Three-dimensional ultrastructural analysis of the interface between an implanted demineralised dentin matrix and the surrounding newly formed bone.

Previous investigators have reported that transplanted demineralised dentin matrix (DDM) influences bone formation in vivo. However, the specific mechanism of how dentinal tubules contribute to bone formation has not been determined with regard to DDM transplantation therapy. In this study, we ultrastructurally investigated how DDM contacted the surrounding newly formed bone using a scanning electron microscopy (SEM) three-dimensional reconstruction method that is based on focused ion beam slicing and SEM (FIB/SEM). A pulverised and processed DDM derived from human teeth was implanted into rat calvarial bone defects, and a series of X-ray computed tomographic images were obtained over 12 weeks. Implants with surrounding new bone were removed and histologically examined using FIB/SEM. After obtaining objective block-face images, the target boundary face was reconstructed three-dimensionally. The osteocytes of the new bone tissue surrounding the DDM formed a network connected by their cellular processes and formed bone tissue. It is also interesting that the cellular processes of the osteocytes extended into the dentinal tubules, and that bone tissue with canaliculi had formed and filled the DDM surface.

Discovery and SAR of a novel series of Natriuretic Peptide Receptor-A (NPR-A) agonists.

Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073µM, indicating 350-fold potency compared to the hit compound 3.

Diagnostic dilemma of IgG4-related primary localized cervical lymphadenopathy associated with aberrant IL-6 expression level.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized inflammatory condition with single- or multi-organ involvement. The disease is characterized by tumefactive lesions with dense IgG4 plasmacytic infiltration (an elevated IgG4(+)/IgG(+) cell ratio of > 40 %), storiform fibrosis, and obliterative phlebitis, with or without elevated serum IgG4 levels. The diagnostic criteria for IgG4-RD, proposed in 2011, were quite comprehensive and practical; however, it is important to remember that other diseases, such as hyper-interleukin (IL)-6 syndromes, may have common histopathological findings. Therefore, the histopathology of suspected IgG4-RD is occasionally not diagnostic. Here, we report a case of IgG4-related primary localized cervical lymphadenopathy without any other organ involvement. To our knowledge, there have been no previous reports of this. Additionally, the disease was associated with a 20-fold increase in IL-6 levels compared to that of the normal range. CASE PRESENTATION: We report the case of a 52-year-old Japanese man who presented with a painless, somewhat diffuse swelling in the left submandibular region. Although the case fulfilled diagnostic criteria for IgG4-RD, the diagnosis was not straightforward due to abnormally high levels of serum IL-6. After systematic evaluation of the patient, a final diagnosis of IgG4-RD was established. Since then, a specialist in connective tissue disorders has evaluated the patient on a regular basis. Two years after his initial visit, no disease progress or systemic involvement has been noted. CONCLUSION: We present a case of an IgG4-related primary localized cervical lymphadenopathy mimicking hyper-IL-6 syndrome. This case can serve as an excellent reminder that the definitive diagnosis of IgG4-RD should be established using a systematic approach, in particular when it appears as an atypical manifestation.

Multiple accessory foramina of the mandibular ramus: risk factor for oral surgery.

A 27-year-old female was referred to our hospital with a chief complaint of removal of an impacted right mandibular third molar. Panoramic radiography showed two small circular radiolucencies on the right mandibular ramus. Computed tomography revealed that one of the radiolucencies was an accessory foramen located lateral to the mandibular ramus, and the other radiolucency was an accessory foramen located medial to the ramus; it was also connected to the mylohyoid groove. Continuity with the mandibular canal was confirmed for both accessory foramina. After explaining the risks of extraction, the patient decided against surgery and the impacted tooth was left in situ. Most patients have at least one or more accessory foramina in the mandible; however, accessory foramina of the lateral aspect of the mandibular ramus have not been reported. The high resolution of cone-beam computed tomography and three-dimensional reconstructed images enable improved detection of accessory foramina. Therefore, additional accessory foramina that are similar to those found in the present case could be found in the future using such imaging modalities.

Metastatic gastric tube cancer detected in a resected mandibular bone with osteoradionecrosis.

Osteoradionecrosis (ORN) of the jaw is an intractable complication of radiotherapy for head and neck cancer. However, osteolytic lesions are often hard to distinguish from malignancies. We report a rare case of metastatic cancer in a resected mandibular bone after segmental resection for ORN of the jaw. A 63-year-old male with a history of subtotal oesophageal resection for oesophageal cancer and reconstruction of the oesophagus with a gastric tube subsequently developed ORN of the jaw. Conservative treatment was unsuccessful and pathological fracture of the necrotic mandible occurred. The patient underwent segmental resection of the mandible and adenocarcinoma was detected in the resected mandibular bone. Immunohistochemical staining for cytokeratin 7 and 20 revealed that the adenocarcinoma had metastasized from the reconstructed gastric tube. This case highlights the fact that cancers of the gastric tube may metastasize to radiation-induced necrotic bone tissue in the mandible.

