Effect of Deep Margin Elevation on Interfacial Gap Development of CAD/CAM Inlays after Thermomechanical Cycling.

METHODS AND MATERIALS: Mesio-occlusal-distal cavities were prepared on 12 extracted mandibular molars. The gingival margin of one proximal box was elevated with resin modified glass ionomer (RMGI) by a height of 2 mm (Group E [elevation]), and the margin of the other side served as a control (Group NE [no elevation]). Lithium disilicate computer-aided design and computer-aided manufacturing (CAD/CAM) inlays were fabricated and bonded with a self-adhesive resin cement. An aging process was simulated on the specimens under thermomechanical cycling by using a chewing simulator. Marginal integration was evaluated under scanning electron miscroscopy (SEM) using epoxy resin replicas before and after cycling. Marginal areas were stained with silver nitrate solution, and the volumetric gap was measured at the bonded interfaces using micro-computed tomography (CT) before and after cycling. Statistical analyses were performed using paired t-tests, the Wilcoxon signed rank test, and the Mann-Whitney test (a<0.05). RESULTS: SEM showed marginal discontinuities in Group NE that increased after thermomechanical cycling. Micro-computed tomography exhibited three-dimensional dye-penetrating patterns at the interfaces before and after cycling. Interfacial disintegration was larger in Group NE before cycling (p<0.05). Thermomechanical cycling increased the gaps in both Groups NE and E (p<0.05). The gap increment from thermomechanical cycling was larger in Group NE (p<0.05). CONCLUSIONS: Thermomechanical cycling induced interfacial disintegration at the lithium disilicate CAD/CAM inlays, with deep proximal margins. Margin elevation with RMGI placement reduced the extent of the interfacial gap formation before and after the aging simulation.

Functional MRI as an Objective Measure of Olfaction Deficit in Patients with Traumatic Anosmia.

BACKGROUND AND PURPOSE: While posttraumatic anosmia is not uncommon, the olfactory function evaluation has strongly relied on subjective responses given by patients. We aimed to examine the utility of fMRI as an objective tool for diagnosing traumatic anosmia. MATERIALS AND METHODS: Sixteen patients (11 men and 5 women; mean age, 42.2 ± 10.4 years) with clinically diagnosed traumatic anosmia and 19 healthy control subjects (11 men and 8 women; mean age, 29.3 ± 8.5 years) underwent fMRI during olfactory stimulation with citral (a pleasant odor) or ß-mercaptoethanol (an unpleasant odor). All patients were subjected to a clinical olfactory functional assessment and nasal endoscopic exploration. Two-sample t tests were conducted with age as a covariate to examine group differences in brain activation responses to olfactory stimulation (false discovery rate-corrected P < .05). RESULTS: Compared with healthy control subjects, patients with traumatic anosmia had reduced activation in the bilateral primary and secondary olfactory cortices and the limbic system in response to ß-mercaptoethanol stimulation, whereas reduced activation was observed only in the left frontal subgyral region in response to citral stimulation. CONCLUSIONS: Brain activation was decreased in the bilateral primary and secondary olfactory cortices as well as the limbic system in response to olfactory stimulation in patients with traumatic anosmia compared with healthy control subjects. These preliminary results may shed light on the potential of fMRI for the diagnosis of traumatic anosmia.

C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression.

C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.

Ex vivo magnetic resonance imaging using hyaluronic acid fillers: Differences between monophasic and biphasic fillers.

BACKGROUND/PURPOSE: Hyaluronic acid (HA) is an anionic, non-sulfated glycosaminoglycan distributed throughout the human skin and injectable HA fillers are the most commonly used in aesthetic field. This study aimed to determine if differences in physical characteristics of HA products (monophasic or biphasic fillers) affect the patterns of magnetic resonance imaging (MRI). METHODS: Twenty biphasic fillers and nine monophasic fillers were obtained from a commercial source, and examined with a 3.0 Tesla MRI scanner. Visual assessments and measurements of signal intensity for region of interest (ROI) were performed. A non-parametric Wilcoxon rank sum test was used to compare the ROI values. RESULTS: Visual assessments by a radiologist did not show significant differences between the two types of fillers. While the signal intensity between the two types of filler did not differ significantly for T1-weighted images, the signal intensity of the biphasic filler was lower than that of the monophasic filler for T2-weighted images (P<.01). CONCLUSION: Monophasic and biphasic HA fillers exhibited different MRI properties. Our findings may provide better insights into the use of in vivo MRI to evaluate aesthetic, procedure-related complications.

Evaluation of the 3dMDface system as a tool for soft tissue analysis.

