Dental-dedicated MRI, a novel approach for dentomaxillofacial diagnostic imaging: technical specifications and feasibility.

MRI is a noninvasive, ionizing radiation-free imaging modality that has become an indispensable medical diagnostic method. The literature suggests MRI as a potential diagnostic modality in dentomaxillofacial radiology. However, current MRI equipment is designed for medical imaging (eg, brain and body imaging), with general-purpose use in radiology. Hence, it appears expensive for dentists to purchase and maintain, besides being complex to operate. In recent years, MRI has entered some areas of dentistry and has reached a point in which it can be provided following a tailored approach. This technical report introduces a dental-dedicated MRI (ddMRI) system, describing how MRI can be adapted to fit dentomaxillofacial radiology through the appropriate choice of field strength, dental radiofrequency surface coil, and pulse sequences. Also, this technical report illustrates the possible application and feasibility of the suggested ddMRI system in some relevant diagnostic tasks in dentistry. Based on the presented cases, it is fair to consider the suggested ddMRI system as a feasible approach to introducing MRI to dentists and dentomaxillofacial radiology specialists. Further studies are needed to clarify the diagnostic accuracy of ddMRI considering the various diagnostic tasks relevant to the practice of dentistry.

Maternal age differences in cognitive regulation: examination of associations and interactions between RSA and EEG frontoparietal alpha power coherence.

Strong cognitive regulation is advantageous for flexible, responsive parenting. Optimal cognitive regulation is reliant on associations between physiological mechanisms of central and peripheral nervous system functioning. Across middle adulthood there may be shifts in how cognitive regulation functions, reflecting changes in the associations and interactions between these physiological mechanisms. Two physiological indicators of cognitive regulation are autonomic regulation of the heart (e.g., respiratory sinus arrhythmia, RSA) and activity of the brain's frontoparietal network (e.g., frontoparietal EEG alpha power coherence, FPc). In the current study we examined maternal age differences (N = 90, age M = 32.35 years, SD = 5.86 years) in correlations and interactions between RSA and FPc in the statistical prediction of cognitive regulation [i.e., executive function (EF), effortful control (EC), cognitive reappraisal (CR)]. Age-related patterns involving interaction between RSA and FPc were found, pointing to a potential shift from optimization to compensation for changes with aging or alternately, the effects of age-based decrements in functioning. Findings are discussed in the context of adult developmental changes in maternal caregiving.

Magnetic resonance imaging in the diagnosis of periodontal and periapical disease.

OBJECTIVES: Early pre-clinical inflammatory changes in periodontal and/or periapical lesions, which typically precede bone loss, are challenging to diagnose using ionizing-radiation-based imaging modalities. MRI provides relevant additional diagnostic information of inflammatory processes in soft and hard tissues. The aim of the present study is to undertake a systematic review of the literature on MRI in the diagnosis of periodontal and/or periapical disease. METHODS AND MATERIALS: The PubMed/MEDLINE and Scopus bibliographic databases were searched (2000-2021) using the search string: ("MRI" or "magnetic resonance imaging") and ("periodontitis" or "periodontal" or "apical pathology" or "endodontic pathology" or "periapical" or "furcation" or "intrabony"). The search was limited to studies published in English. The studies were assessed independently by three reviewers, focusing on the MRI sequences, imaging modalities (radiographs, cone beam CT (CBCT), and MRI), disease definition, assessed parameters, and outcome measurements. RESULTS: The search strategy yielded 34 studies, from which 13 were included. Overall, the findings of MRI were in agreement with CBCT. The studies showed that MRI provided diagnostic information of the hard and soft tissue components affected by periodontal and/or periapical disease with a fairly high sensitivity and specificity. However, the assessed parameters (e.g. MRI acquisition protocols, and disease definition) differed substantially. CONCLUSIONS: The included studies indicate that the use of MRI in the diagnosis of periodontal and/or periapical disease is feasible and promising. More studies are needed to define the accuracy of this non-ionizing-radiation-based diagnostic modality, in the assessment of periodontal and/or periapical lesions.

Early detection of external cervical resorption in posterior teeth: a radiographic, cross-sectional study of an adolescent population.

