Theory-based analysis of anti-inflammatory effect of infliximab on Crohn’s disease and rheumatoid arthritis

In Japan, the recommended dosage regimens of infliximab (IFX) for treatment of rheumatoid arthritis (RA) and Crohn’s disease (CD) are different. However, the differences have not been analyzed theoretically. In a previous study, we constructed a pharmacokinetic–pharmacodynamic model to investigate the effects of IFX for CD and found it useful to establish a rational dosage regimen of IFX for individual patients with CD. In the present study, we investigated whether the theory-based model could be used for cases of RA and also used it to evaluate the validity of the dosage regimen. The results obtained with our model were in good agreement with observed tender joint count (TJC) ratio data, which was considered to show the validity of our analysis. Thus, we concluded that the model could be used for patients with RA. Furthermore, a second administration of IFX given 2 weeks after the first infusion was important to achieve remission in the early stage of RA. We also compared the estimated pharmacodynamic parameters of RA with those of CD. The elimination rate constant of inflammation in RA was greater than that in CD, suggesting that the recovery from inflammation in RA is faster than that in CD, and indicating a reason for the difference in dosage between RA and CD. In conclusion, use of our model in light of the individual quantitative factor of tumor necrosis factor (TNF)-α allows establishment of IFX dosage regimens for individual patients.     

A new space of the face: The bucco‐mandibular space

Our previous studies based on intraoral dissection of fresh cadavers demonstrated the fissure and loose connective tissues behind the mucosa between the incisivus labii inferioris (ILI) and buccinator (BM) muscles. However, this raised new questions about the relationship among these muscles, the fissure and the buccal space. To our knowledge, no pathway to the oral cavity from the buccal space has been previously demonstrated, although such a pathway would better explain some routes of infection. Therefore, the aim of this study was to clarify the relationship among the mimetic muscles attached to the mandible, the fissure, and the buccal space. Twenty sides from 10 fresh frozen adult cadaveric Caucasian heads were used. The relationships among the ILI, BM, mandible, and buccal space were investigated with dissection and fluoroscopy. In all specimens, the fissure between the lateral border of the ILI and the anterior border of the BM formed the entrance of a space (here termed the bucco‐mandibular space), which corresponded to the buccal mucosa in the premolar region. The superior border of this space was formed by the platysma and associated fascia, which was continuous with the masseteric fascia. This fascia clearly separated this space from the buccal space, which was located lateral to the BM and superior to this space. Clin. Anat. 30:958–962, 2017. © 2017 Wiley Periodicals, Inc.     

Chromosomal and microsatellite instability in sporadic gastric cancer

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.     

Two-stage hepatectomy for multiple bilobular liver metastases from colorectal cancer

BACKGROUND/AIMS: To determine an appropriate surgical treatment for patients with multiple liver metastases, we evaluated the efficacy of two-stage hepatectomy in patients with multiple bilobular liver metastases from colorectal carcinoma. METHODOLOGY: Some patients with multiple liver metastases are not candidates for a complete resection by a single hepatectomy, even when downstaged by chemotherapy, after portal embolization. In two-stage hepatectomy, the highest possible number of tumors is resected in a first, noncurative intervention, and the remaining tumors are resected after a period of liver regeneration. Two-stage hepatectomy was performed in 11 patients. RESULTS: Two-stage hepatectomy was feasible in all of the 11 patients. In 3 of them, the first stage was a major resection (more extensive than a lobectomy). This first hepatectomy was uneventful in all patients. The second hepatectomy was also uneventful in nine patients, but in one of the other two, a perihepatic fluid infection occurred, and in the other, postoperative liver failure developed due to a right subphrenic abscess. However, all patients were discharged. The percentage of the expected resection volume at one time, calculated from CT volumetry, was 75.5+/-1.2% and the prognostic score as surgical risk was 56.6+/-4.5. In two-stage hepatectomy cases, the percentage of the resected volume and the prognostic score in the first hepatectomy were 25.4+/-6.4% and 6.7+/-7.3, and in the second, 45.7+/-4.5% and 28.5+/-5.8. During the follow-up procedures, a residual hepatic recurrence was observed in 6 patients, and pulmonary recurrence in 9. The 1- and 3-year survival rates after the first hepatectomy were 90% and 45%, with median survivals of 18 months from the first hepatectomy. CONCLUSIONS: Two-stage hepatectomy is a surgical modality intended for patients with initial unresectable metastases. However, following such surgery, protective treatment against residual liver recurrence and lung metastasis will be a most important issue.     

Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids

We have recently shown that long-term use of inhaled corticosteroids decreases bone mineral density (BMD) of the lumbar spine in postmenopausal asthmatic women. The present study aimed to evaluate the efficacy of alendronate in comparison with that of alfacalcidol (1-alpha-hydroxyvitamin D(3)) for the treatment of BMD reduction in postmenopausal asthmatic patients who had inhaled corticosteroid therapy without regular use of systemic corticosteroids. Twenty-eight postmenopausal asthmatic patients with BMD T score of -1.0 or less were randomized to receive alendronate (5 mg/d) or alfacalcidol (1 microg/d). Bone mineral density was determined at baseline and 12 months after the treatment, and biochemical markers of bone metabolism were measured at baseline and after 6 and 12 months of treatment. The mean (+/-SD) BMD values at the lumbar spine, the total hip, and the Ward's triangle significantly increased by 4.9 +/- 4.5% (P = .0005), 2.4 +/- 2.2% (P = .0005), and 3.6 +/- 5.2% (P = .02) at 12 months in the alendronate group, whereas the corresponding values did not significantly change in the alfacalcidol group. In the alendronate group, urinary N-telopeptide (NTx), serum osteocalcin, and serum alkaline phosphatase concentrations significantly decreased, and serum intact parathyroid (PTH) level significantly increased, from baseline at both 6 and 12 months. In the alfacalcidol group, urinary NTx showed modest but significant decrease, although the extent of the change was smaller than that in the alendronate group. We concluded that alendronate was effective to improve reduced BMD in postmenopausal asthmatic patients on inhaled corticosteroid therapy through the mechanism of inhibiting bone resorption.     

New therapeutic approach for impaired arteriogenesis in diabetic mouse hindlimb ischemia.

BACKGROUND: The combined treatment of sustained-release basic fibroblast growth factor (Sr-bFGF) and a 5-hydroxytryptamine(2A) blocker, sarpogrelate, was evaluated to see whether it reversed the impaired collateral circulation in diabetic (DM) mouse hindlimb ischemia. METHOD AND RESULTS: Diabetic and normal mice with ischemic hindlimb were randomly assigned to 1 of 5 experimental groups (no treatment, sarpogrelate 50 mg . kg(-1) . day(-1), 20 microg or 50 microg Sr-bFGF and a combined treatment of 20 microg Sr-bFGF and sarpogrelate), and treated for 4 weeks. Tissue blood perfusion (TBP), vascular density (angiogenesis) and the number of mature vessels (arteriogenesis) were checked by the use of standard methods. Although angiogenesis was comparable (161+/-14 vs 154+/-12 vessels/mm(2)), the laser Doppler perfusion image index (LDPII) (0.43+/-0.11 (SD) vs 0.63+/-0.08, p<0.05) and arteriogenesis (8+/-3 vs 12+/-4 vessels/mm(2), p<0.05) were significantly lower in DM mice than those in normal mice. The dose of Sr-bFGF for the sufficient number of mature vessels (>or=45 vessels/mm(2)) and LDPII (>or=0.9) was 20 microg for the normal mice, and 50 microg for the DM mice, which was reduced with the aid of sarpogrelate. Conclusions A combined therapy of Sr-bFGF and sarpogrelate is effective for neovascularization to reverse the impaired arteriogenesis and TBP in DM mice.     

Prevalence of gastroesophageal reflux symptoms in a large unselected general population in Japan

AIM：To examine the prevalence of gastroesophageal reflux disease （GERD） symptoms in a large unselected general population in Japan.
METHODS： In Japan, mature adults are offered regular check-ups for the prevention of gastric cancer. A notice was sent by mail to all inhabitants aged 〉 40 years. A total of 160 983 Japanese （60 774 male, 100 209 female; mean age 61.9 years） who underwent a stomach check up were enrolled in this study. In addition, from these 160 983 subjects, we randomly selected a total of 82 894 （34 275 male, 48 619 female; mean age 62.4 years） to evaluate the prevalence of abdominal pain. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a 1 mo period.
RESULTS： The respective prevalences of the symptoms in males and females were： heartburn, 15.8% vs 20.7%; dysphagia, 5.4% vs 7.8%; and abdominal pain, 6.6% vs 9.6%. Among these symptoms, heartburn was significantly high compared with the other symptoms, and the prevalence of heartburn was significantly more frequent in females than in males in the 60-89-year agegroup. Dysphagia was also significantly more frequent in female patients.
CONCLUSION： The prevalence of typical GERD symptoms （heartburn） was high, at about 20% of the Japan population, and the frequency was especially high in females in the 60-89 year age group.     

Assessment of Hepatic Functional Reserve in Cirrhotic Patients by Computed Tomography of the Caudate Lobe

In order to investigate whether the size of thecaudate lobe of the cirrhotic liver is related to thehepatic functional reserve, the morphometric analysis ofthe caudate lobe was preformed retrospectively using computed tomography in 106 consecutivepatients of whom 67 had compensated (group 1), and 39uncompensated (group 2) liver cirrhosis. In 51 patients,hepatic measurements were repeated in follow-up. Age- and gender-matched controls were studied.The size of the caudate lobe and the ratio of thecaudate to right lobe were correlated with liverfunction. The caudate lobe was larger in the studypatients than in the controls, and larger in group 1than in group 2 (P < 0.01). The caudate to right loberatios were also greater in the study patientsespecially in group 1 (P < 0.01). In follow-up, the regression coefficient for the caudate to rightlobe ratio was positive in group 1 and negative in group2 (P < 0.05). Even though the caudate lobe ofpatients with uncompensated liver cirrhosis was larger than that of the controls, patients withcompensated liver cirrhosis had a larger caudate lobeand higher caudate to right lobe ratio compared to thepatients with uncompensated liver cirrhosis. The caudate lobe may have played an importantrole in maintaining proper liver function in thesepatients.     

Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat

Abstract: In the present study, we investigated the role of the spleen in experimental hepatic ischemia/reperfusion in the rat. After a 90-min period of ischemia in the left and middle hepatic lobes, the ischemia was released and the liver was reperfused for up to 24 h. Plasma alanine aminotransferase reached a peak 3 h after the onset of reperfusion, and gradually decreased thereafter. A histological examination revealed evidence of hepatocellular necrosis and degeneration, especially 24 h after the onset of reperfusion. In addition, there was a noticeable accumulation of polymorphonuclear cells in the liver following ischemia/reperfusion. A splenectomy performed just prior to ischemia/reperfusion reduced both biochemical and histological hepatocellular injury. The number of polymorphonuclear cells in the liver following ischemia/reperfusion was significantly reduced in rats subjected to splenectomy, suggesting that the increase in polymorphonuclear cells may contribute to liver injury. The number of mononuclear cells also increased in the marginal zones of the spleen following ischemia/reperfusion, and appeared to be derived from the splenic monocyte/macrophage population, based on immunohistochemical studies. The spleen plays an important role in the pathogenesis of hepatic ischemia/reperfusion injury and the splenic monocyte/macrophage population contributes to liver damage.