OBJECTIVES: To evaluate the accuracy of three-dimensional stereophotogrammetry by comparing values obtained from direct anthropometry and the 3dMDface system. To achieve a more comprehensive evaluation of the reliability of 3dMD, both linear and surface measurements were examined. SETTING AND SAMPLE POPULATION: UCLA Section of Orthodontics. Mannequin head as model for anthropometric measurements. MATERIAL AND METHODS: Image acquisition and analysis were carried out on a mannequin head using 16 anthropometric landmarks and 21 measured parameters for linear and surface distances. 3D images using 3dMDface system were made at 0, 1 and 24 hours; 1, 2, 3 and 4 weeks. Error magnitude statistics used include mean absolute difference, standard deviation of error, relative error magnitude and root mean square error. Intra-observer agreement for all measurements was attained. RESULTS: Overall mean errors were lower than 1.00 mm for both linear and surface parameter measurements, except in 5 of the 21 measurements. The three longest parameter distances showed increased variation compared to shorter distances. No systematic errors were observed for all performed paired t tests (P<.05). Agreement values between two observers ranged from 0.91 to 0.99. CONCLUSIONS: Measurements on a mannequin confirmed the accuracy of all landmarks and parameters analysed in this study using the 3dMDface system. Results indicated that 3dMDface system is an accurate tool for linear and surface measurements, with potentially broad-reaching applications in orthodontics, surgical treatment planning and treatment evaluation.

Appropriate Minimal Dose of Gadobutrol for 3D Time-Resolved MRA of the Supra-Aortic Arteries: Comparison with Conventional Single-Phase High-Resolution 3D Contrast-Enhanced MRA.

BACKGROUND AND PURPOSE: The development of nephrogenic systemic fibrosis and neural tissue deposition is gadolinium dose-dependent. The purpose of this study was to determine the appropriate minimal dose of gadobutrol with time-resolved MRA to assess supra-aortic arterial stenosis with contrast-enhanced MRA as a reference standard. MATERIALS AND METHODS: Four hundred sixty-two consecutive patients underwent both standard-dose contrast-enhanced MRA and low-dose time-resolved MRA and were classified into 3 groups; group A (a constant dose of 1 mL for time-resolved MRA), group B (2 mL), or group C (3 mL). All studies were independently evaluated by 2 radiologists for image quality by using a 5-point scale (from 0 = failure to 4 = excellent), grading of arterial stenosis (0 = normal, 1 = mild [<30%], 2 = moderate [30%-69%], 3 = severe to occlusion [≥70%]), and signal-to-noise ratio. RESULTS: The image quality of time-resolved MRA was similar to that of contrast-enhanced MRA in groups B and C, but it was inferior to contrast-enhanced MRA in group A. For the grading of arterial stenosis, there was an excellent correlation between contrast-enhanced MRA and time-resolved MRA (R = 0.957 for group A, R = 0.988 for group B, R = 0.991 for group C). The SNR of time-resolved MRA tended to be lower than that of contrast-enhanced MRA in groups A and B. However, SNR was higher for time-resolved MRA compared with contrast-enhanced MRA in group C. CONCLUSIONS: Low-dose time-resolved MRA is feasible in the evaluation of supra-aortic stenosis and could be used as an alternative to contrast-enhanced MRA for a diagnostic technique in high-risk populations.

Clinical benefit of nomogram for predicting positive resection margins in breast conserving surgery.

PURPOSE: Previously, we reported a nomogram for the prediction of positive resection margin (RM) after breast conserving surgery (BCS). This study was conducted to evaluate the clinical usefulness of the nomogram. METHODS: Prospective patients who underwent operations using the nomogram between July 2012 and August 2013 (nomogram group; N = 260) were compared with past control patients who underwent operations between July 2010 and October 2011 and underwent frozen section biopsy (FSB) without use of the nomogram (N = 266). In the nomogram group, an intraoperative assessment of RM using FSB was only performed when the nomogram score was higher than predefined cut-off (>80). In addition, we conducted retrospective analysis of additional 181 patients who received BCS in another institute (Kyoto University Hospital). These patients did not undergo FSBs for RMs. RESULTS: Of 260 patients, 161 (61.9%) presented low nomogram scores and avoided FSB. The surgical decision to use the nomogram did not significantly increase reoperation rate due to positive RM compared with the control FSB group (4.6% vs. 3.8%, p = 0.47). The surgery time was significantly reduced by 18.1% (mean 14.7 min) in nomogram group (p < 0.001). Of 99 nomogram high-score patients, 14 presented with positive RM on FSB and 11 of them avoided reoperation. In the Kyoto cohort, the reoperation rate was significantly lower in low-score patients than in high-score patients (2.7% vs. 11.4%, p < 0.001). CONCLUSIONS: We showed that our nomogram is useful to reduce FSBs without increasing reoperation rate for surgeons who perform routine FSBs. For most surgeons, it can give useful information about the possibility of tumor-positive RMs.

