotho, and FGF2 (100 ng/mL) as a control. Neither FGF23 nor Klotho exposure affected proliferation of day 4 growth phase cells or mineralization of day 14 cultures. In contrast, FGF23 + Klotho resulted in inhibition of mineralization and osteoblast activity markers at day 14, and a slight, reproducible induction of proliferation. Inhibition of FGFR1, but not FGFR2 or FGFR3, completely restored FGF23 + Klotho-induced inhibition of alkaline phosphatase (ALP) activity at day 7. ALP activity was partially restored by the MAPK inhibitor U0126 but not inhibitors p38 and P13K. Thus, soluble Klotho enables FGF23 signaling in MC3T3.E1 cells, likely through FGFR 1(IIIc). Elevated FGF23 actions, in part, appear to parallel FGF2 with lower potency. In addition to affecting bone via indirect phosphate wasting pathways, supraphysiological FGF23 and soluble Klotho may directly impact bone in diseases with elevated FGF23 levels.

Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.

HIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation-π interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion-pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion-pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.

Perceptions of first year foundation dentists on oral health education and its role in general dental practice.

UNLABELLED: To explore the perceptions of first year foundation dentists (FD1s) regarding oral health education (OHE) and its role in general dental practice. DESIGN: Focus group discussions. SETTING: Postgraduate training venues and general dental practices utilised for foundation training in South Wales, UK. SUBJECTS (MATERIALS) AND METHODS: Nineteen FD1s accepted an invitation to take part in a series of focus groups. Focus groups were transcribed and data analysed using a constructive process of thematic content analysis to identify themes and theories relating to the FD1s' understanding of OHE and its role in the delivery of care as general dental practitioners. RESULTS: The data fell into three broad categories: the teaching of OHE delivery at undergraduate level; factors influencing the 'frequency and content' of OHE delivery; and barriers to 'effective and successful' OHE. The first category identified perceptions of the 'gold standard' of OHE following undergraduate experiences. The practicalities of the acquisition of technical skills had created a simplistic compartmentalised view of OHE which was not a priority in adult dental care. The second category covered triggers for delivering OHE; in general these were reactive rather than preventive. The last category dealt with successful OHE; unsuccessful OHE was attributed to the patient although communication barriers were recognised. CONCLUSION: The subtle but important difference between OHE and oral health promotion (OHP) in terms of its role in general dental practice is recognised theoretically but not as a reality in practice. OHE is often compartmentalised and a simplistic approach to its delivery is taken. Against a backdrop of commissioning to improve health this has implications in developing organisational processes within general dental practice and training in order to achieve this.