Osteochondroma of the right coronoid process (Jacob disease): a case report.

Oscar Jacob was the first to describe osteochondroma of the coronoid process, naming it "Jacob disease." Jacob disease rarely occurs in the oral and maxillofacial regions. The tumor usually grows progressively, leading to a mushroom-shaped enlargement of the process, and a joint-like structure is found between the coronoid process and the inner aspect of the zygomatic arch. Most of these lesions grow like a mushroom on, and do not destroy, the coronoid process. The major symptoms include restricted mouth opening and morphological changes to the zygoma. The authors present a case report on an 18-year-old male patient with pain in the right zygoma. Interincisal maximum mouth opening was 51 mm. An intraoral coronoidectomy was performed.

Intramolecular 1,3-dipolar cycloaddition-mediated stereoselective synthesis of disubstituted cyclopentane: a simple model for the cyclopentane ring system of polycyclic oroidine alkaloids.

We present a diastereoselective synthesis of disubstituted cyclopentane 8 having a nitrogen-containing quaternary carbon center, which is found in axinellamine A (5) and related compounds. During this work, we found that the 1,3-dipolar cycloaddition product 24 immediately underwent intramolecular redox reaction at the newly formed morpholin-2-one moiety, thus affording disubstituted cyclopentane containing a tertiary amine (9) stereoselectively in good yield. The amine 9 was successfully converted into guanidine 31, which corresponds to 8, through iminium cation-enamine isomerization.

[Clinical analyses of oral squamous cell carcinoma patients showing a complete response to chemotherapy with S-1 alone].

The purpose of this study was to investigate the effectiveness and safety of palliative chemotherapy using S-1 alone. We clinically analyzed 8 oral squamous cell carcinoma patients showing a complete response(CR)to chemotherapy with S-1 alone. These patients received chemotherapy consisting of 2 weeks' administration, including 5-days' administration and 2- days' termination, following a 1-week rest. Adverse effects were observed in 4 patients. However, all of them were grade 1 toxicities. The average length of S-1 administration before achieving CR was 9. 8 ± 3. 1 weeks(3. 3 ± 1. 0 courses). Seven patients had a recurrence. The prognosis of this group was 5 deaths by local recurrence, and 1 death by lymph node metastasis. The average length of disease progression was 447. 4 ± 479. 5 days. Two patients, one who received surgery and the other who received irradiation after chemotherapy by S-1, are alive without tumors. The 1-year and 3-year disease-free survival rates were 100% and 37. 5%, respectively.

Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na(V)1.4 and Na(V)1.5.

Skeletal analogues of saxitoxin (STX) that possess a fused-type tricyclic ring system, designated FD-STX, were synthesized as candidate sodium ion channel modulators. Three kinds of FD-STX derivatives 4a-c with different substitution at C13 were synthesized, and their inhibitory activity on sodium ion channels was examined by means of cell-based assay. (-)-FD-STX (4a) and (-)-FD-dcSTX (4b), which showed moderate inhibitory activity, were further evaluated by the use of the patch-clamp method in cells that expressed Na(V)1.4 (a tetrodotoxin-sensitive sodium channel subtype) and Na(V)1.5 (a tetrodotoxin-resistant sodium channel subtype). These compounds showed moderate inhibitory activity towards Na(V)1.4, and weaker inhibitory activity towards Na(V)1.5. Uniquely, however, the inhibition of Na(V)1.5 by (-)-FD-dcSTX (4b) was "irreversible".

Primary gingival angiosarcoma successfully treated by radiotherapy with concurrent intra-arterial chemotherapy.

The occurrence of angiosarcoma in the oral cavity is extremely rare, and optimal management of this tumor is undefined. These tumors are aggressive, with a high propensity for local recurrence. We present here a case of primary gingival angiosarcoma successfully treated by intra-arterial chemotherapy concurrent with radiation therapy. A 69-year-old female with a primary angiosarcoma in the right maxillary gingiva was admitted to our hospital. The diagnosis of angiosarcoma was established by immunohistochemistry. The patient refused surgical treatment, and so intra-arterial cisplatin and concurrent radiation were given. The gingival tumor disappeared after completion of the therapeutic regimen. However, the patient died 8 months after initial treatment because of multiple lung metastases. Locoregional control was achieved up to her death. To our knowledge, this is the first report of this treatment for angiosarcoma of the oral cavity.

Total synthesis of (+)-dibromophakellin and (+)-dibromophakellstatin.