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease.

BACKGROUND: Azathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount. AIM: To provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in IBD. METHODS: A literature search up to July 2015 was performed in PubMed using a combination of relevant MeSH terms. RESULTS: Pre-treatment thiopurine S-methyltransferase typing plus measurement of 6-tioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3-7%, and to improve efficacy by 15-30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association between AOX activity and AZA dose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate-linked moiety X-type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S-transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice. CONCLUSIONS: Measurement of thiopurine-related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.

The structural connectivity of the recurrent transient global amnesia.

BACKGROUND: One of recent interesting hypotheses of transient global amnesia (TGA) pathophysiology is the preexisting vulnerability of the memory network in patients with TGA. AIM OF THE STUDY: To verify the hypothesis that patients with recurrent amnestic attacks may have more disrupted structural connectivity than patients of a single TGA event, we compared the brain imaging of patients with repeated episodes of TGA with those who experienced a single attack. METHODS: Seven patients who were having recurrent TGA and 14 age- and sex-matched control subjects who had only a single episode of TGA participated in the study. Diffusion tensor images from both groups were assessed and analyzed using tract-based spatial statistics. RESULTS: The fractional anisotropy and mean diffusivity values were not reduced in any lesion within the memory pathway of recurrent patient group when compared with those of single event group. CONCLUSION: No disruptions in the structural connectivity of the memory pathway were observed in patients with recurrent TGA attacks, refuting the hypothesis that recurrent TGA patients present predisposing weakness of the memory network. The stability of structural connectivity suggests that repeated hippocampal lesions associated with TGA do not affect the microstructure of the brain.

Efficacy and safety of certolizumab pegol for Crohn's disease in clinical practice.

BACKGROUND: Certolizumab pegol (CZP) is Food and Drug Administration (FDA)-approved to treat Crohn's disease (CD). However, the efficacy and safety of CZP outside clinical trials are not well established. AIM: To report the efficacy, safety and predictors of response to CZP in CD patients treated during a 6-year period since FDA-approval at a tertiary care centre. METHODS: All CD patients who received CZP at our institution between 2008 and 2013 were evaluated through retrospective medical record-based review of steroid-free complete response (SCR), loss of response and safety. RESULTS: A total of 358 patients were included. One hundred twelve patients (31.3%) and 189 (52.8%) received CZP as their second and third biological agent, respectively. The probability of SCR at 26 week was 19.9% (95% CI, 15.9-24.5). The probability of survival free of loss of response at 2 year was 45.7% (95% CI, 32.5-59.5). A predictor of SCR was age at CD diagnosis of >40 years old (hazard ratio, HR relative to those <17, 4.69; 95% CI, 1.75-12.61). Negative predictors included present perianal fistula (HR, 0.39; 95% CI, 0.16-0.98) and prior primary nonresponse to adalimumab (ADA; HR relative to secondary loss of response, 0.18; 95% CI, 0.04-0.76). Twenty-three patients (6.4%) experienced serious adverse events and 19 patients (5.3%) discontinued CZP due to adverse events. CONCLUSIONS: Certolizumab pegol was both effective and well tolerated for the treatment of Crohn's disease in this large tertiary care centre enriched with biologics-exposed patients. It may be more effective in patients without early-aged Crohn's disease diagnosis, prior primary nonresponse to adalimumab and present perianal fistula.

Role of second-look ultrasound examinations for MR-detected lesions in patients with breast cancer.

PURPOSE: To assess the clinical value of second-look ultrasound (US) examination for the evaluation of additional enhancing lesions detected on magnetic resonance (MR) imaging. MATERIALS AND METHODS: Between May 2008 and February 2011, 794 consecutive patients with histologically confirmed breast cancer underwent breast MR imaging. We included 101 patients with 132 additional enhancing breast lesions detected on MR imaging who underwent second-look US.  The imaging features and lesion category according to the Breast Imaging and Reporting and Data System (BI-RADS) were assessed with MR and US imaging, respectively. RESULTS: According to the BI-RADS system, 67 lesions (50.8 %) were classified as category 0, 33 lesions (25.0 %) as category 3, and 32 lesions (24.2 %) as category 4. Of the 67 indeterminate lesions on MR imaging, 34 (50.7 %) were demonstrated on second-look US. 11 of these 34 lesions showed suspicious sonographic features, including 1 lesion that showed malignancy (9.1 %, 1/11). Most of the suspicious lesions on MR imaging (26 of 32 BI-RADS category 4 lesions, 81.3 %) were demonstrated on second-look US, and 17 were malignant (65.4 %, 17/26). Of the 6 BI-RADS category 4 lesions without sonographic correlation, 1 was malignant (16.7 %, 1/6). CONCLUSION: Second-look US examination was useful for evaluating MR-detected lesions in patients with breast cancer.

