Association Between Antidiabetic Drugs and Delirium: A Study Based on the Adverse Drug Event Reporting Database in Japan.

BACKGROUND AND OBJECTIVE: Several associations between diabetes mellitus and delirium have been reported; however, they have been inconsistent, and evidence on the effects of antidiabetic medications on delirium is also limited. This study aimed to investigate whether the use of antidiabetic drugs is a risk factor for delirium development. METHODS: Using the Japanese Adverse Event Reporting Database, we analyzed 662,899 reports between 2004 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) for delirium associated with diabetes and using each antidiabetic medication were calculated after adjusting for potential confounders. RESULTS: Overall, 8892 of the reports analyzed were associated with delirium. A comparison of the incidence of delirium between patients with and without diabetes showed no significant difference, with 1.34% in patients without diabetes and 1.37% in those with diabetes. In each antidiabetic medication, signals for delirium were detected for sulfonylurea (crude ROR, 1.35; 95% CI 1.21-1.51) and insulin (crude ROR, 1.28; 95% CI 1.13-1.44). These results were maintained even after adjusting for factors with potential confounders (sulfonylurea: adjusted ROR, 1.75; 95% CI 1.54-2.00, insulin: adjusted ROR, 1.35; 95% CI 1.20-1.54). CONCLUSIONS: Our results suggest no association between diabetes and delirium; however, using sulfonylurea and insulin may be associated with delirium development. Nonetheless, these findings should be validated in future studies.

Human Recombinant Lactoferrin Promotes Differentiation and Calcification on MC3T3-E1 Cells.

Lactoferrin (LF), known to be present in mammalian milk, has been reported to promote the proliferation of osteoblasts and suppress bone resorption by affecting osteoclasts. However, the mechanisms underlying the effects of human sources LF on osteoblast differentiation have not yet been elucidated, and almost studies have used LF from bovine sources. The presented study aimed to characterize the molecular mechanisms of bovine lactoferrin (IF-I) and human recombinant lactoferrin (LF-II) on MC3T3-E1 pre-osteoblast cells. MC3T3-E1 cells were treated with LF, ascorbic acid, and ß-glycerophosphate (ß-GP). Cell proliferation was analyzed using the MTT assay. Alkaline phosphatase activation and osteopontin expression levels were evaluated via cell staining and immunocytochemistry. The differentiation markers were examined using quantitative real-time PCR. The cell viability assay showed the treatment of 100 µg/mL LF significantly increased; however, it was suppressed by the simultaneous treatment of ascorbic acid and ß-GP. Alizarin red staining showed that the 100 µg/mL treatment of LF enhanced calcification. Quantitative real-time PCR showed a significant increase in osterix expression. The results suggest that treatment with both LFs enhanced MC3T3-E1 cell differentiation and promoted calcification. The mechanisms of calcification suggest that LFs are affected by an increase in osterix and osteocalcin mRNA levels.

Modulation of osteoblast differentiation and bone mass by 5-HT2A receptor signaling in mice.

Recent studies reported that serotonin (5-hydroxytryptamine, 5-HT) may be an endogenous paracrine and/or autocrine factor that is used for intercellular communication in bone cells and between multiple organs regulating bone homeostasis. In the present study, we showed that the administration of MDL11939, a selective 5-HT2A receptor antagonist, reduced bone mass in mice. The loss of bone mass in MDL11939-treated mice was associated with impaired bone formation in vivo, as demonstrated by the lower expression of osterix (Osx) and osteocalcin than that in vehicle-treated mice. On the other hand, no significant differences were observed in osteoclast numbers between MDL11939- and vehicle-treated mice. The pharmacological blockade of 5-HT2A receptor signaling significantly decreased alkaline phosphatase activity in osteoblastic cells. In addition, the knockdown of the 5-HT2A receptor by a siRNA treatment decreased Osx, but not Runx2 gene expression in MC3T3-E1 cells. These results suggest that 5-HT2A receptor signaling mediated bone mass by regulating osteoblast differentiation.

Fluvoxamine moderates reduced voluntary activity following chronic dexamethasone infusion in mice via recovery of BDNF signal cascades.