OBJECTIVES: To establish the prevalence and severity of external cervical resorption (ECR) in posterior teeth observed in bitewing (BW) radiographs in an epidemiological study of a 17-year-old patient population from community dentistry. Furthermore, to assess the potential predisposing factors for ECR. METHODS: Posterior BWs from 5596 patients (2717 females, 2879 males; mean age 17.8 years) were assessed by three observers in order to detect ECR (using Heithersay's classification system, severity classes 1-4). When ECR was suspected, cone beam CT (CBCT) was offered to verify diagnosis. Prevalence was estimated based on ECR suspected in BWs and finally in CBCT. Possible predisposing factors (orthodontic treatment, trauma, and periodontal disease) were recorded and assessed for association with ECR. RESULTS: In 41 patients, ECR was suspected in BWs (suspected prevalence 0.73%). 32 patients accepted CBCT examination, of which eight were verified to have ECR (final prevalence 0.18%). In 24 patients, other disease entities and abnormal tooth morphology, that had mimicked ECR in BWs, excluded ECR in CBCT. ECR severity ranged from class 1-3 in BW and 2-4 in CBCT. All but one case had not been diagnosed by the patient's community dentist. No statistically significant association between predisposing factors and ECR was identified. CONCLUSIONS: ECR had low prevalence in this adolescent population, as observed in both BWs and CBCT. Still, early detection of ECR is important for treatment prognosis, and attention should be paid to this disease entity when assessing BWs obtained for other diagnostic purposes. CBCT may subsequently aid in verifying the disease.

Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects.

Rolapitant (Varubi) is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin-1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug-drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open-label, drug-drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1-hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration-time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration-time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant.

Specificity in Sociality: Mice and Prairie Voles Exhibit Different Patterns of Peer Affiliation.

Social behavior is often described as a unified concept, but highly social (group-living) species exhibit distinct social structures and may make different social decisions. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that often reside in extended family groups, and exhibit robust preferences for familiar social partners (same- and opposite-sex) during extended choice tests, although short-term preferences are not known. Mice (Mus musculus) are gregarious and colonial, but in brief laboratory tests of social preference they typically prefer social novelty. This preference for novel vs. familiar peers may represent a species-specific difference in social decision-making between mice and prairie voles. However, the tests used to measure preferences in each species differ markedly in duration and degree of contact, such that the behaviors cannot be directly compared. We assessed whether social preferences for novelty or familiarity differed between mice and prairie voles of both sexes when assessed with matching protocols: the sociability/social preference test (SPT) typically used in mice (short, no direct contact), and the partner preference test (PPT) used in voles (long, direct contact). A subset of voles also underwent a PPT using barriers (long, no direct contact). In the short SPT, behavior did not differ between species. In the longer test, pronounced partner preferences emerged in prairie voles, but mice exhibited no social preferences and rarely huddled. No sex differences were evident in either test. Direct physical contact was required for partner preferences in huddling time in voles, but preference for the partner chamber was evident with or without contact. Both prairie voles and mice are social, but they exhibit important differences in the specificity and extent of their social behavior. While mice are often used to study social approach and other behaviors, voles are a more suitable species for the study of selective social relationships. Consideration of these differences will be important for studies examining the neural mechanisms supporting different kinds of peer social behavior.

Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P-glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers.

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.

Bioequivalence of Intravenous and Oral Rolapitant: Results From a Randomized, Open-Label Pivotal Study.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30-minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least-squares means (GLSMs) for the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ) and AUC from time 0 extrapolated to infinity (AUC0-∞ ) for rolapitant were within 0.80-1.25. Mean rolapitant systemic exposure and half-lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80-1.25 range for AUC0-t (0.94-1.09) and AUC0-∞ (0.93-1.10). The incidence of treatment-emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5-mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180-mg oral dose and was well tolerated.

Community Environmental Contamination of Toxigenic Clostridium difficile.

