Reduction of osteoclasts in a critical embryonic period is essential for inhibition of mouse tooth eruption.

Alveolar bone resorption by osteoclasts is essential for tooth eruption. Osteoclast-deficient Csfm(op) homozygous (op/op) mice, which lack functional macrophage colony-stimulating factor (M-CSF), suffer from osteopetrosis and completely lack tooth eruption. Although osteoclasts appear, and osteopetrosis is cured with age in op/op mice, tooth eruption is never seen. This fact suggests that there is a critical period when osteoclasts are required for tooth eruption. In this study, to detect the critical period, we administered an antagonistic antibody directed against c-Fms, a receptor for M-CSF, to inbred C57BL/6 mice for various periods. Administration of this antibody decreased tartrate-resistant acid phosphatase-positive (TRAP) osteoclasts, and incisor eruption was completely inhibited by continual administration of this antibody from embryonic day 15.5 (E15.5) until postnatal day 12.5 (D12.5). A 1-day delay of this administration abolished the inhibition of incisor eruption. The number of TRAP-positive osteoclasts was significantly reduced between E16.5 and E18.5 in the mice treated with antibody from E15.5 compared with those treated from E16.5. These results indicate that this period, during which the number of osteoclasts decreases significantly, is critical for inhibiting incisor eruption in C57BL/6 mice.     

Contribution of Monoamine Oxidase(MAO) to the Binding of Tertiary Basic Drugs in Isolated Perfused Rat Lung

The effect of tertiary basic drugs on mitochondrial MAO activity and the effect of MAO inhibitors (MAOIs) on basic drug accumulation in the isolated perfused rat lung were studied to clarify the role of MAO in drug binding to lung tissue. In the perfused lung preparation, the inhibition of MAO by basic drugs correlated well with their lipid solubilities and followed competitive kinetics. The inhibitory rank order (imipramine diphenhydramine > quinine > metoclopramide > procainamide) also correlated with their accumulation in the perfused lung. Moreover, MAOI treatment decreased the accumulation of basic drugs in the lung, and the potency of MAOIs to inhibit drug accumulation in the lung correlated with their MAO inhibitory activity. These results indicate that lung MAO has specific binding sites for basic drugs and may function as a drug reservoir.     

Evaluation of Ki-67 and p53 expression in primary and repeated liver metastases of GISTs

There has been little research evaluating changes related to tumor cell proliferation between primary and metastatic tumors of gastrointestinal tumors in the same case. We herein report the case of a 50-year-old woman with a gastric gastrointestinal stromal tumor (GIST), who developed metastatic liver tumors three times in the 7 years after proximal gastrectomy for GIST. The primary and all the metastatic liver tumors, except the second, showed fascicular/storiform architecture and the short spindle cell type. The diffuse epithelioid cell proliferation was observed in the second metastatic liver tumor. Although the immunostaining pattern with respect to GIST differentiation markers had been preserved in the primary tumor as well as in all of the metastatic tumors, the latter showed weaker positivity of both Ki-67 and p53 than the primary GIST. The primary tumor showed diffuse positive p53, and the highest value of Ki-67 labeling index (LI) among them. The metastatic liver tumors showed focal, negative or sporadic positive appearances of p53, however, Ki-67 LI were scattering among them. Immunohistochemical assessment of Ki-67 LI and p53 might be useful for evaluating changes related to tumor cell proliferation between primary and metastatic tumors of GISTs.     

The effect of an elemental diet on oral mucositis of esophageal cancer patients treated with DCF chemotherapy: a multi-center prospective feasibility study (EPOC study)

Purpose

Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy.

Methods

We performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system.

Results

Fourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade?≥?2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p?=?0.046).

Conclusions

An ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study.

Clinical trial

The date of submission: Dec 08th, 2017.

     

A New Therapeutic Antibody Removal Method Using Antigen Positive Red Cells: Application to M-Incompatible Pregnant Women

A study was made for the therapeutic removal of red cell antibodies using antigen positive red cells. With preliminary experiments in vitro, the criteria for the optimal absorption of anti-M with O MM red cells were estimated to be the following: an incubation time of 10min, an incubation temperature of 0–4°C (in an ice-water bath), and a red cell-to-plasma ratio of 1:2.5.
On the basis of these in vitro experiments, the following procedure was designed. One unit (about 90 ml) of O MM packed red cells was added to a bag containing 250 ml of patient's plasma, the mixture was incubated in an ice-water bath for 10 min. Following centrifugation, autologous plasma from which the antibodies were removed was reinfused. After absorption the titer of anti-M fell from 512 to 4. No variation in the level of other plasma components was detected and no hemolysis was seen. After 2.5 *** of patient's plasma was treated using the above described method, the antibody titer usually decreased one log₂ unit.
When this method was compared with exchange plasmapheresis, no significant abnormalities in the immunoglobulin and hemostatic factors could be detected, but a moderate decrease in platelet count was seen after plasmapheresis. Thus, it appears that our method provides a rational therapeutic modality for specifically removing antibodies.     