Major depression is a complex disorder characterized by genetic and environmental interactions. Selective serotonin reuptake inhibitors (SSRIs) effectively treat depression. Neurogenesis following chronic antidepressant treatment activates brain derived neurotrophic factor (BDNF) signaling. In this study, we analyzed the effects of the SSRI fluvoxamine (Flu) on locomotor activity and forced-swim behavior using chronic dexamethasone (cDEX) infusions in mice, which engenders depression-like behavior. Infusion of cDEX decreased body weight and produced a trend towards lower locomotor activity during darkness. In the forced-swim test, cDEX-mice exhibited increased immobility times compared with mice administered saline. Flu treatment reversed decreased locomotor activity and mitigated forced-swim test immobility. Real-time polymerase chain reactions using brain RNA samples yielded significantly lower BDNF mRNA levels in cDEX-mice compared with the saline group. Endoplasmic reticulum stress-associated X-box binding protein-1 (XBP1) gene expression was lower in cDEX-mice compared with the saline group. However, marked expression of the XBP1 gene was observed in cDEX-mice treated with Flu compared with mice given saline and untreated cDEX-mice. Expression of 5-HT2A and Sigma-1 receptors decreased after cDEX infusion compared with the saline group, and these decreases normalized to control levels upon Flu treatment. Our results indicate that the Flu moderates reductions in voluntary activity following chronic dexamethasone infusions in mice via recovery of BDNF signal cascades.

Cancer of the small intestine in patients with Crohn's disease.

Due to an increase in the number of long-term cases of Crohn's disease, the risk of combined cancer in these patients has been assessed in numerous articles. Most of these reports have involved patients with cancer of the large intestine, while cases of cancer of the small intestine combined with Crohn's disease are very rare. We experienced two cases of cancer of the small intestine combined with Crohn's disease. In both cases, the patients had suffered from Crohn's disease for over 10 years and a second operation was performed after a long period without treatment following the first operation, which had achieved a favorable outcome. In both cases of combined cancer, the patients experienced ileus; however, it was difficult to discern this from ileus due to the presence of Crohn's disease. Therefore, making a definitive diagnosis of combined cancer was not possible before surgery, and the definitive diagnosis was obtained based on an intraoperative pathological diagnosis. It is thought that tumor markers transition in a manner parallel to the progression of cancer, providing a clue for cancer diagnosis. In patients with Crohn's disease, there is a pressing need to establish a method for diagnosing cancer of the small intestine at an early stage.

Vldlr overexpression causes hyperactivity in rats.

BACKGROUND: Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients. METHODS: We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features. RESULTS: Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function. CONCLUSIONS: Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities.

The effect of lentinan combination therapy for unresectable advanced gastric cancer.

BACKGROUND: Developed as a biological response modifier (BRM), lentinan mitigates patients' symptoms by boosting the immune system. In combination with S-1 (tegafur, gimeracil, oteracil), lentinan is reported to mitigate adverse reactions to therapy for unresectable recurrent gastric cancer and prolong survival. However, there are few reports from actual clinical practice, and precise methods of using lentinan have not yet been established. This study retrospectively examined the usefulness of lentinan in patients. PATIENTS AND METHODS: The subjects of this study were 39 patients who were diagnosed with unresectable gastric cancer, based on preoperative examinations or findings at laparotomy in our Department. These patients underwent S-1/paclitaxel therapy. Nineteen of the patients received lentinan while 20 did not, and these two groups of patients were compared. RESULTS: There were no significant differences in patients' characteristics such as the male:female ratio, age at the start of chemotherapy, and staging classification of the 19 patients receiving lentinan and the 20 patients not receiving lentinan. Comparison of the two groups revealed no significant differences in overall survival time, but comparison of the duration of therapy revealed that therapy tended to be longer for the group taking lentinan than the group not taking lentinan. Adverse events were noted in 61.5% (24 patients) of the total patients group; such events tended to occur less frequently in the group receiving lentinan. CONCLUSION: Lentinan inclusion in therapy did not seem to prolong survival. Nevertheless, the duration of therapy tended to be longer for patients taking lentinan. This may be due to the fact that adverse events tended to occur less frequently in these patients during therapy. A decline in the incidence of adverse events increases the duration of therapy and improves the patients' quality of life (QOL); it may also prolong survival. Optimal methods of using lentinan need to be established.

Decreased voluntary activity and amygdala levels of serotonin and dopamine in ovariectomized rats.

Estrogen is involved in numerous activities in the brain, such as learning, memory, fear, anxiety and mood. However, little is known about the pathways involved in the effects of estrogen in the brain. Therefore, to improve our understanding of the effects of estrogen, we examined the effects of ovariectomy (OVX)-a model of estrogen deficiency and menopause-on psychiatric functions, including voluntary activity. Female Wistar rats underwent OVX or sham operation. Voluntary momentum and circadian activity were monitored at 2 and 6 weeks, respectively. Rats also underwent microdialysis of the amygdala to determine serotonin (5-HT) and dopamine levels. Although the circadian rhythm was unchanged at 2 weeks, voluntary activity at 6 weeks was significantly lower in OVX rats than that in sham rats. This was due to significantly reduced voluntary activity in the 12-h dark phase, while no significant difference was detected in the 12-h light phase. Both 5-HT and dopamine levels in the amygdala were significantly lower in OVX rats than those in sham rats at 6 weeks after the procedure. In conclusion, these results indicate that estrogen is an important mediator of voluntary activity in rats, particularly during the dark phase. These effects of estrogen appear to involve reduced 5-HT and dopamine release in the amygdala. Further studies are needed to determine whether estrogen (and its deficiency) influences the synthesis, vesicular packaging, release, re-uptake and degradation of these transmitters.

Clinical course of colorectal cancer in patients with ulcerative colitis.

BACKGROUND: Colorectal cancer that develops as a complication of ulcerative colitis (UC) is a serious problem that affects the patient's prognosis. Such cancer is characterized by development at an early age, a high incidence of multiple tumors, poorly differentiated carcinoma and mucinous carcinoma. Special attention should therefore be paid to the diagnosis and treatment of such cancer. PATIENTS AND METHODS: One hundred and seventy-four patients with UC underwent surgery in our Department between July of 1985 and December of 2009. Of these, 22 had concomitant colorectal cancer. We performed a retrospective study to investigate these patients. RESULT: The incidence of colorectal cancer as a complication of UC was 12.6%. The male:female ratio was 14:8, and the average age at surgery was 54.6 (32-79) years. In addition, when examining the lesion type of UC, it was revealed that the total colitis type accounted for 77.3% of colorectal cancer cases in UC patients. Regarding the site of development of colorectal cancer, 14 out of the 22 patients had cancer in the distal end. The average period from the development of UC to the diagnosis of colorectal cancer was 14.7 (0.6-40.5) years. The cumulative incidence rates over 10 and 20 years were 5.1% and 17.5%, respectively. Histologically, poorly differentiated adenocarcinoma and mucinous carcinoma were confirmed in 38.1% of the patients, and dysplasia was also confirmed in 53.8%. In addition, multiple tumors were confirmed at a rate as high as 27.3%. Cancer detection through surveillance has increased, and colorectal cancer was detected in 13 out of the 22 patients by routine surveillance. In cases where cancer was detected by surveillance colonoscopy, 46.2% of lesions were early cancer. We therefore consider that surveillance is useful. However, we experienced a case that could not be diagnosed by endoscopy that was successfully diagnosed by fluoroscopy. The case was noted to have stricture. CONCLUSION: The cumulative incidence rates over 10 and 20 years were 5.1% and 17.5%, respectively. Since the average period from the onset of UC to the diagnosis of colorectal cancer was 14.7 years, routine surveillance examinations are necessary for patients with a history of UC of at least 10 years. In addition, patients with strictures must be examined using both colonoscopy and fluoroscopy because diagnosis with colonoscopy alone may be inadequate.

Clinical features of and chemotherapy for cancer of the small intestine.

BACKGROUND: Cancer of the small intestine is a rare disease, and its clinical features have not been clearly elucidated. Techniques such as double balloon endoscopy and capsule endoscopy allow the preoperative diagnosis of cancer of the small intestine, but this cancer is often detected at an advanced state and in many cases postoperative chemotherapy is required. This study evaluated the pre- and postoperative clinical course of cancer of the small intestine and the effectiveness of chemotherapy. PATIENTS AND METHODS: Patients who underwent surgery for cancer of the small intestine in this Department from July 1985 to December 2008 were included in this study. Duodenal cancer has vastly different origins, methods of diagnosis, and surgical procedures, so this form of cancer was excluded. There were 8 cases of jejunal or ileal cancer treated during the study period. The pre- and postoperative course of these cases was reviewed, as well as the effectiveness of chemotherapy in cases of recurrence. RESULTS: The male:female ratio of the 8 patients was 6:2, the mean age at surgery was 59.7±15.9 (35-76) years, and the mean postoperative follow-up was 41.1±48.0 (7-152) months. Six patients underwent a partial resection of the small intestine, and a right hemicolectomy, and a bypass were performed in one case each. The tumor type according to Borrmann's classification indicated that 5 tumors were type 2, 2 were type 3, and 1 was type 5; the mean tumor size was 6.3±5.3 (2.5-18.0) cm. TNM staging indicated that 3 tumors were stage II, 1 was stage III, and 4 were stage IV. Six patients underwent postoperative chemotherapy. One patient underwent adjuvant chemotherapy of, and 5 patients with recurring or advanced cancer underwent therapeutic chemotherapy of. The course of chemotherapy for the 5 patients with recurrent or advanced cancer resulted in 4 patients with progressive disease (PD) and 1 with stable disease (SD). Three out of the four patients with PD died. CONCLUSION: The basic treatment for cancer of the small intestine is surgical resection. Palliative surgery and chemotherapy are considered in cases where resection is not possible or the cancer recurs. Nevertheless, there is no established regimen for such chemotherapy. Cancer of the small intestine is currently being treated with chemotherapy based on the treatment strategies for colon cancer, but there are few reports of its success. Chemotherapy was unsuccessful in treating any of the patients with recurring or advanced cancer reviewed in this report. The diagnosis must therefore be improved and postoperative chemotherapy will be needed to treat cancer of the small intestine given its increasing incidence, and therefore physicians are working as quickly as possible to establish an optimal treatment regimen. Compiling and studying such cases are crucial to accomplishing that goal.

A study of the postoperative course in cases of GIST of the stomach. The efficacy of imatinib in cases of recurrence.

BACKGROUND: The postoperative course of cases of gastrointestinal stromal tumor (GIST) of the stomach was studied in patients who underwent surgery in this Department. In addition, treatment with the molecular-targeted drug imatinib was studied in cases of recurrence. PATIENTS AND METHODS: We studied 40 cases with a diagnosis of GIST of the stomach where the patient subsequently underwent surgery in this Department between July 1985 (when this facility opened) and December 2007. Six of these cases involved patients with carcinoma or carcinoid tumors, which could have affected the procedure and prognosis, and 2 cases involved patients who developed cancer during the postoperative course of the GIST. Therefore these 8 patients were excluded, thus resulting in the study of a total of 32 patients. RESULTS: The male:female ratio for the 32 patients was 17:15, the average tumor size was 4.7+/-3.4 cm (with a range of 1.3-16.0 cm), and the median follow-up was 92.2+/-73.7 months (with a range of 2-238 months). Recurrence occurred in 6 out of the 32 patients (18.8%) and was observed in the liver of 5 patients, in the lungs of 2 patients, in the peritoneum of 2 patients, locally in 1 patient, and in the bone of 1 patient (including patients with multiple sites). With respect to the tumor size, the incidence of recurrence of tumors smaller than 2 cm was 0%, 16.7% for patients with tumors 2 to 5 cm in size, and 27.3% for these with tumors larger than 5 cm. The incidence of recurrence was particularly marked in patients with tumors larger than 10 cm (66.7%). The treatment for recurrence was transcatheter arterial embolization for 1 patient and imatinib for 5 patients. In cases where imatinib was administered, 1 patient exhibited partial response, 1 patient exhibited stable disease, and 3 patients exhibited progressive disease, indicating a response rate of 20%. Postoperative recurrence of GIST of the stomach in this study occurred in 6 of 32 patients (18.8%). The incidence of recurrence of tumors larger than 10 cm was 2 out of 3 patients. CONCLUSION: In cases of recurrence, the response rate to imatinib was 20%. Imatinib was effective against GIST that were positive for KIT protein, but future study is needed to clarify the risk factors for recurrence and indications for adjuvant therapy in cases of GIST.