BACKGROUND: Clostridium difficile infection is often considered to result from recent acquisition of a C difficile isolate in a healthcare setting. However, C difficile spores can persist for long periods of time, suggesting a potentially large community environmental reservoir. The objectives of this study were to assess community environmental contamination of toxigenic C difficile and to assess strain distribution in environmental versus clinical isolates. METHODS: From 2013 to 2015, we collected community environmental swabs from homes and public areas in Houston, Texas to assess C difficile contamination. All positive isolates were tested for C difficile toxins A and B, ribotyped, and compared with clinical C difficile isolates obtained from hospitalized patients in Houston healthcare settings. RESULTS: A total of 2538 environmental samples were collected over the study period. These included samples obtained from homes (n = 1079), parks (n = 491), chain stores (n = 225), fast food restaurants (n = 123), other commercial stores (n = 172), and hospitals (n = 448). Overall, 418 environmental isolates grew toxigenic C difficile (16.5%; P < .001) most commonly from parks (24.6%), followed by homes (17.1%), hospitals (16.5%), commercial stores (8.1%), chain stores (7.6%), and fast food restaurants (6.5%). A similar distribution of ribotypes was observed between clinical and environmental isolates with the exception that ribotype 027 was more common in clinical isolates compared with environmental isolates (P < .001). CONCLUSIONS: We identified a high prevalence of toxigenic C difficile from community environs that were similar ribotypes to clinical isolates. These findings suggest that interventions beyond isolation of symptomatic patients should be targeted for prevention of C difficile infection.

Dynamic glucocorticoid-dependent regulation of Sgk1 expression in oligodendrocytes of adult male rat brain by acute stress and time of day.

Recent studies support plasticity in adult brain white matter structure and myelination in response to various experiential factors. One possible contributor to this plasticity may be activity-dependent modulation of serum- and glucocorticoid-inducible kinase 1 (Sgk1) expression in oligodendrocytes. We examined whether Sgk1 expression in adult rat brain white matter is increased by acute stress-induced elevations in endogenous corticosterone and whether it fluctuates with diurnal variations in corticosterone. We observed rapid increases (within 30 min) in Sgk1 mRNA in the corpus callosum in response to acute stress, as well as large increases at the beginning of the rat's active period (the time of peak corticosterone secretion). These increases were absent in adrenalectomized rats. Corticosterone treatment of adrenalectomized rats also rapidly increased corpus callosum Sgk1 mRNA. The majority of Sgk1 mRNA in corpus callosum was co-localized with myelin basic protein mRNA, suggesting that mature oligodendrocytes respond dynamically to acute stress and circadian rhythms. The regulation of Sgk1 expression by acute stress and time of day was selective for white matter, with limited alteration of Sgk1 expression by these factors in hippocampus and somatosensory cortex. These results indicate a unique sensitivity of oligodendrocyte Sgk1 expression to activity-dependent fluctuations in corticosterone hormone secretion, and raises the prospect that hypothalamic-pituitary-adrenal axis dysregulation or glucocorticoid pharmacotherapy may compromise the normal activity-dependent interactions between oligodendrocytes and neurons.

Septal oxytocin administration impairs peer affiliation via V1a receptors in female meadow voles.

The peptide hormone oxytocin (OT) plays an important role in social behaviors, including social bond formation. In different contexts, however, OT is also associated with aggression, social selectivity, and reduced affiliation. Female meadow voles form social preferences for familiar same-sex peers under short, winter-like day lengths in the laboratory, and provide a means of studying affiliation outside the context of reproductive pair bonds. Multiple lines of evidence suggest that the actions of OT in the lateral septum (LS) may decrease affiliative behavior, including greater density of OT receptors in the LS of meadow voles that huddle less. We infused OT into the LS of female meadow voles immediately prior to cohabitation with a social partner to determine its effects on partner preference formation. OT prevented the formation of preferences for the partner female. Co-administration of OT with a specific OT receptor antagonist did not reverse the effect, but co-administration of OT with a specific vasopressin 1a receptor (V1aR) antagonist did, indicating that OT in the LS likely acted through V1aRs to decrease partner preference. Receptor autoradiography revealed dense V1aR binding in the LS of female meadow voles. These results suggest that the LS is a brain region that may be responsible for inhibitory effects of OT administration on affiliation, which will be important to consider in therapeutic administrations of OT.

In the Endemic Setting, Clostridium difficile Ribotype 027 Is Virulent But Not Hypervirulent.

BACKGROUND: Conflicting reports have been published on the association between Clostridium difficile ribotypes and severe disease outcomes in patients with C. difficile infection (CDI); several so-called hypervirulent ribotypes have been described. We performed a multicenter study to assess severe disease presentation and severe outcomes among CDI patients infected with different ribotypes. METHODS: Stool samples that tested positive for C. difficile toxin were collected and cultured from patients who presented to any of 7 different hospitals in Houston, Texas (2011-2013). C. difficile was characterized using a fluorescent PCR ribotyping method. Medical records were reviewed to determine clinical characteristics and ribotype association with severe CDI presentation (ie, leukocytosis and/or hypoalbuminemia) and severe CDI outcomes (ie, ICU admission, ileus, toxic megacolon, colectomy, and/or in-hospital death). RESULTS: Our study included 715 patients aged 61±18 years (female: 63%; median Charlson comorbidity index: 2.5±2.4; hospital-onset CDI: 45%; severe CDI: 36.7%; severe CDI outcomes: 12.3%). The most common ribotypes were 027, 014-020, FP311, 002, 078-126, and 001. Ribotype 027 was a significant independent predictor of severe disease (adjusted odds ratio [aOR], 2.24; 95% confidence interval [CI], 1.53-3.29; P<.001) and severe CDI outcomes (aOR, 1.71; 95% CI, 1.02-2.85; P=.041) compared with all other ribotypes in aggregate. However, in an analysis using all common ribotypes as individual variables, ribotype 027 was not associated with severe CDI outcomes more often than other ribotypes. CONCLUSION: Ribotype 027 showed virulence equal to that of other ribotypes identified in this endemic setting. Clinical severity markers of CDI may be more predictive of severe CDI outcomes than a particular ribotype.

Is thermography useful for assessment of postoperative inflammation after surgical removal of mandibular third molars when methylprednisolone is administered and how does it correlate with patients' perception of swelling?

PURPOSE: To assess the differences in facial skin temperature after mandibular third molar removal when patients received methylprednisolone and placebo, respectively and to assess the correlation between patient-reported swelling using a visual analog scale (VAS) and facial skin temperature measured using thermography. PATIENTS AND METHODS: The study involved patients with 2 mandibular third molars with an indication for removal. The patients received either methylprednisolone or placebo in a randomized, crossover study design. Thermograms and the swelling VAS score were recorded 2 days after surgery. The outcome variable was the temperature difference (Δt) between the operated and control sides. A 2-sample t test analyzed the difference in Δt between the first and second operations. Spearman's rank correlation analysis was used to assess the correlation between the swelling VAS scores and the Δt. RESULTS: A total of 124 patients (67 males, 57 females, mean age 25 years) had both mandibular third molars removed on 2 separate occasions. No difference in Δt was found when methylprednisolone and placebo were given (P = .07). In addition, the correlation between the swelling VAS score and Δt was 0.30 (P = .001) and 0.09 (P = .3) after the first and second operation, respectively. CONCLUSIONS: Thermography does not seem sensitive enough to detect differences in the inflammatory response when patients received methylprednisolone or placebo. The correlation between the Δt and patient-reported swelling was low (≤0.3).

Efficiency of bupivacaine versus lidocaine and methylprednisolone versus placebo to reduce postoperative pain and swelling after surgical removal of mandibular third molars: a randomized, double-blinded, crossover clinical trial.

PURPOSE: To compare 4 treatment combinations to reduce postoperative pain and swelling after surgical removal of mandibular third molars. PATIENTS AND METHODS: Patients scheduled for bilateral mandibular third molar removal were randomized to 1 of 4 treatment groups in a double-blinded crossover design: 1) first operation: lidocaine and placebo, second operation: bupivacaine and methylprednisolone; 2) first operation: bupivacaine and methylprednisolone, second operation: lidocaine and placebo; 3) first operation: lidocaine and methylprednisolone, second operation: bupivacaine and placebo; 4) first operation: bupivacaine and placebo, second operation: lidocaine and methylprednisolone. Patient-reported pain and swelling were recorded using visual analog scales 2, 4, 6, 8, and 12 hours after surgery and daily during the first postoperative week. The treatment effects were estimated as contrasts between the average differences within the treatment groups and assessed by stratified t tests. RESULTS: A total of 126 patients (57 women and 69 men; mean age, 25.0 years) were included in the analysis. No significant interactions between local analgesia and methylprednisolone were observed. The administration of bupivacaine resulted in less postoperative pain up to 12 hours after surgery (P < .004) and more postoperative swelling 4 to 12 hours after surgery (P < .001) compared with lidocaine. The administration of methylprednisolone resulted in less postoperative pain 4 to 12 hours and 2 days after surgery (P < .05) and less postoperative swelling 6 and 12 hours and 1 to 3 days after surgery (P < .04) compared with placebo. CONCLUSIONS: Bupivacaine combined with methylprednisolone reduced the postoperative pain and swelling compared with the use of lidocaine and placebo, lidocaine and methylprednisolone, or bupivacaine and placebo.

Diagnostic accuracy of panoramic radiography, stereo-scanography and cone beam CT for assessment of mandibular third molars before surgery.

OBJECTIVE: To compare the diagnostic accuracy of panoramic imaging, stereo-scanography and cone beam computed tomography (CBCT) for assessment of mandibular third molars. MATERIAL AND METHODS: One hundred and twelve patients (147 third molars) underwent radiographic examination by panoramic imaging, stereo-scanography and CBCT. Tooth angulation, root morphology, number of roots and relation to the mandibular canal were assessed. The same variables were assessed intra- and post-operatively and served as reference for the radiographic assessments. The diagnostic accuracy for each variable was compared between the three modalities and accuracy was further expressed as sensitivity and specificity and tested between the modalities for identifying the relation to the mandibular canal. RESULTS: There were no significant differences between the modalities regarding tooth angulation, root morphology and number of roots. However, CBCT was more accurate than stereo-scanography for determining root bending in the bucco-lingual plane (p = 0.02). Moreover, sensitivity for direct contact to the mandibular canal (panoramic imaging: 0.29, stereo-scanography: 0.57, CBCT: 0.67) was higher for CBCT than for panoramic images (p = 0.05) and specificity for no direct contact to the mandibular canal (panoramic imaging: 0.78, stereo-scanography: 0.53, CBCT: 0.68) was higher for panoramic images and CBCT than for scanograms (p < 0.001). CONCLUSION: Panoramic imaging, stereo-scanography and CBCT seem equally valuable for examination of tooth angulation, number and morphology of roots of mandibular third molars. However, CBCT was more accurate for assessment of root bending in the bucco-lingual plane and more accurate than panoramic images to identify direct contact to the mandibular canal.

Should removal of lower third molars be included in the pre-graduate curriculum for dental students? An evaluation of post-operative complications after student operations.

OBJECTIVE: To evaluate guidelines for selection of lower third molars (M3) to be removed by dental students (DS) and to compare M3 surgery performed by oral surgeons (OS) and DSs with regard to operation time and post-operative complications. MATERIALS AND METHODS: Three hundred and thirteen patients with 313 lower M3 were assigned to be operated by either a DS or an OS, depending on the estimated difficulty of the surgery. During the post-operative week patients recorded pain (VAS) and other complications. Complications were also recorded objectively 1 week post-operatively. RESULTS: Operations performed by DSs lasted longer than operations performed by OSs (P < 0.001). There was no difference in immediate post-operative pain intensity between the two groups. There were no differences in patients' perception of bleeding, trismus, bad taste, use of analgesics, absence from work/school and seeking professional help between the two groups. Dry socket occurred more frequently though in patients in the DS group (P = 0.008). There was no difference in the frequency of objectively assessed swelling, paraesthesia or infection. CONCLUSIONS: When appropriately selected, patients operated by DSs did not perceive more immediate post-operative pain or complications than patients operated by OSs. However, dry socket and the risk of severe pain caused by this condition occurred more frequently in patients operated by DSs. The criteria used for selection of operations for DSs seem acceptable.

Patient discomfort and retakes in periapical examination of mandibular third molars using digital receptors and film.

OBJECTIVE: The aim was to compare patient discomfort and evaluate the frequency of retakes using intraoral digital receptors and conventional film for radiographic examination of mandibular third molars. STUDY DESIGN: Both mandibular third molar regions were examined in 110 patients with 2 of 5 digital intraoral receptors. Discomfort was scored on a visual analog scale (VAS) for each receptor and for film as a reference. If the whole tooth was not imaged on the digital image, a retake was performed using film. t Tests evaluated differences in VAS score, chi-squared tests evaluated differences in frequency of remakes, and logistic regression analyses evaluated factors predisposing for retake. RESULTS: No significant difference existed in VAS scores between right and left sides for film (P = .24). The digital receptors were more uncomfortable than film (P < .001), and CDR-APS was more uncomfortable than Digora (P = .049) and Vista (P = .002). The frequency of retakes was higher for solid-state sensors than photostimulable phosphor plates (PSPs) (P < .018). Gender (P = .022), type of receptor (P < .021), and VAS score (P = .001) were predisposing factors for a retake. CONCLUSION: Patients accepted film better than digital intraoral receptors, and retake frequency was lower for PSPs compared with solid-state sensors.

Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux.

Over-expression of P-glycoprotein (Pgp+) has been related to resistance to classical Topo II inhibitors used in the treatment of AML and is common in patients with poor-prognosis, such as those with secondary AML (sAML). Since clinical trials with amonafide, a unique ATP-independent Topo II inhibitor, in combination with cytarabine, have shown significant efficacy for remission induction in patients with sAML, we compared the cytotoxic effect of amonafide (amonafide l-malate, Xanafide) to the classical Topo II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone) in K562 leukemia cells and in the MDR subline, K562/DOX. Pgp expression was found to be approximately 6.5-fold greater in K562/DOX and causes the rapid efflux of these drugs from the leukemia cell. As a consequence, the LC(50) values for the classical Topo II inhibitor drugs tested were each increased up to 3 log units. A similar result was also observed in murine P388 and P388/ADR leukemia cells. Addition of cyclosporin A reversed K562/DOX resistance for the classical Topo II inhibitors, decreasing their LC(50) values to the levels observed with wild type cells but had no effect on amonafide potency in Pgp+ or wild type cells. Further examination of amonafide in bidirectional Caco-2 and MDR1-MDCK models confirmed that amonafide is neither a substrate nor inhibitor of Pgp. These observations suggest that amonafide is a promising therapeutic candidate directed toward bypassing this common mechanism of drug resistance encountered in the treatment of patients with AML, and possibly in other resistant hematological malignancies as well.

Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk.

Morphine tolerance in vivo is reduced following blockade of the orphanin FQ/nociceptin (OFQ/N)/opioid receptor-like 1 (ORL1) receptor system, suggesting that OFQ/N contributes to the development of morphine tolerance. We previously reported that a 60-min activation of ORL1 receptors natively expressed in BE(2)-C cells desensitized both mu and ORL1 receptor-mediated inhibition of cAMP. Investigating the mechanism(s) of OFQ/N-mediated mu and ORL1 receptor cross-talk, we found that pretreatment with the protein kinase C inhibitor, chelerythrine chloride (1 microM), blocked OFQ/N-mediated homologous desensitization of ORL1 and heterologous desensitization of mu opioid receptors. Furthermore, depletion of PKC by 12-O-tetradecanoylphorbol-13-acetate exposure (48 h, 1 microM) also prevented OFQ/N-mediated mu and ORL1 desensitization. OFQ/N pretreatment resulted in translocation of PKC-alpha, G protein-coupled receptor kinase 2 (GRK2) and GRK3 from the cytosol to the membrane, and this translocation was also blocked by chelerythrine. Reduction of GRK2 and GRK3 levels by antisense, but not sense DNA treatment blocks ORL1 and mu receptor desensitization. This suggests that PKC-alpha is required for GRK2 and GRK3 translocation to the membrane, where GRK can inactivate ORL1 and mu opioid receptors upon rechallenge with the appropriate agonist. Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions.