Genomically Stable Gastric Cancer Characterized by Hypomethylation in Wnt Signal Cascade.

INTRODUCTION: Gastric cancer is divided into four subtypes by their molecular features linked with genetic alterations, e.g., Epstein-Barr virus (EBV), microsatellite instability-high (MSI-high), chromosomal instability (CIN), and genomically stable (GS), called as TCGA classification. In this study, we tried to clarify the epigenetic features of the four GC subtypes according to aberrant methylation status in 23 loci. METHODS: A total of 98 gastric cancers and their normal gastric mucosa samples were included in this study. We divided gastric cancers into TCGA subtypes which were determined in line with MSI-high, EBV, CIN, to GS by their molecular features. The 13 loci of polymorphic microsatellite sequences were used to determine loss of heterogeneity for the detection of CIN. The MSI status was determined by three mononucleotide repeat markers. Infection of EBV was determined by recovering EBV BNRF1 sequence from genomic DNA collected from gastric cancers. Methylation status of 23 loci was investigated by the combined bisulfite restriction analysis. Status of other findings, e.g., KRAS mutations, HER2 expression status, and infection of helicobacter pylori were confirmed. RESULTS: Gastric cancers were divided into MSI (13%), EBV (7%), CIN (53%), and GS (27%). By histological classification, poorly differentiated adenocarcinoma was more in tumors categorized in MSI-high, and GS and signet-ring cell carcinoma (sig) were more in GS. Among the 23 loci investigated their methylation status, 18 loci were significantly hypermethylated in caner tissues. An unsupervised clustering divided gastric cancers into two clusters and revealed that most GS tumors clustered together in a cluster that exhibited lower methylation levels, distinct from the other subtypes. The inter-variable clustering revealed that a cluster contained the three loci (SFRP2-region 1/2 and APC) belonging to the Wnt signal cascade (Wnt-associated loci). The mean methylation score of Wnt-associated loci was the lowest in GS tumors (MSI-high: 2.7 [95% confidence interval, 2.3-2.9]; EBV: 2.1 [1.2-3.1]; CIN: 2.4 [2.2-2.7]; GS: 1.3 [0.8-0.7]). In contrast, the mean methylation score of the other 15 loci was significantly higher in MSI-high, while that in GS was as same as that in EBV or CIN (MSI-high: 10.4 [8.3-12.4]; EBV: 5.7 [1.7-9.7]; CIN: 4.4 [3.6-5.1]; GS: 3.4 [2.2-4.6]). Additionally, the lower methylation score of Wnt-associated loci was observed only in sig tumors. CONCLUSIONS: GS subtype tumors have the potential to possess distinct signatures in DNA hypomethylation profiles in Wnt signaling pathway, especially in sig.

Validation of the initial brain metastasis velocity in non-small cell lung cancer at a single cancer center.

PURPOSE: The initial brain metastasis velocity (iBMV) was recently reported as a survival predictor after brain metastases (BM) in patients treated by stereotactic radiosurgery. In this study, we validated whether iBMV is a prognostic tool, regardless of treatment modality, in patients with non-small cell lung cancer (NSCLC) with metachronous BM. METHODS: We retrospectively reviewed consecutive 3,792 new lung cancer cases in which no BM was found on magnetic resonance (MR) screening between February 2014 and December 2019, and enrolled 176 NSCLC patients with subsequent BM. Overall survival (OS) was calculated from the date of MR to identify the time from BM to death. RESULTS: The median iBMV score was 1.9. We used an iBMV score of 2.0 as the cutoff level, as previously reported. An iBMV score ≥ 2.0 was significantly associated with older age, high neutrophil-to-lymphocyte ratio, and Stage IV (P = 0.04, 0.02, and 0.02, respectively). The median OS was 0.92 years. The median OS for patients with iBMV score ≥ 2.0 and < 2.0 were 0.59 years and 1.33 years, respectively (P < 0.001). Multivariate analysis showed that an iBMV score ≥ 2.0, ECOG performance status score of 1-3, Stage IV, and non-adenocarcinoma histology were independent poor prognostic factors (hazard ratio (HR), 1.94; P = 0.0001; HR, 1.53; P = 0.04; HR, 1.45; P = 0.04; and HR, 1.14; P = 0.03, respectively). Patients with iBMV scores of < 2.0 were more likely to undergo craniotomy or stereotactic irradiation. CONCLUSIONS: An iBMV score ≥ 2.0 is an independent predictor of survival in NSCLC patients with metachronous BM, regardless of the treatment modality.

Potential relationship between high wall shear stress and plaque rupture causing acute coronary syndrome.

The relationship between high wall shear stress (WSS) and plaque rupture (PR) in longitudinal and circumferential locations remains uncertain. Overall, 100 acute coronary syndrome patients whose culprit lesions had PR, documented by optical coherence tomography (OCT), were enrolled. Lesion-specific three-dimensional coronary artery models were created using OCT data. WSS was computed with computational fluid dynamics analysis. PR was classified into upstream-PR, minimum lumen area-PR, and downstream-PR according to the PR's longitudinal location, and into central-PR and lateral-PR according to the disrupted fibrous cap circumferential location. In the longitudinal 3-mm segmental analysis, multivariate analysis demonstrated that higher WSS in the upstream segment was independently associated with upstream-PR, and thinner fibrous cap was independently associated with downstream-PR. In the PR cross-sections, the PR region had a significantly higher average WSS than non-PR region. In the cross-sectional analysis, the in-lesion peak WSS was frequently observed in the lateral (66.7%) and central regions (70%) in lateral-PR and central-PR, respectively. Multivariate analysis demonstrated that the presence of in-lesion peak WSS at the lateral region, thinner broken fibrous cap, and larger lumen area were independently associated with lateral-PR, while the presence of in-lesion peak WSS at the central region and thicker broken fibrous cap were independently associated with central-PR. In conclusion, OCT-based WSS simulation revealed that high WSS might be related to the longitudinal and circumferential locations of PR.

Mass spectrometry imaging reveals local metabolic changes in skeletal muscle due to chronic training.

Muscle atrophy is a major health problem that needs effective prevention and treatment approaches. Chronic exercise, an effective treatment strategy for atrophy, promotes muscle hypertrophy, which leads to dynamic metabolic changes; however, the metabolic changes vary among myofiber types. To investigate local metabolic changes due to chronic exercise, we utilized comprehensive proteome and mass spectrometry (MS) imaging analyses. Our training model exhibited hypertrophic features only in glycolytic myofibers. The proteome analyses demonstrated that exercise promoted anabolic pathways, such as protein synthesis, and significant changes in lipid metabolism, but not in glucose metabolism. Furthermore, the fundamental energy sources, glycogen, neutral lipids, and ATP, were sensitive to exercise, and the changes in these sources differed between glycolytic and oxidative myofibers. MS imaging revealed that the lipid composition differs among myofibers; arachidonic acid might be an effective target for promoting lipid metabolism during muscle hypertrophy in oxidative myofibers.

Neoadjuvant fractionated stereotactic radiotherapy followed by piecemeal resection of brain metastasis: a case series of 20 patients.

BACKGROUND: The safety and effectiveness of neoadjuvant fractionated stereotactic radiotherapy (FSRT) before piecemeal resection of brain metastasis (BM) remains unknown. METHODS: We retrospectively reviewed 20 consecutive patients with BM who underwent neoadjuvant FSRT followed by piecemeal resection between July 2019 and March 2021. The prescribed dose regimens were as follows: 30 Gy (n = 11) or 35 Gy (n = 9) in five fractions. RESULTS: The mean follow-up duration was 7.8 months (range 2.2-22.3). The median age was 67 years (range 51-79). Fourteen patients were male. All patients were symptomatic. All tumors were located in the supratentorial compartment. The median maximum diameter and volume were 3.7 cm (range 2.6-4.9) and 17.6 cm3 (range 5.6-49.7), respectively. The median time from the end of FSRT to resection was 4 days (range 1-7). Nausea (CTCAE Grade 2) occurred in one patient and simple partial seizures (Grade 2) in two patients during radiation therapy. Gross total removal was performed in seventeen patients and sub-total removal in three patients. Postoperative complications were deterioration of paresis in two patients. Local recurrence was found in one patient (5.0%) who underwent sub-total resection at 2 months after craniotomy. Distant recurrence was found in six patients (30.0%) at a median of 6.9 months. Leptomeningeal disease recurrence was found in one patient (5.0%) at 3 months. No radiation necrosis developed. CONCLUSIONS: Neoadjuvant FSRT appears to be a safe and effective approach for patients with BM requiring piecemeal resection. A multi-institutional prospective trial is needed.

[A case of incipient pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm, confirmed by multiregion sequencing analysis].

Concomitant pancreatic ductal adenocarcinoma (PDA) is observed in a subset of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and early detection of those progressing lesions is difficult. We present a case with a de novo carcinoma in situ (CIS) discovered incidentally around the resection margin of IPMNs. A man in his 70s with a history of acute pancreatitis at the age of 50 years and no family history of PDA had a pancreatoduodenectomy for three isolated branch duct IPMNs that caused recurrent pancreatitis. During the 2-year follow-up period, the index lesion in the pancreatic head grew significantly, whereas the other cysts remained small and without mural nodules. The majority of the cysts are histologically composed of low-grade dysplasia and are classified as gastric-type IPMN. CIS with nuclear overexpression of p53 was located in the main pancreatic duct and adjacent brunch duct, which involved the pancreatic resection margin. The precise pathological analysis combined with multiregion sequencing revealed the CIS harbored KRAS G12V and TP53 R248W. Conversely, IPMNs contained GNAS mutant cells as well as components containing additional KRAS mutations. These findings suggested that the CIS formed independently of the multiple IPMNs and appeared to be an early manifestation of concomitant PDA with coexisting IPMNs. Despite widespread agreement on the resection of the radiographically significant IPMN lesion (s), the latent invasive cancer was not eradicated. A detailed pathological and molecular assessment of the resected materials may aid in a better management strategy for concurrent lesions.

[Determination of Caffeine, Theobromine, and Theophylline in Chocolate Using LC-MS].

A simultaneous determination method for caffeine, theobromine, and theophylline in chocolate was developed. Three compounds were ultrasonically extracted twice (15 min at 50℃) in an acetonitrile-water (1 : 1, v/v). The extract was purified using Oasis HLB SPE cartridge, and the purified processed by LC-MS. The method exhibited recoveries of 97.4-100.2%, RSDs of repeatability of 1.0-2.8%, and RSDs of within-laboratory reproducibility of 2.0-7.9%. This method was simpler and more selective than existing methods, and was practical for caffeine, theobromine, and theophylline analysis in chocolate.

[Detection of Ciguatoxins from Fish Introduced into a Wholesale Market in Japan].

Ciguatera fish poisoning (CFP), one of the most frequently occurring seafood poisonings due to marine finfish consumption, mainly affects the tropical and subtropical Indo-Pacific region and the Caribbean Sea. The principal class of toxins, ciguatoxins (CTXs) from the Pacific, includes more than 20 derivatives and are classified into two groups, CTX1B and CTX3C congeners, based on their skeletal structures. As part of risk management of CFP by the Japanese government, the import of certain species of fish into Japan is prohibited. Additionally, local governments recommend rejecting certain fish species caught in Japan. In this study, we used LC-MS/MS to analyze CTXs from 18 fish specimens belonging to 7 species that had been brought to a wholesale market but were disapproved for sale because of their potential danger of CFP. CTXs were detected in four specimens of Lutjanus bohar and one specimen of Variola louti. It was estimated that the two most poisonous specimens (no. 5: 0.348 µg/kg, no. 8: 0.362 µg/kg) had a toxicity of 0.05 MU/g. Consumption of 200 g of flesh from these fish could cause CFP. Thus, the guidance of the local government to disallow the sale of these fish species in the market contributed to the prevention of CFP.Only CTX1B congeners were detected in L. bohar (specimen no. 5), which had no record of the area where it captured from. It is presumed that the origin of specimen no. 5 was the same as that of the Okinawan L. bohar because the CTX compositions were similar. In two specimens (nos. 6 and 8) from Wakayama, both CTX1B and CTX3C congeners were detected. This is the first report to reveal the CTX profile in fish collected off the Honshu island in Japan.

Rapid identification of histamine-producing bacteria isolated from fish using MALDI-TOF MS.

Histamine-producing bacteria (HPB) produce histamine from histidine contained in food through the action of histidine decarboxylase. To identify HPB isolated from food, it is necessary to detect histamine produced by the bacteria. In this study, we concurrently identified HPB and detected histamine by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. After 24 h of incubation, 30 of 34 bacterial strains were correctly identified. Histamine was detected in all HPB cultured on Niven's medium, and 94% of HPB cultured in histidine broth, except for two strains with low histamine production. This method may greatly simplify the procedure and reduce the time required to identify HPB.

Tonic Suppression of the Mesolimbic Dopaminergic System by Enhanced Corticotropin-Releasing Factor Signaling Within the Bed Nucleus of the Stria Terminalis in Chronic Pain Model Rats.

Although dysfunction of the mesolimbic dopaminergic system has been implicated in chronic pain, the underlying mechanisms remain to be elucidated. We hypothesized that increased inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA) during chronic pain may induce tonic suppression of the mesolimbic dopaminergic system. To test this hypothesis, male Sprague Dawley rats were subjected to spinal nerve ligation to induce neuropathic pain and then spontaneous IPSCs (sIPSCs) were measured in this neuronal pathway. Whole-cell patch-clamp electrophysiology of brain slices containing the dlBNST revealed that the frequency of sIPSCs significantly increased in VTA-projecting dlBNST neurons 4 weeks after surgery. Next, the role of corticotropin-releasing factor (CRF) signaling within the dlBNST in the increased sIPSCs was examined. CRF increased the frequency of sIPSCs in VTA-projecting dlBNST neurons in sham-operated controls, but not in chronic pain rats. By contrast, NBI27914, a CRF type 1 receptor antagonist, decreased the frequency of sIPSCs in VTA-projecting dlBNST neurons in the chronic pain rats, but not in the control animals. In addition, histological analyses revealed the increased expression of CRF mRNA in the dlBNST. Finally, bilateral injections of NBI27914 into the dlBNST of chronic pain rats activated mesolimbic dopaminergic neurons and induced conditioned place preference. Together, these results suggest that the mesolimbic dopaminergic system is tonically suppressed during chronic pain by enhanced CRF signaling within the dlBNST via increased inhibitory inputs to VTA-projecting dlBNST neurons.SIGNIFICANCE STATEMENT The comorbidity of chronic pain and depression has long been recognized. Although dysfunction of the mesolimbic dopaminergic system has been implicated in both chronic pain and depression, the underlying mechanisms remain to be elucidated. Here, we show that the inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area increase during chronic pain. This neuroplastic change is mediated by enhanced corticotropin-releasing factor signaling within the dlBNST that leads to tonic suppression of the mesolimbic dopaminergic system, which may be involved in the depressive mood and anhedonia under the chronic pain condition.

[Complete Remission of Advanced Gastric Cancer with Tumor Embolism in the Right Gastric Vein Treated with Radical Resection after Chemotherapy].

A 74-year-old man presented to our hospital with the chief complaint of epigastric pain; upper gastrointestinal endoscopy revealed a 7-cm-sized type 3 gastric cancer in the lesser curvature of the lower part of the stomach. Abdominal contrast computed tomography revealed a tumor embolus in the right gastric vein; the preoperative diagnosis was cT4a(SE) N3aH0P0M0, cStage ⅢC. Because the cancer could spread during surgical manipulation, performing a safe radical resection was difficult; therefore, we decided to initiate chemotherapy. The patient received 3 courses of trastuzumab plus CapeOX, which led to reduction of the primarylesion, peri-gastric lymph node, and right gastric vein tumor embolus. Partial remission was achieved after chemotherapy; therefore, distal gastrectomy, D2 lymph node dissection, and Roux-en-Y reconstruction were performed. Histopathological examination did not reveal viable tumor cells in the primarylesion, lymph nodes, or tumor embolus, and the histological effect was Grade 3. Currently, the patient is alive without relapse at 9 months post operation. Advanced gastric cancer accompanied with tumor embolism in the gastric vein is commonly observed in patients with liver metastasis and in those with severely progressed state of cancer; many of these patients have poor prognosis. Preoperative chemotherapymaybe effective in cases in which tumor embolism in the gastric vein is identified through preoperative diagnostic imaging.

C-X-C Motif Chemokine 12 Enhances Lipopolysaccharide-Induced Osteoclastogenesis and Bone Resorption In Vivo.

C-X-C motif chemokine 12 (CXCL12) belongs to the family of CXC chemokines. Lipopolysaccharide (LPS) induces inflammation-induced osteoclastogenesis and bone resorption, and in recent years, stimulatory effects of CXCL12 on bone resorption have also been reported. In the present study, we investigated the effects of CXCL12 on LPS-induced osteoclastogenesis and bone resorption. LPS was administered with or without CXCL12 onto mouse calvariae by daily subcutaneous injection. Numbers of osteoclasts and bone resorption were significantly elevated in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. Moreover, receptor activator of NF-kB ligand (RANKL) and tumor necrosis factor-α (TNF-α) mRNA levels were higher in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. These in vitro results confirmed a direct stimulatory effect of CXCL12 on RANKL- and TNF-α-induced osteoclastogenesis. Furthermore, TNF-α and RANKL mRNA levels were elevated in macrophages and osteoblasts, respectively, co-treated in vitro with CXCL12 and LPS, in comparison with cells treated with LPS alone. Our results suggest that CXCL12 enhances LPS-induced osteoclastogenesis and bone resorption in vivo through a combination of increasing LPS-induced TNF-α production by macrophages, increasing RANKL production by osteoblasts, and direct enhancement of osteoclastogenesis.

[A Rapid and Simple Method for Detection of Colchicum autumnale Using PCR].

Colchicum autumnale is a perennial, toxic plant that originated in Europe and North Africa. Although inedible, it is occasionally consumed accidentally because it resembles the edible Allium victorialis and other related species. This misidentification has led to episodes of food poisoning in Japan. However, determining the causative agent of a food poisoning outbreak by observing the sample visually or analyzing the chemical composition is challenging when dealing with small samples. Therefore, we developed a novel set of PCR primers that anneal to the internal transcribed spacer (ITS) region of C. autumnale ribosomal DNA, designed to detect the presence of C. autumnale in small samples. These primers successfully detected C. autumnale in all samples in which it was present, and did not give a positive PCR band in the 48 other distinct crop species tested, in which it was not present. Further, our method could amplify DNA from samples of C. autumnale that had been heat-treated and digested using artificial gastric fluids. Thus, this PCR strategy is highly specific and can be used to distinguish C. autumnale simply and rapidly from various other crops.

[Bilateral Metastatic Lung Tumor with Different Primary Organs].

A 72-year-old woman with a history of surgery for left breast cancer was found to have sigmoid colon cancer and solitary pulmonary tumor of left upper lobe. We diagnosed adenocarcinoma of the unknown origin by a transbronchial biopsy. We performed left upper segmentectomy and sigmoidectomy. Left pulmonary tumor was diagnosed metastatic lung tumor from breast cancer. A right pulmonary tumor was confirmed by chest computed tomography(CT) after sigmoidectomy. It was also considered to be metastasis from breast cancer and treated with vinorelbine ditartrate. Since no effect was observed by chemotherapy, tumor was surgically removed by wedge resection. Right pulmonary tumor was pathologically diagnosed as metastasis from sigmoid colon cancer. In suspicious case of pulmonary metastases from double cancer, the possibility of different lesions from different primary site should be kept in mind.

Outcome of the Modified Hughes Procedure for Eyelid Sebaceous Carcinoma.

Purpose: To report the outcomes of reconstruction of eyelids by modified Hughes method in patients with sebaceous carcinoma of the eyelid. Method: Nineteen patients were diagnosed as having sebaceous carcinoma in the Department of Ophthalmology, Tokyo medical University from 2009 through 2013. Tumors were resected and eyelids were reconstructed by the modified Hughes method. We retrospectively evaluated the patients' background and outcome of the surgery. Results: Average age of the patients was 71 years old, and average follow up period after surgery was 24 months. Average size of the tumor was 10.2 mm in upper eyelid and 7.8 mm in lower eyelid. After resection of the tumor, the defect of the eyelid was reconstructed by tarsoconjunctival flap (Hughes flap) and by stretching the surrounding eyelid skin. Pedicle was divided at an average of 33 days after surgery. Post-operative complications included mild entropion in 3 patients, ectropion in 3 patients, superficial punctate keratitis in 3 patients, and 1 ptosis that required surgical repair. One patient who showed local recurrence of the tumor underwent extended resection and reconstruction of the eyelid. Conclusion: The modified Hughes method is effective for reconstruction of the resected eyelids with sebaceous carcinoma. Especially, postoperative complications of the ocular surface tend to be limited.

Purification and properties of 4-methyl-5-hydroxyethylthiazole kinase from Escherichia coli.

4-Methyl-5-hydroxyethylthiazole kinase (ThiM) participates in thiamin biosynthesis as the key enzyme in its salvage pathway. We purified and characterized ThiM from Escherichia coli. It has broad substrate specificity toward various nucleotides and shows a preference for dATP as a phosphate donor over ATP. It is activated by divalent cations, and responds more strongly to Co(2+) than to Mg(2+).

A Preliminary Study of How the Viscosity of Dietary Fluids and Videofluoroscopy Fluids can be Matched.

This study examined the method by which the viscosity of mealtime and videofluoroscopy fluid can be matched through adjustment of the amount of xanthan gum-based thickener added to them. Viscosity measurement was made with a cone-plate viscometer. Samples were tested at 5, 25, 45, and 65 ± 0.1 °C and shear rates of 5-200 s(-1). We found that the adjusted amount of thickener differs depending on the shear rate and temperature, and that the amount of thickener added to samples without barium sulfate should be increased by 26.8-37.5 % as compared to samples with barium sulfate at a shear rate of 50 s(-1) and temperature of 25 °C. Further research is needed in terms of the shear rate and temperature during swallowing.

Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Meloxicam with Enhanced Dissolution Property and Storage Stability.

The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and (1)H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.

Two cases of aortoenteric fistula with gastrointestinal bleeding.

Aortoenteric fistula (AEF) is a life-threatening condition that can present with gastrointestinal (GI) bleeding. AEFs have been classified into primary and secondary types. Primary AEF (PAEF) is a direct communication between the aorta and the GI tract. Secondary AEF (SAEF) is the result of a previous abdominal aortic aneurysm repair involving placement of a synthetic aortic graft. Diagnosis of AEF, especially PAEF, is difficult largely because AEF is so rarely encountered in practice. Computed tomography (CT) and endoscopic gastroduodenoscopy (EGD) are most frequently used to diagnose AEF, with abdominal contrast-enhanced CT being the preferred initial diagnostic test of choice. Although EGD can exclude other common causes of GI hemorrhage, it cannot be used to rule out AEF when another source of bleeding is identified, as the two conditions can coexist. We discuss here two patients with GI bleeding who were diagnosed as PAEF and SAEF. We tried to diagnose and treat with EGD, but failed. That bleeding was due to an AEF became evident when abdominal CT scans revealed direct extravasation of contrast media from the abdominal aorta into the GI tract. The lack of awareness of AEF, coupled with the inaccessibility to the distal duodenum via EGD, were probably responsible for initial misdiagnosis and delay of appropriate management. We suggest that the diagnosis of AEF remains dependent on the clinician's heightened suspicion.

Effect of interleukin-4 on orthodontic tooth movement and associated root resorption.

OBJECTIVES: Interleukin-4 (IL-4) is a recognized immunomodulatory cytokine that regulates bone homeostasis. However, the influence of IL-4 on orthodontic tooth movement (OTM) and subsequent root resorption is still unknown. Therefore, the purpose of this study was to investigate the effect of IL-4 on tooth movement and its associated root resorption in a mouse model. MATERIALS AND METHODS: The maxillary first molars of four male mice for each experimental group were subjected to mesial force by a nickel titanium coil spring for 12 days. Control mice were not given appliances and injections. Varying doses of IL-4 were injected locally, adjacent to the first molar. Two sets of experiments were designed. The first set was composed of three groups: the control, treatment with phosphate-buffered saline (PBS), or 1.5 µg/day of IL-4. The second set was composed of five groups: the control, treatment with 0 (PBS only), 0.015, 0.15, or 1.5 µg/day of IL-4. The distance of OTM was measured and tartrate-resistant acid phosphatase positive cells along the loaded alveolar bone and root surface were identified. The root resorption associated with OTM was evaluated by a scanning electron microscope. RESULTS: The amount of OTM and the number of osteoclasts were significantly decreased in the IL-4-treated mice. Moreover, IL-4 significantly suppressed force-induced odontoclasts and root resorption. CONCLUSION: IL-4 inhibits tooth movement and prevents root resorption in the mouse model. These results suggest that IL-4 could be used as a useful adjunct to regulate the extent of OTM and also to control root resorption.