Infliximab treatment for anal fistula in patients with Crohn's disease.

BACKGROUND: Infliximab has played a central role in the treatment of luminal Crohn's disease (CD) due to its great usefulness. Although the seton placement has been widely used for the treatment of anal fistula in patients with CD, we have used infliximab for severe cases in which improvement was not achievable by the seton placement, or for patients in whom improvement of quality of life (QOL) could be expected. PATIENTS AND METHODS: The anal region of 383 patients with CD was examined during the period from July 1985 to December 2005 and the presence of a lesion in the anal region was confirmed in 326 patients. Among them, the number of cases with fistula was highest (245), followed by those with skin tags (115), those with fissures (106), those with anal tumefaction and enlarged papillae (61), and those with anal stenosis (56). The seton placement was used for 93 patients with anal fistula; of these, 86 patients received the treatment for one year or more. During the treatment, infliximab was used for 19 patients and their pathology and progress were evaluated. RESULTS: Infliximab was used for 11 severe cases in which improvement had not been achieved using the seton placement, and for 8 patients for improvement of their QOL. For evaluation, the patients who did not undergo additional treatment after infliximab administration were assigned to the good response group, those who underwent additional treatment other than surgical treatment to the intermediate response group and those who required surgical treatment to the poor response group. The good, intermediate and poor response groups included 8 (42.1%), 5 (26.3%) and 6 (31.6%) patients, respectively. A study of the relationship between the diagnostic indications of magnetic resonance imaging (MRI) and the course of disease showed that most of the patients with a localized inflammation of the anal fistula had better courses and most of the patients with diffuse inflammation had poor courses. CONCLUSION: Approximately 70% of the patients required no surgical treatment. In addition, it was considered important to appropriately select patients for infliximab treatment. MRI was useful as a examination to be performed before infliximab administration because it enabled close examination of the localization of anal fistula and the range of inflammation.

Study of colorectal cancer with Crohn's disease.

BACKGROUND: Crohn's disease (CD) cases have been increasing and prolonged cases are now frequent. In addition, in Japan, more cases with concomitant malignant disease have also recently been reported. There is a particularly high risk of cancer occurring simultaneously in the lower rectum and the anal area. PATIENTS AND METHODS: Two-hundred and eighty-six patients with CD had undergone surgery at this department, up to December, 2005. We studied malignant diseases concomitant with CD, based on empirical examples. RESULTS: Thirteen (4.5%) were cases concomitant with malignant disease: six patients had colorectal cancer, 1 had rectal carcinoid, 1 had stomach cancer, 1 had uterine cancer, 1 had thyroid cancer, 1 had skin cancer and 2 had acute leukemia. Regarding the seven cases other than colorectal cancer, they were all juvenile patients under the age of 50, except for the stomach cancer case (69 years of age). Among the 6 cases of colorectal cancer, 5 cases were anorectal cancer and 1 was lower rectal cancer. The average age was 42.8 years (30-54 years) and the average term from CD occurrence to cancer diagnosis was 208 months (69-387 months). The one case with lower rectal cancer was intramucosal cancer which did not recur after surgery. The five cases of anorectal cancer were advanced, with invasion of the adjacent organs and 2 of them were unresectable. Four cases were of the infiltrative type, and regarding the histological findings, 4 cases were cancer with mucous production and 1 case was a poorly-differentiated endocrine tumor. Four cases had a history of anal fistula, but there was no clear causal relationship. CONCLUSION: In Japan, prolonged CD cases have been increasing and more and more cases of malignant disease with concomitant CD have been reported. There is a particularly high risk of cancer occurring simultaneously in the lower rectum and the anal area. Therefore, careful observation, taking all appropriate diagnostic surveillance modalities into consideration, is thus believed to be important in order to achieve an early detection of such cancer.