Effect of kihito extract granules on cognitive function in patients with Alzheimer's-type dementia

Background:   It has been recently suggested that Japanese herbal (kampo) medicines, such as kami-untan-to, may improve cognitive function in elderly subjects with Alzheimer's disease. Polygalae radix is thought to be a useful component of kami-untan-to because it enhances the activity of choline acetyltransferase in cultured neuronal cells. The purpose of the present study was to investigate the safety and usefulness of kihito extract granules, a commercially available Japanese herbal medicine that contains P. radix , for elderly patients with senile dementia.
Methods:   Seventy-five elderly subjects (84.4 ± 6.4 years) with senile dementia of Alzheimer type according to Diagnostic and Statistical Manual of Mental Disorders , 4th edition criteria were randomly assigned to the non-treatment, goshajinkigan (control kampo medicine) or kihito groups. Each medicine was given three times a day for 3 months.
Results:   There was no severe adverse event in any of the groups. We examined the Mini-Mental State Examination (MMSE), the activities of daily living (ADL) scale and cerebrovascular single photon emission computed tomography (SPECT) before and after treatment. MMSE scores were significantly improved only in the kihito group (+1.65 ± 0.53) but not in the non-treatment (−0.3 ± 0.67) and goshajinkigan (−0.58 ± 0.49) groups. ADL scores remained unchanged in all groups. Treatment with kihito was not associated with an increase in cerebral blood flow.
Conclusion:   These results propose that kihito may be useful and has potential to be tested as a medicine for Alzheimer's-type senile dementia, although further examination is required to clarify the mechanism of the improving effect of kihito on cognitive function.     

Suture Granuloma With False-Positive Findings on FDG-PET/CT Resected via Laparoscopic Surgery

A 61-year-old woman who had undergone total hysterectomy 16 years previously exhibited a pelvic tumor on computed tomography (CT). F-18 fluorodeoxyglucose (FDG) combined positron emission tomography (PET)/CT imaging revealed a solitary small focus of increased FDG activity in the pelvis. A gastrointestinal stromal tumor originating in the small intestine or another type of tumor originating in the mesentery (desmoid, schwannoma, or foreign body granuloma) was suspected; therefore, laparoscopic resection was conducted. A white, hard tumor was found to originate from the mesentery of the sigmoid colon and adhered slightly to the small intestine. The tumor was resected with a negative margin, and the pathologic diagnosis was suture granuloma. The possibility of suture granuloma should be kept in mind in cases of tumors with positive PET findings and a history of surgery close to the lesion. However, it is difficult to preoperatively diagnose pelvic tumors using a biopsy. Therefore, considering the possibility of malignancy, it is necessary to achieve complete resection without exposing the tumor.Key words: Suture granuloma, Laparoscopy, Positron emission tomography (PET)It is very difficult to diagnose suture granulomas preoperatively. F-18 fluorodeoxyglucose (FDG) combined positron emission tomography (PET)/computed tomography (CT) imaging is often used to differentiate benign from malignant tumors that are difficult to diagnose on other modalities, such as ultrasound (US), CT, and magnetic resonance imaging. However, it is not easy to differentiate tumors associated with inflammation or malignancy using FDG-PET/CT. Suture granulomas are known to be benign; however, false-positive findings were observed on PET/CT in our case. In the literature, there are few reports of suture granulomas showing false-positive findings on PET/CT.^1–5 We report here a case in which it was not possible to rule out the potential for malignancy using CT or FDG-PET/CT and the lesion was confirmed to be a suture granuloma based on a pathologic examination following laparoscopic resection.     

Predictor of respiratory disturbances during gastric endoscopic submucosal dissection under deep sedation

BACKGROUND Sedation is commonly performed for the endoscopic submucosal dissection(ESD) of early gastric cancer. Severe hypoxemia occasionally occurs due to the respiratory depression during sedation.AIM To establish predictive models for respiratory depression during sedation for ESD.METHODS Thirty-five adult patients undergoing sedation using propofol and pentazocine for gastric ESDs participated in this prospective observational study. Preoperatively, a portable sleep monitor and STOP questionnaires, which are the established screening tools for sleep apnea syndrome, were utilized. Respiration during sedation was assessed by a standard polysomnography technique including the pulse oximeter, nasal pressure sensor, nasal thermistor sensor, and chest and abdominal respiratory motion sensors. The apnea-hypopnea index(AHI) was obtained using a preoperative portable sleep monitor and polysomnography during ESD. A predictive model for the AHI during sedationwas developed using either the preoperative AHI or STOP questionnaire score.RESULTS All ESDs were completed successfully and without complications. Seventeen patients(49%) had a preoperative AHI greater than 5/h. The intraoperative AHI was significantly greater than the preoperative AHI(12.8 ± 7.6 events/h vs 9.35 ± 11.0 events/h, P = 0.049). Among the potential predictive variables, age, body mass index, STOP questionnaire score, and preoperative AHI were significantly correlated with AHI during sedation. Multiple linear regression analysis determined either STOP questionnaire score or preoperative AHI as independent predictors for intraoperative AHI ≥ 30/h(area under the curve [AUC]: 0.707 and 0.833, respectively) and AHI between 15 and 30/h(AUC: 0.761 and 0.778, respectively).CONCLUSION The cost-effective STOP questionnaire shows performance for predicting abnormal breathing during sedation for ESD that was equivalent to that of preoperative portable sleep monitoring.     

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.Zinc (Zn) has wide-ranging effects on immunity. Zn deficiency has uncovered the importance of Zn homeostasis in immune cell maintenance and function (1). Dramatic effects of Zn on immunity have been observed in several immune and allergy-related cells, including lymphocytes such as B cells (2–6). B cells develop in the bone marrow (BM); the initial commitment to pro-B cells is followed by their differentiation into pre-B cells, and subsequently into immature B cells, which express the B-cell receptor on their surface (7). The immature B cells reach the spleen as transitional B cells, further differentiating into follicular or marginal zone mature B cells (7). Although the perturbation of Zn homeostasis causes splenic atrophy associated with lymphocyte reduction, and compromises cellular and humoral immune responses (6), the mechanisms underlying how Zn controls immune cell function, and in particular, the impact on early B-cell development, have been largely unknown.Zn homeostasis is tightly controlled by Zn transporter family members, Zrt- and Irt-like proteins (ZIPs, Zn importers) and zinc transporters (ZnTs, Zn exporters) (8), and recent studies revealed that alterations in Zn homeostasis mediated by specific Zn transporters play indispensable roles in a variety of cellular events (9). The intestinal Zn transporter ZIP4 is important for the initial absorption of dietary Zn, and patients with mutations in the SLC39A4/ZIP4 gene suffer from the inherited disorder acrodermatitis enteropathica (10, 11). ZIP13 controls the formation of bone, teeth, and connective tissues by modulating BMP/TGF-β signaling (12), and its loss-of-function mutation causes spondylocheiro dysplastic Ehlers-Danlos syndrome in humans (12, 13). ZIP14 controls systemic growth by regulating G protein-coupled receptor (GPCR) signaling (14), and ZIP8 is involved in osteoarthritis (15) and negatively manipulates NF-κB activation (16). In addition, ZnT5 regulates cytokine production by controlling the activation of protein kinase C upon antigen exposure in mast cells (17). Thus, Zn homeostasis mediated by Zn transporters is linked to a wide variety of biological and regulatory functions, and the disruption of a Zn transporter-Zn axis can lead to various symptoms in the absence of redundant machinery (18).Here we demonstrate a definitive role of ZIP10 in early B-cell development. We found that a loss of ZIP10 during an early B-cell stage specifically abrogated cell survival, resulting in the absence of mature B cells, which led to splenoatrophy and reduced Ig levels. The inducible deletion of Zip10 in pro-B cells increased the caspase activity because of the reduced intracellular Zn level, leading to cell death. This phenomenon was mimicked by the intracellular chelation of Zn. These findings indicated that Zn homeostasis via ZIP10 plays an indispensable role in early B-cell survival. We also demonstrated that the ZIP10 expression levels were regulated by STAT3/STAT5 activation, and that ZIP10 was highly expressed in human B-cell lymphoma samples in which both STAT proteins were activated, indicating that the JAK-STAT-ZIP10-Zn signaling axis is important for B-cell maintenance. Our results establish a functional link between ZIP10 and the survival of early stages of B cells, revealing a molecular mechanism underlying the requirement of Zn for maintenance of the immune system.