Positive correlation between organic anion transporter 1B function indicated by plasma concentration of coproporphyrin-I and blood concentration of cyclosporin A in real-world patients.

AIMS: Cyclosporin A (CyA) has potent inhibitory activity on organic anion transporting polypeptide 1B (OATP1B), causing drug-drug interactions with its substrate drugs. 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a uraemic toxin, has also been suggested to inhibit OATP1B activity. Recent study has identified coproporphyrin-I (CP-I) as a specific endogenous substrate for OATP1B, which is useful to indicate OATP1B activity. We investigated the relationship of CP-I with CyA and CMPF concentrations in patients taking CyA. METHODS: In total, 121 blood samples from 74 patients who took CyA and underwent routine therapeutic drug monitoring were divided into trough and peak samples. RESULTS: CyA and CP-I concentrations were significantly higher in peak samples than in trough samples. A positive correlation between CP-I and CyA concentrations was found in all samples and in trough and peak samples, while no correlation was observed between CP-I and CMPF concentrations. Multiple regression analysis identified CyA and C-reactive protein concentrations as independent factors affecting CP-I concentration, with blood CyA concentration having markedly greater contribution to plasma CP-I concentration. CONCLUSION: The present study suggests that CyA inhibits OATP1B activity in a concentration-dependent manner in clinical setting, and that dose adjustment of OATP1B substrate drugs coadministered with CyA according to plasma CMPF concentration may not be necessary.

Nonexposed antiresorptive agent-related osteomyelitis of the jaw: a single-center cohort study.

INTRODUCTION: The nonexposed variant of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) presents with nonspecific clinical findings. The diagnosis of nonexposed ARONJ poses a critical challenge, and there is little evidence regarding its treatment and outcomes. This study aimed to examine the clinical outcomes in patients with nonexposed antiresorptive agent-related osteomyelitis of the jaw (AROMJ). The terms ARONJ and AROMJ were used separately in this study. MATERIALS AND METHODS: We enrolled patients with nonexposed AROMJ (osteomyelitis of the jaw without bone exposure associated with antiresorptive agents) with partial reference to an existing position paper on ARONJ. The initiating event of osteomyelitis was limited to periodontitis. Based on the findings of bone scintigraphy, panoramic radiography, computed tomography, and histopathological examination, we also used the hierarchical diagnostic criteria (HDC) for osteomyelitis of the jaw. RESULTS: There were 58 confirmed cases of nonexposed AROMJ based on the HDC. All patients had sufficient clinical findings to be diagnosed with nonexposed AROMJ as osteomyelitis underwent extraction with bone debridement. The healing rate was 93.1% (54/58). Univariable analysis showed a strong association between the healing status and malignant disease, while multivariable analysis showed no strong association between them. CONCLUSIONS: The present study had a relatively large sample size of patients with nonexposed AROMJ. The primary disease in patients with nonexposed AROMJ may not have a strong association with the healed status of the lesion. Based on its high healing rate, extraction with bone debridement in confirmed nonexposed AROMJ may prevent progression.

High-Sensitivity and High-Throughput Quantification of Everolimus in Human Whole Blood Using Ultrahigh-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry.

BACKGROUND: Rigorous dose adjustment by therapeutic drug monitoring (TDM) is recommended when everolimus (EVR) is administered for immunosuppression. In this study, the authors developed a highly sensitive ultrahigh-performance liquid chromatography coupled with the tandem mass spectrometry (UHPLC-MS/MS) method for measuring EVR concentrations in whole blood using a high-throughput solid-phase extraction method for sample pretreatment. Furthermore, the blood EVR concentrations in routine TDM samples from patients who underwent renal transplantation measured using the established UHPLC-MS/MS method were compared with those measured using the latex agglutination turbidimetric immunoassay (LTIA). METHODS: Blood samples were pretreated by solid-phase extraction using a 96-well HLB µElution plate. The clinical application of the newly developed method was evaluated using 87 blood samples from 19 patients who underwent kidney transplant. RESULTS: The calibration curve showed good linearity over a wide range of 0.1-50 ng/mL, with relative error ≤15% obtained from the back calculation of calibrators, and ≤20% for the lower limit of quantification. Within-batch and batch-to-batch accuracies and precisions fulfilled the acceptance criteria of the US Food and Drug Administration guidelines for bioanalytical method validation. The extraction recovery rates were good (≥65.2%), and almost no matrix effects were found in any of the quality control samples. Blood EVR concentrations measured by UHPLC-MS/MS were positively correlated with those measured by LTIA. A Bland-Altman plot indicated that the UHPLC-MS/MS method yielded better measurements than the LTIA method, regardless of the concentration. CONCLUSIONS: Therefore, the authors succeeded in developing a novel high-sensitivity and high-throughput method for measuring blood EVR concentration by UHPLC-MS/MS using a µElution plate for sample pretreatment.

Orthognathic Surgery in Hereditary Angioedema With Normal C1 Inhibitor: A Clinical Response to Concentrated C1 Inhibitor Against Angioedema Attack.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by episodes of localized swelling, often of life-threatening severity. HAE due to C1 inhibitor (C1-INH) deficiency is common and is divided into types 1 and 2, but HAE with normal C1-INH is exceedingly rare. Herein, we describe the case of a patient with HAE with normal C1-INH undergoing orthognathic surgery. A 24-year-old woman came to our hospital with a diagnosed jaw deformity and commenced preoperative orthodontic treatment before scheduled orthognathic surgery. During the preoperative period, she experienced mild hoarseness. The hoarseness worsened, and computed tomography revealed mild laryngeal edema. Serum C1-INH, C3, C4, and CH50 levels were normal. Her younger sister had reportedly experienced a similar episode of lip edema previously. These findings supported a diagnosis of HAE with normal C1-INH. She underwent orthognathic surgery in close consultation with a hematologist and anesthesiologist at the age of 33 years. The surgery was completed without complications. She reported throat tightness 4 days after surgery, although her facial swelling was consistent with the procedure performed and was not remarkable. Concentrated C1-INH was administered, and the throat tightness slowly resolved within approximately 1 hour. Twenty-five days after surgery, she was discharged with reduced facial swelling. In the present case, orthognathic surgery was performed successfully in a patient with the exceedingly rare condition of HAE with normal C1-INH, in close consultation with a hematologist and an anesthesiologist. Postoperative throat tightness was successfully treated via the administration of concentrated C1-INH. Concentrated C1-INH administration can be considered in patients with HAE and normal C1-INH who experience angioedemic attack, keeping in mind that it may be slow to take effect.

Sensitive, wide-range and high-throughput quantification of cyclosporine in whole blood using ultra-performance liquid chromatography coupled to tandem mass spectrometry and comparison with an antibody-conjugated magnetic immunoassay.

Because either trough or peak concentration at 2 h after administration is measured in routine therapeutic drug monitoring for cyclosporine A (CyA), a quantification method with a wide-range calibration curve capable of simultaneously measuring both concentrations is required. We developed a sensitive, wide-range and high-throughput quantification method for CyA in whole blood using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and compared patients' blood CyA levels measured by UPLC-MS/MS and antibody-conjugated magnetic immunoassay (ACMIA). Whole blood samples were prepared by solid-phase extraction using Oasis HLB µElution plate. The UPLC-MS/MS assay showed excellent linearity over a wide calibration range of 5-2500 ng/mL. Within-batch accuracy and precision as well as batch-to-batch accuracy and precision fulfilled the criteria of US Food and Drug Administration guidelines. The blood CyA concentrations measured by the UPLC-MS/MS assay correlated strongly with those measured by ACMIA. A Bland-Altman plot showed a fixed error between CyA concentrations measured by the two methods, and the concentrations measured by the UPLC-MS/MS method were consistently lower than those measured by ACMIA. We have succeeded to develop a sensitive, wide-range and high-throughput quantification method for CyA in whole blood using UPLC-MS/MS.

Synthesis of lactone-fused pyrroles by ruthenium-catalyzed 1,2-carbon migration-cycloisomerization.

A ruthenium-catalyzed cycloisomerization of 3-amino-4-alkynyl-2H-chromen-2-ones via 1,2-carbon migration was developed. Various 1-arylchromeno[3,4-b]pyrrol-4(3H)-ones were synthesized in good to excellent yields. The reaction was applied to the formal total synthesis of marine natural products Ningalin B and Lamellarin H. The efficient synthesis of γ-butyrolactone-fused pyrrole derivatives was also achieved.

Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylstyrenes via 1,2-Carbon Migration That Leads to Substituted Naphthalenes.

A ruthenium-catalyzed carbocyclization of 2-alkynylstyrenes that involves a very rare 1,2-carbon migration of internal alkynes is reported. Various 1,2-di -and 1,4,7-trisubstituted naphthalenes are synthesized. Mechanistic studies revealed that this reaction proceeds via a disubstituted vinylidene complex as the key intermediate by 1,2-carbon migration of the 2-alkynylstyrenes.

Maxillary Hypoplasia With Congenital Oligodontia Treated by Maxillary Distraction Osteogenesis.

It is known that congenitally missing teeth can often cause differences in craniofacial morphology; however, there are few reported cases of orthognathic surgical treatment for these patients. Herein, the authors report a rare case of maxillary hypoplasia with congenital oligodontia treated by maxillary distraction osteogenesis with internal device. A 17-year-old male presenting with multiple tooth agenesis and maxillary recession was referred to our hospital for orthognathic surgical treatment. Preoperative simulation surgery was performed using Full-Color 3-dimensional salt model. After surgery, improvement in maxillary recession and occlusal stability was observed. This report demonstrates the advantages of the method used herein, which includes reduction in operating time with increase in the safety of the procedure.

Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylanilides: Synthesis of 3-Substituted Indoles by 1,2-Carbon Migration.

We developed ruthenium-catalyzed cycloisomerization of alkynylanilides that gave 3-substituted indoles in high yields. The reaction proceeded via the disubstituted vinylidene ruthenium complex that was formed by the 1,2-carbon migration.

Efficacy of foam sclerotherapy with polidocanol for the management of oral venous malformations.

The present aimed to examine the effectiveness of polidocanol-based foam sclerotherapy for oral venous malformations (OVMs). The present study performed a retrospective analysis of patients with OVMs who underwent sclerotherapy using polidocanol. Patients achieving the complete resolution of OVM were categorized as having a complete response (CR), those with a reduction in size from the initial diagnosis were categorized as having a partial response (PR), those with no change in size as stable disease (SD), and those with an increase in size as progressive disease (PD). A total of 16 patients, comprising 4 males and 12 females, underwent treatment with polidocanol foam therapy, covering 22 affected areas. The treatment administered resulted in CR in 6 cases and PR in 10 cases, with no instances of SD or PD. Apart from localized injection site pain or swelling, there were no severe side-effects reported, such as circulatory dynamic changes or skin necrosis. On the whole, these findings underscore the effectiveness of foam sclerotherapy with polidocanol as a viable treatment for venous malformations in the oral and maxillofacial regions.

Pseudoaneurysm of the superficial temporal artery after sagittal split ramus osteotomy: A case report.

Sagittal split ramus osteotomy (SSRO) is a widely performed orthognathic surgery; however, among the various reported complications of SSRO, pseudoaneurysms are rarely reported. Pseudoaneurysms are rare vascular lesions formed by damage to the arterial wall that can occur after trauma or postoperatively, causing uncontrolled bleeding. The present report describes a case of a pseudoaneurysm that occurred after SSRO in a 22-year-old female patient. Le Fort I osteotomy and bilateral SSRO were performed under general anesthesia to improve the gummy smile and mandibular asymmetry of the patient. While osteotomizing the medial side of the left SSRO, major bleeding occurred from the soft tissue of the posterior margin of the mandibular branch. Direct compression with gauze and a local hemostatic agent stopped the bleeding. Immediately after returning to the ward, bleeding was observed from the left wound site and marked swelling of the left buccal area occurred. Contrast-enhanced computed tomography revealed a pseudoaneurysm of the left superficial temporal artery (STA). Subsequently, arterial embolization for the pseudoaneurysm was performed. Overall, the present report describes a rare case of pseudoaneurysm of the STA as a postoperative complication of SSRO.

Methotrexate­related other iatrogenic immunodeficiency­associated lymphoproliferative disorder in the CNS and medication­related osteonecrosis of the jaw occurring simultaneously: A case report.

Methotrexate-related other iatrogenic immunodeficiency-associated lymphoproliferative disorder (MTX-OIIA-LPD) is prone to extranodal involvement but rarely involves the central nervous system (CNS). The present study reports a case of MTX-OIIA-LPD of the CNS discovered during medication-related osteonecrosis of the jaw (MRONJ) treatment in a 76-year-old woman with rheumatoid arthritis (RA). The chief complaint of the patient was bone exposure and pain in the right mandibular molar. The patient had been receiving MTX for RA and alendronate sodium hydrate for osteoporosis, followed by denosumab. Treatment was initiated based on a diagnosis of MRONJ. However, the patient experienced lightheadedness and floating dizziness afterwards. Examinations revealed scattered neoplastic lesions in the brain. The histopathological diagnosis was diffuse large B-cell lymphoma. A systemic search also revealed adrenal involvement. Since the patient was taking MTX, a diagnosis of MTX-OIIA-LPD was made and MTX was discontinued. Chemotherapeutic agents were administered since the central lesions became symptomatic. The MTX-OIIA-LPD lesions in the brain and adrenal glands completely resolved 8 months after onset. The physical condition of the patient improved, and the bone-exposed areas became epithelialized. Reports on MTX-LPD in the oral and maxillofacial region are few, which may delay its diagnosis. Therefore, biopsy of oral lesions in patients with MRONJ who are taking MTX and collaboration with related diagnostic departments, such as rheumatology and hematology, must be done to initiate the diagnosis and treatment of extraoral MTX-LPD.

bmp-2 Gene-Transferred Skeletal Muscles with Needle-Type Electrodes as Efficient and Reliable Biomaterials for Bone Regeneration.

BACKGROUND: Bone morphogenetic protein-2 (bmp-2) has a high potential to induce bone tissue formation in skeletal muscles. We developed a bone induction system in skeletal muscles using the bmp-2 gene through in vivo electroporation. Natural bone tissues with skeletal muscles can be considered potential candidates for biomaterials. However, our previous system using plate-type electrodes did not achieve a 100% success rate in inducing bone tissues in skeletal muscles. In this study, we aimed to enhance the efficiency of bone tissue formation in skeletal muscles by using a non-viral bmp-2 gene expression plasmid vector (pCAGGS-bmp-2) and needle-type electrodes. METHODS: We injected the bmp-2 gene with pCAGGS-bmp-2 into the skeletal muscles of rats' legs and immediately placed needle-type electrodes there. Skeletal tissues were then observed on the 21st day after gene transfer using soft X-ray and histological analyses. RESULTS: The use of needle-type electrodes resulted in a 100% success rate in inducing bone tissues in skeletal muscles. In contrast, the plate-type electrodes only exhibited a 33% success rate. Thus, needle-type electrodes can be more efficient and reliable for transferring the bmp-2 gene to skeletal muscles, making them potential biomaterials for repairing bone defects.

An experience of displaced third molar roots removed using computer-assisted navigation system.

The frequency of displacement of a third molar root is low and considered a rare incident. A computer-assisted navigation system is a surgical support system that allows the patient to confirm the surgical site in three dimensions during surgery has recently been introduced to oral and maxillofacial surgery. We used a computer-assisted navigation system to remove a displaced third molar root in the floor of the mouth without complications and report the outline of the procedure and the effectiveness of the computer-assisted navigation system safety. This was a 56-year-old male who underwent extraction of the mandibular right third molar at a referral clinic. At that time, the proximal root fracture remained in the extraction socket, and the distal root fracture displaced to floor of the mouth. The patient was referred to our hospital immediately after tooth extraction. We extracted the displaced third molar root fracture under general anesthesia using a computer-assisted navigation system to accurately locate the root fracture and performed minimally invasive extraction. The root extraction was performed 18 days after the initial tooth extraction. No lingual nerve exposure was observed during surgery. No sensory abnormalities in the lower lip or tongue were observed postoperatively. Computer-assisted navigation system is a useful surgical support system that enables oral and maxillofacial surgical procedures and prevents postoperative complications such as lingual nerve palsy safety.

A rare case of a branchial cyst with calcification: A case report.

Branchial cysts are relatively rare lesions with lymphoid tissue in the underlying epithelium of the cyst wall. The present study describes the case of a branchial cyst with keratinization and calcification that occurred in the right submandibular region, along with a review of the literature. A 49-year-old female patient presented with a complaint of swelling in the right submandibular region. Computed tomography revealed a well-defined, cystic lesion located anterior to the sternocleidomastoid muscle, outside the hyoid bone, and in front of the submandibular gland. The cystic cavity presented an opaque image suggestive of calcification. Magnetic resonance imaging showed high-intensity lesions on both T2-weighted and short-τ inversion recovery images on the anterior margin of the right sternocleidomastoid muscle, just below the platysma muscle, with a clear demarcation from the surrounding tissue, and posterior compression and flattening of the submandibular gland. Cystectomy was performed under general anesthesia, and histopathological examination confirmed the diagnosis of branchial cyst with keratinized and calcified substances. The patient recovered well and had no complications or recurrence at ~2-year follow-up. This case highlights the rare occurrence of a branchial cyst containing calcification in the cystic cavity and provides a literature review of the factors contributing to the calcification.

Congenital factor XI deficiency with multiple tooth extractions (Case report).

Congenital factor XI deficiency (CFXI) is a rare blood disorder that occurs in one of every one million individuals. Given its rarity, there are very few reports of surgical procedures performed in the oral region CFXI patients. The present study reports the case of a 43-year-old man with CFXI who experienced multiple tooth extractions. It also conducted a review of the literature and treatment outline. We preoperatively administered fresh frozen plasma (FFP) before the tooth extraction and continued to transfuse FFP at the rate of 2 units per day from day 1 to 4 of admission. The extractions were divided into two parts, maxillary and mandibular and the teeth extracted on days 2 and 4 of admission. The patient was discharged on day 6 of admission because there was good progress and no postoperative bleeding. Therefore, it was possible to perform multiple tooth extractions without abnormal bleeding in the oral cavity; the chance of bleeding was reduced by administering FFP and increasing local hemostasis in CFXI patients.

Associations Among Tooth Loss, Periodontitis, and Carotid Intima-Media Thickness: the Nagahama Study.

AIMS: This study aimed to clarify the relationships among tooth loss, periodontal condition, and subclinical atherosclerosis from the aspect of intensity, extent, and duration of inflammation. METHODS: This cross-sectional study included 9,778 people from the Nagahama Study, a large-scale, general population-based study conducted in Japan. The number of teeth and periodontal status, including the attachment level (AL) and pocket depth (PD) of representative teeth from six regions, were evaluated by dentists. The maximum intima-media thickness (IMT) of the common carotid artery was used as an index of atherosclerosis. RESULTS: In the multivariate analysis adjusted for conventional risk factors, a large number of missing teeth (＜9 remaining teeth), which related to long-lasting inflammation indicative of the highest stage of periodontitis, was identified as an independent determinant of IMT in a general population (coefficient: 0.042; 95% confidence interval [CI]: 0.016 to 0.068). The presence of two or more regions with an AL ≥4 mm, which is indicative of the progressing, long-lasting stages of periodontal inflammation, was also independently associated with IMT (coefficient: 0.016; 95% CI: 0.004 to 0.028). On the contrary, PD, a measure of the early and reversible phases of periodontal inflammation, and loss of AL in the group without tooth loss were not significantly associated with IMT, because of the limited degree of accumulated periodontitis. CONCLUSION: The present results suggest that the association between periodontitis and atherosclerosis depends on the inflammation intensity, extent, and duration.

Recurrence of odontogenic keratocyst in the buccal space.

Odontogenic keratocyst (OKC) rarely appears in the buccal space. It is aggressive and infiltrative, and simple enucleation results in high recurrence. This case report describes an OKC located in the buccal space recurring twice in a 62-year-old man with a 25 mm diameter cystic lesion in the right pterygomandibular space. The multicystic lesion was enucleated. Subsequently, a recurrence was observed, and the gourd-shaped recurrent lesion was also enucleated. The difficulty in detaching the mass from the scar tissue resulted in the perforation of the cystic wall. Thereafter, a second recurrence was observed, and the tissue surrounding the unicystic recurrent lesion was excised. The histopathological features were consistent with those of OKC. The present case is the 11th reported case of OKC in the buccal space and the first with apparent recurrence. Since complete enucleation in the pterygomandibular space is difficult, excision along with the surrounding tissues could prevent recurrence.

Maxillary unicystic ameloblastoma: a rare presentation.

Unicystic ameloblastoma (UAM), a rare variant of ameloblastoma, is an odontogenic epithelial neoplasm typically appearing in the mandible. We report an extremely rare case of maxillary UAM with an impacted canine and supernumerary tooth. The patient was a woman in her late 30s who presented with a slight expansion of the left anterior maxilla due to a cystic lesion with impacted teeth. Under a clinical diagnosis of dentigerous cyst, the cystic lesion was completely enucleated by extracting the impacted teeth. Based on the clinical features and pathological findings, the final diagnosis was intraluminal UAM in the anterior maxilla. In the present case, despite the rarity of UAM with impacted teeth in the anterior maxilla, it should be considered during differential diagnosis. Careful clinical examination is required for diagnostic accuracy since the clinical findings of tooth-containing ameloblastoma and dentigerous cyst are very similar.

Unusual manifestation of methotrexate-associated lymphoproliferative disorder as a palatal mass.

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) can occur in the oral cavity, and only a few cases with palatal involvement have been reported. Chemotherapy may be needed if there is no remission after the withdrawal of MTX. We report a case of MTX-LPD presenting with a swelling of the palate that required chemotherapy. A woman in her 70s with rheumatoid arthritis reported a swelling on the left side of the palate. Her condition was diagnosed as Epstein-Barr virus-negative diffuse large B-cell lymphoma (MTX-LPD). Since the mass did not remit after MTX withdrawal, she underwent five courses of chemotherapy. Currently, the patient is in complete remission. In patients on MTX who develop a swelling on the palate, MTX-LPD should be included among the differential diagnostic possibilities. Diagnosis and treatment of MTX-LPD call for consultation with a haematologist. If the mass fails to regress following withdrawal of MTX, appropriate chemotherapy is indicated.