Relationship between multiple water swallows and gastroesophageal reflux in patients with normal esophageal motility.

Multiple water swallows (MWS) stimulates neural inhibition, resulting in abolition of contractions in the esophageal body and complete lower esophageal sphincter relaxation, which is followed by peristalsis and the lower esophageal sphincter contraction. We assessed the relationship between MWS and gastroesophageal reflux in patients with esophageal symptoms and with normal findings by high-resolution manometry (HRM). We retrospectively reviewed the clinical records of patients who underwent HRM and a 24-hour ambulatory impedance-pH study. Correlation between the findings of the impedance-pH study and abnormal MWS responses without motility disorders was evaluated. Independent t-tests were used for statistical analysis. Of 28 patients, 20 (71%) had abnormal MWS responses: four (20%) had abnormal responses during MWS, six (30%) had abnormal responses after MWS, and 10 (50%) had abnormal responses both during and after MWS. Total acid exposure times were significantly longer in patients with abnormal MWS responses than in patients with normal MWS responses. In particular, upright acid exposure time and all reflux percent times were significantly longer in patients with abnormal MWS responses. However, bolus clearance time and longest reflux episode were not different between the two groups. Abnormal MWS responses predicted increased acid exposure times in patients with normal findings of HRM by the Chicago classification.

The effect of water bolus temperature on esophageal motor function as measured by high-resolution manometry.

BACKGROUND: Ingestion of cold fluids may induce pain in patients with esophageal motility disorders. Hot fluids, on the other hand, may help to relieve pain. We studied changes in esophageal motility as a variable of water bolus temperature using high-resolution manometry (HRM) in healthy human. METHODS: Thirty-two healthy subjects were recruited at Kosin University Hospital. HRM was performed in a sitting position, with room temperature (RT, 25 °C), hot (45 °C), and cold (2 °C) water swallowed in that order. This exam included single swallowing (10 swallows of 5 mL water, 30 s intervals) and multiple water swallows (MWS; 100 mL water within 30 s). KEY RESULTS: In the single swallowing, hot water caused a decrease in lower esophageal sphincter (LES) residual pressure (5.87 ± 4.20 mmHg vs 7.45 ± 4.17 mmHg (RT), p = 0.001) and duration of esophageal body (EB) contraction (3.01 ± 0.80 s vs 3.15 ± 1.16 s (RT), p = 0.009). Cold water caused an increase in the duration of EB contraction (3.52 ± 0.87 s vs 3.15 ± 1.16 s (RT), p = 0.001) and a decrease in contractile front velocity (CFV) (4.43 ± 1.50 cm/s vs 4.90 ± 2.53 cm/s (RT), p = 0.007). Similarly, in the MWS, hot water caused a decrease in the duration of EB contraction (12.95 ± 5.02 s vs 16.33 ± 5.94 s (RT), p = 0.024) and an increase in the amplitude of EB contraction (114.27 ± 83.36 mmHg vs 82.70 ± 46.77 mmHg (RT), p = 0.007). Cold water caused an increase in the duration of EB contraction (27.38 ± 2.89 s vs 16.33 ± 5.94 s (RT), p = 0.03) and a decrease in the amplitude of EB contraction (51.68 ± 33.94 mmHg vs 82.70 ± 46.77 mmHg (RT), p = 0.001). CONCLUSIONS & INFERENCES: This study showed changes in esophageal motility to be dependent on water temperature. Especially, MWS showed clear changes in esophageal motility at different temperatures of water.

On the nature of the sea ice albedo feedback in simple models.

We examine the nature of the ice-albedo feedback in a long-standing approach used in the dynamic-thermodynamic modeling of sea ice. The central issue examined is how the evolution of the ice area is treated when modeling a partial ice cover using a two-category-thickness scheme; thin sea ice and open water in one category and "thick" sea ice in the second. The problem with the scheme is that the area evolution is handled in a manner that violates the basic rules of calculus, which leads to a neglected area evolution term that is equivalent to neglecting a leading-order latent heat flux. We demonstrate the consequences by constructing energy balance models with a fractional ice cover and studying them under the influence of increased radiative forcing. It is shown that the neglected flux is particularly important in a decaying ice cover approaching the transitions to seasonal or ice-free conditions. Clearly, a mishandling of the evolution of the ice area has leading-order effects on the ice-albedo feedback. Accordingly, it may be of considerable importance to reexamine the relevant climate model schemes and to begin the process of converting them to fully resolve the sea ice thickness distribution in a manner such as remapping, which does not in principle suffer from the pathology we describe.

Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat.

AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non-nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation.