Cellular mechanism of oral absorption of solidified polymer micelles.

Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. FROM THE CLINICAL EDITOR: Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers.

Pre-Eruptive Intracoronal Resorption (PEIR): A Case Report.

Pre-Eruptive Intracoronal Resorption (PEIR) is a rare yet significant phenomenon in which an abnormal, well-circumscribed, radiolucent area develops in the tooth prior to eruption. This case report outlines the treatment of a 12 year old Hispanic female who was referred for endodontic evaluation of tooth #31 and subsequently diagnosed with PEIR. The patient's chief complaint was recorded as "spontaneous pain" in the lower right quadrant of her jaw. Clinical examination revealed a partially erupted tooth #31 with no visible decay. Radiographic examination, including a cone beam computed tomography scan, led to the detection of a radiolucent area surrounding the pulp chamber on the mesial aspect of tooth #31. Radiographically, the enamel appeared intact with no signs of perforation. Based on the clinical and radiographic evaluation, tooth #31 was determined to have PEIR, with the pulpal and periapical diagnosis of "Symptomatic Irreversible Pulpitis" and "Normal Apical Tissue," respectively. The Orthodontic consultation obtained for this patient recommended that tooth #31 be maintained at least until tooth #32 appeared in the oral cavity and could be used as a replacement. Therefore, a treatment plan involving vital pulp therapy and gingivectomy was selected. During the procedure, granulation tissue was excavated and sent for histological evaluation, which concluded the presence of "granulation tissue with acute and chronic inflammation". No caries were detected. Following the procedure, the tooth was found to be asymptomatic with continued root development. A positive response to Electric Pulp Test was achieved after 3.5 years of follow up.

Ingestion and surgical retrieval of an endodontic file: a case report.

Ingestions and aspirations of foreign bodies are rare, but do occasionally occur during dental treatment. Although reports exist, few include photos demonstrating the extensive surgical intervention that may be necessary to manage such events. Perhaps this lack of visualization, and associated lack of awareness, is one of the reasons some clinicians still provide non-surgical root canal therapy (NSRCT) without a rubber dam. This case report outlines the medical treatment of a 30-year-old male who initially presented to a general dentist's office (not associated with the authors) for NSRCT of their mandibular right first molar. A rubber dam was not used for this procedure, during which the accidental ingestion of an endodontic K-file occurred. The patient was subsequently hospitalized for evaluation and treatment, consisting of numerous imaging studies, endoscopic evaluation, and surgical removal of the file from his small intestine. The ingestion of foreign bodies, and the associated complications, can be reduced through the routine use of a rubber dam, which is considered the standard of care for NSRCT. This case graphically illustrates the potential consequences associated with deviating from the standard of care and should remind clinicians that a rubber dam is necessary for all cases of NSRCT.

Incidental Findings in Small Field of View Cone-beam Computed Tomography Scans, Part 2: Interpretation with Aid of a Checklist.

INTRODUCTION: Cone-beam computed tomography (CBCT) scans are routinely used by endodontic residents and faculty at Tufts University School of Dental Medicine for diagnostic purposes but are not routinely read for pathologic findings by a radiologist. In a 2017 study by Oser et al (part 1), endodontic residents and a radiologist interpreted CBCT scans taken for endodontic diagnostic purposes, and their findings were compared. The results demonstrated that a radiologist is significantly more likely to report incidental findings in small field of view (FOV) scans. A limitation of this study was that the radiologist used a checklist of common findings to review the scans. The purpose of this study was to examine whether the use of a checklist would improve the sensitivity of the endodontic residents' reporting of incidental findings in small FOV CBCT scans. METHODS: The 203 small FOV CBCT scans used in part 1 were obtained and reviewed by endodontic residents in a systematic fashion. Radiographic findings were reported using a blank checklist. The results were compared with those previously reported. RESULTS: The radiologist reported abnormalities in 176 of the 203 subjects (87%), and the residents reported abnormalities in 184 of the 203 subjects (91%). There was an increase in false positive findings when the residents were using a checklist. CONCLUSIONS: The use of a checklist improved the sensitivity but decreased the specificity of the reporting of incidental findings in small FOV CBCT scans by endodontic residents.

Clinical Response to COVID-19 and Utilization of an Emergency Dental Clinic in an Academic Institution.

INTRODUCTION: The spread of coronavirus disease 2019 (COVID-19) in the spring of 2020 resulted in the temporary suspension of elective dental procedures and clinical dental education in academic institutions. This study describes the use of the Tufts University School of Dental Medicine emergency dental clinic during the peak surge in COVID-19 cases in Massachusetts, highlighting the number of endodontic emergencies. METHODS: Aggregate data from clinical encounters and call records to an emergency triage phone line from March 30 through May 8, 2020, were used to describe the characteristics of dental emergencies, clinical encounters, and procedures performed. RESULTS: A total of 466 patient interactions occurred during this period, resulting in 199 patients advised by phone and 267 clinical encounters. The most common dental emergencies were severe dental pain from pulpal inflammation (27.7% of clinical encounters) followed by a surgical postoperative visit (13.1%). The most frequent procedures were extractions (13.9% of clinical encounters) and surgical follow-up (13.5%); 50.2% of the clinical encounters were categorized as aerosol generating, and 86.1% of encounters would have required treatment in a hospital emergency department if dental care was not available. There were no known transmissions of severe acute respiratory syndrome coronavirus-2 among clinic providers, patients, or staff during this period. CONCLUSIONS: These results highlight the importance of endodontic diagnosis and treatment in the provision of emergency dental care during a pandemic and demonstrate that dental treatment can be provided in a manner that minimizes the risk of viral transmission, maintaining continuity of care for a large patient population.

The Association between Choice of Diagnostic Imaging Modality and Long-term Treatment Outcomes for Patients Undergoing Nonsurgical Root Canal Treatment on Maxillary First Molars.

INTRODUCTION: Radiography has played a fundamental role in the advancement of nonsurgical root canal therapy (NSRCT), allowing for more accurate diagnosis and treatment. Typically, providers choose to perform NSRCT using periapical (PA) radiographs alone or, often in more difficult cases, in conjunction with cone-beam computed tomographic (CBCT) imaging. This study aimed to evaluate the outcomes of NSRCT based on imaging modality selection for the initial treatment of maxillary first molars. METHODS: A retrospective chart review was conducted using 1385 cases of NSRCT on maxillary first molars. Charts were reviewed for patient demographics and treatment outcomes. Based on the imaging modality used, patients were stratified into 2 groups (PA radiographs alone or PA radiographs + CBCT imaging). Those who required additional treatment(s) after the completion of NSRCT were classified as having "posttreatment disease." Statistical analysis was performed to assess the differences between groups. RESULTS: After the completion of primary endodontic therapy, 5.8% (n = 81) of the entire sample had posttreatment disease. CBCT imaging was used in 13.4% (n = 185) of NSRCTs. Although not significant, cases that were difficult enough to require the use of CBCT imaging had a higher rate of posttreatment disease compared to those that could be completed with PA radiographs alone (8.6% vs 5.4%, P > .05). Results from a multivariable logistic regression model showed that the need for CBCT imaging had a nonsignificant positive association with posttreatment disease (P > .05). CONCLUSIONS: The decision to use CBCT imaging appears to serve as a proxy for case complexity and the associated increase in risk of posttreatment disease. This is important to keep in mind when assessing treatment prognosis.

Jumpstart Mirror Trainer: A New Device for Teaching Mirror Skills to First-Year Dental Students.

Learning indirect vision with a dental mirror is challenging and can be overwhelming for beginning dental students. The Jumpstart Mirror Trainer is a new device that allows students to become proficient with mirror use before the start of preclinic without requiring in-class practice sessions. The aim of this study, conducted in 2017, was to compare the effectiveness of the Jumpstart Mirror Trainer with the Mirroprep for teaching indirect motor skills. Forty-seven first-year dental students were randomized into three groups to use the Jumpstart Mirror Trainer, Mirroprep, or a control device for 15 minutes a day for ten days. To assess indirect motor skills improvement, students performed a maxillary cavity preparation before and after using their devices. A survey was used to assess students' comfort level with mirror skills and perceived helpfulness of the exercises. Forty students completed the study. The Jumpstart Mirror Trainer activities improved the students' scores significantly more than the Mirroprep activities (p=0.04) and the control device (p=0.006). Students in the Jumpstart Mirror Trainer group rated their device as being significantly more helpful than the control group rated its device in preparing them for the evaluation (p=0.001). There was no statistically significant difference in perceived helpfulness between the Mirroprep group and the control group (p=0.75). These results suggest that the Jumpstart Mirror Trainer may be able to improve students' indirect motor skills without requiring in-class practice sessions and to do so more effectively than other existing methods.

Incidental Findings in Small Field of View Cone-beam Computed Tomography Scans.

INTRODUCTION: The use of cone-beam computed tomography (CBCT) in endodontics has increased in recent years. In clinical application of small field of view (FOV) CBCTs, these scans are not reviewed routinely by a radiologist. Studies of large FOV CBCT scans show the prevalence of incidental findings to be greater than 90%. The purpose of this study was to evaluate the prevalence of missed findings by endodontic residents as compared with a radiologist on small FOV CBCT scans. METHODS: Two hundred three small FOV CBCTs obtained for endodontic purposes were analyzed by an endodontic resident and a medical radiologist. The reported findings of each practitioner were compared to evaluate for missed incidental findings by the endodontic resident. RESULTS: The radiologist reported abnormalities in 176 of the 203 subjects (87%), with a total of 310 abnormalities reported. The endodontic resident reported abnormalities in 102 of the 203 subjects (50%), with a total of 126 abnormalities reported. The percentage of scans with any abnormality reported by the radiologist was significantly greater than the endodontic resident (P < .001). There was no significant difference between jaw locations in percentage of missed findings for the 3 most common types of finding-rarefying osteitis, sinusitis/mucosal lining thickening, and excess restorative material in the periapical area. Rarefying osteitis was missed significantly less than the other 2 types of findings (P < .001). CONCLUSIONS: A radiologist is significantly more likely to identify incidental findings in small FOV CBCT scans than an endodontic resident. Scan location had no significant association with the rate of missed findings.

Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study.

PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNalpha-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 micro g/kg/wk of pegylated IFNalpha-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 micro g/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNalpha-2b at 12 weeks was 6.0 micro g/kg/wk. One year of 6.0 micro g/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNalpha-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNalpha-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 micro g/kg/wk.

Toothache caused by trigeminal neuralgia of vestibular schwannoma: a case report. [Corrected].

INTRODUCTION: Vestibular schwannoma, also called acoustic neuroma, is a tumor composed of Schwann cells that most commonly involves the vestibular division of the 8th cranial nerve. A thorough medical and dental history and properly conducted diagnostic testing and radiographic evaluation are essential in differentiating odontogenic tooth pain from tooth pain of a nonodontogenic origin. METHODS: This report discusses a case of acoustic neuroma mimicking odontogenic pain. A 61-year-old man presented with pain in the lower left quadrant. Medical history revealed peripheral neuropathy and prior exposure to Agent Orange. Diagnostic testing on teeth #19, #20, and #21 ruled out an odontogenic cause for the pain. Brushing of a specific region of the face elicited pain that resembled the patient's chief concern. The patient was referred to a craniofacial pain center with the tentative diagnosis of trigeminal neuralgia. Treatment for trigeminal neuralgia was not successful, prompting referral to the neurosurgery department where magnetic resonance imaging was performed. RESULTS: Magnetic resonance imaging revealed a moderate-size, lobular, left cerebellopontine angle mass lesion consistent with acoustic neuroma with compression of the left trigeminal nerve secondary to the lesion. CONCLUSIONS: Acoustic neuroma can cause tooth pain secondary to compression of the trigeminal nerve.

The corneal micropocket assay: a model of angiogenesis in the mouse eye.

The mouse corneal micropocket assay is a robust and quantitative in vivo assay for evaluating angiogenesis. By using standardized slow-release pellets containing specific growth factors that trigger blood vessel growth throughout the naturally avascular cornea, angiogenesis can be measured and quantified. In this assay the angiogenic response is generated over the course of several days, depending on the type and dose of growth factor used. The induction of neovascularization is commonly triggered by either basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). By combining these growth factors with sucralfate and hydron (poly-HEMA (poly(2-hydroxyethyl methacrylate))) and casting the mixture into pellets, they can be surgically implanted in the mouse eye. These uniform pellets slowly-release the growth factors over five or six days (bFGF or VEGF respectively) enabling sufficient angiogenic response required for vessel area quantification using a slit lamp. This assay can be used for different applications, including the evaluation of angiogenic modulator drugs or treatments as well as comparison between different genetic backgrounds affecting angiogenesis. A skilled investigator after practicing this assay can implant a pellet in less than 5 min per eye.

Rubber dam use during post placement influences the success of root canal-treated teeth.

INTRODUCTION: Salivary leakage after root canal therapy is of great concern and can lead to failure of the endodontic therapy. The aim of this study was to investigate whether the use of a rubber dam (RD) during post placement impacts the success of root canal-treated teeth. METHODS: Retrospective chart reviews of 185 patients with an average recall of 2.7 years were assessed for the incidence of a new periapical lesion (periapical index score >2) after root canal therapy and post placement. The patients were divided into 2 groups based on the presence or absence of an RD clamp in the verification radiograph during post placement. RESULTS: Twenty-six patients (30 teeth) had a post placed with the use of an RD, and 159 patients (174 teeth) had a post placed without an RD. In the non-RD group, 128 (73.6%) teeth were considered successful at follow-up. In the RD group, 28 (93.3%) teeth were considered successful at follow-up. Based on the bivariate GEE model, the difference in success between these 2 groups was statistically significant (P = .035). CONCLUSIONS: The use of an RD during prefabricated post placement provides a significantly higher success rate of root canal-treated teeth. Using an RD is already considered a standard of care for nonsurgical root canal therapy; in addition, using an RD during restorative procedures that involve open teeth should also become a standard of care.

Suppression of autoimmune retinal inflammation by an antiangiogenic drug.

Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4(+) T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4(+) T cells, and a general normalization of the systemic immune reaction.

An orally delivered small-molecule formulation with antiangiogenic and anticancer activity.

Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.