A new method for the preparation of quaternary chiral aminals has been developed that employs an enamide-type Overman rearrangement process. This methodology was applied to enantioselective total syntheses of (+)-dibromophakellin and (+)-dibromophakellstatin.

Total synthesis of (+)-decarbamoylsaxitoxin and (+)-gonyautoxin 3.

Facile construction of the complex saxitoxin (STX) skeleton is carried out by using a novel, conformationally controlled, guanidine cyclization process that relies on the use of neighboring group participation. The utility of this methodology is verified by its employment in syntheses of both natural and unnatural STX derivatives.

Clinical relevance of thymidylate synthase (TS) activity for S-1-based chemotherapy in squamous cell carcinoma of the oral cavity.

S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of oral squamous cell carcinoma (SCC). Thymidylate synthase (TS) is the rate-limiting enzyme in the de novo DNA biosynthetic pathway, and improves clinical response to chemotherapy with fluoropyrimidines. We have retrospectively evaluated the predictive value of thymidylate synthase activity in 75 patients with oral SCC with an enzyme-linked immunosorbent assay (ELISA). Mean (SD) activity (pmol/mg) in the specimens was 0.078 (0.080) (median 0.059). The median value was taken as the cut-off value based on which the patients were divided into high and low activity groups. Both the clinical and histopathological responses to chemotherapy and radiochemotherapy were higher in the group with low TS activity. The group with low TS activity also differed significantly in their clinical response to S-1-based chemotherapy (p<0.05). However, there was no significant difference in cause-specific survival. Measurement of TS activity may aid in predicting the clinical response to chemotherapy including S-1 for oral SCC.

Total synthesis of (+)-dibromophakellin.

Two members of a family of pyrrole-imidazole marine alkaloids, (+)-dibromophakellin and the nonnatural congener (+)-phakellin, were synthesized enantioselectively from 4-hydroxy-L-proline. The chiral aminal at C10 was constructed efficiently by means of an Overman-type [3,3] sigmatropic rearrangement of an enamide (see scheme).

Total synthesis of (-)- and (+)-decarbamoyloxysaxitoxin and (+)-saxitoxin.

Playing the sax: The enantioselective total syntheses of (-)- and (+)-decarbamoyloxysaxitoxin (doSTX) and (+)-saxitoxin (STX) are reported. A new methodology was developed for the synthesis of STXs, featuring discriminative reduction of the nitro group and N-O bond in nitroisoxazolidine. Enantioselective total syntheses of (-)- and (+)-decarbamoyloxysaxitoxin (doSTX) and (+)-saxitoxin (STX) were achieved. The characteristic spiro-fused cyclic guanidine structure of STX was constructed by oxidation at the C4 position with IBX via an alpha-iminium carbonyl intermediate and acid-promoted cyclization of guanidine at the C5 position. A second-generation methodology was developed for the synthesis of STX, featuring discriminative reduction of the nitro group and N-O bond in nitroisoxazolidine. This approach provides efficient access to the key diamine intermediate for STXs.

[Clinical evaluation of palliative chemotherapy with S-1 for oral cancer patients].

The purpose of this study was to investigate the effectiveness and safety of palliative chemotherapy using S-1. We treated 19 advanced oral SCC patients including 8 men and 11 women with S-1. Of the 19 patients studied, two patients were classified as UICC Stage II, two patients as Stage III, 14 patients as Stage IV A, and one patient was classified as StageIV C. The ages varied from 54 to 9 1 years (mean ages; 78.3 years-old). The patients received this chemotherapy (80-120 mg/day) consisting of 2 weeks' administration including 5-days' administration and 2-days' termination (named 'Weekday-on/Weekend-off administration schedule' ) following 1 week rest. After this treatment, 7 CR and 4 PR were achieved, but the toxicities were only anorexia, leukopenia, thrombocytopenia, and uritication of NCI-CTC grade 1. The prognosis of 19 cases was 7 terminal by primary disease, 3 terminal by other disease, 7 lives with tumor bearing, and 2 lives without tumor bearing. We concluded that our novel S-1 administration method was extremely effective for oral SCC, including lymph node metastasis, providing high potential without any severe adverse effects for palliative therapy.

Ramsay-Hunt syndrome with vesicular stomatitis in a 4-year-old infant.

Ramsay-Hunt syndrome (RHS) usually affects adults, but rare cases of preschool children with RHS have been reported. We report a case of RHS in a healthy 4-year-old girl. At the age of 4 years and 5 months, she complained of pain in her mouth and herpes zoster vesicles were noted on the left soft palate and tongue without left pinna, and complete left facial paralysis subsequently developed. She was treated with acyclovir and steroids. Six months later, her facial paralysis had almost fully resolved.