Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model.

Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.

Effect of intraperitoneal docetaxel on ovarian function in mice.

Taxanes are important chemotherapeutic agents used to manage breast cancer and gynaecological malignancies. However, ovarian toxicity induced by the taxane docetaxel (DOC) is of great concern. We investigated DOC-induced toxicity in the ovaries of female CD1 strain mice. The mice were divided into control (saline), DOC-5 (5 mg/kg DOC), and DOC-10 (10 mg/kg DOC) groups and administered saline or DOC on the first day of the study and two weeks later. Two weeks after the second dose, the ovaries were removed for analysis after inducing superovulation. Ovary weight, the number of secondary follicles, and the total number of follicles were reduced after DOC administration. Additionally, the expression levels of caspase-3 and the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) increased. Our findings suggest that high-dose DOC induces damage to growing follicles; however, it may not affect primordial follicles.Impact statementWhat is already known on this subject? Docetaxel (DOC) is one of the most effective chemotherapeutic agents used to manage various cancers. Some in-vitro studies have examined paclitaxel-induced ovarian toxicity; however, limited research on DOC is available.What do the results of this study add? We investigated DOC-induced ovarian toxicity in female CD1 strain mice at 5 mg/kg and 10 mg/kg. We found that DOC reduced ovary weight, the number of secondary follicles, and the total number of follicles, with the higher dose having a higher effect.What are the implications of these findings for clinical practice and/or further research? We believe that our study makes a significant contribution to the knowledge about the effect of DOC on ovarian function.

Association between early-term birth and hypoglycaemia in large-for-gestational-age neonates:A retrospective cohort study.

BACKGROUND: The effect of early-term birth on the development of hypoglycaemia in large-for-gestational-age (LGA) neonates is yet to be clarified. This study aimed to clarify the association between hypoglycaemia and early-term birth in LGA neonates. METHODS: This single-centre retrospective cohort study evaluated LGA neonates born at term at Tsurugi Municipal Handa Hospital, Japan. Blood glucose levels were measured immediately and at 1, 2, and 4 hours after birth. The association between early-term birth and hypoglycaemia was evaluated using logistic regression analysis. The prevalence of severe hypoglycaemia and hypoglycaemia according to its timing of development was analysed using Fisher's exact test. RESULTS: In total, 295 neonates were included. Among them, 113 neonates (38.3%) were born at early term and 91 infants (30.8%) had hypoglycaemia. Logistic regression analysis showed a significant association between early-term birth and hypoglycaemia (adjusted odds ratio [95% confidence interval]:2.691 [1.597 to 4.535]). However, there was no significant between-group difference among those with severe hypoglycaemia. CONCLUSIONS: Among LGA neonates, early-term birth is positively associated with neonatal hypoglycaemia. This indicates that among LGA neonates, those born at early term require more careful observation for hypoglycaemia than do those born at later term. J. Med. Invest. 70 : 476-482, August, 2023.

Clorgyline inhibits orexin-A-induced arousal in layer-type chicks.

We previously demonstrated that intracerebroventricular (ICV) injection of orexin-A induces arousal and increased metabolic turnover rates of norepinephrine, dopamine, and serotonin in layer (egg-type) chicks. Because monoamine oxidase-A (MAO-A) is a potent degrading enzyme of these monoamines, we hypothesized that orexin-A may mediate its arousal-inducing effects through MAO-A. Therefore, we simultaneously injected clorgyline, a specific inhibitor of MAO-A, with orexin-A and examined behavior of chicks. Behaviors associated with arousal were attenuated in the group of chicks that received clorgyline and orexin-A compared with those that received orexin-A alone. For the monoamine turnover rate, enhancement of the turnover rate of serotonin by orexin-A was attenuated by clorgyline. Therefore, we conclude that orexin-A-induced arousal is dependent upon monoamine neural activities stimulated by MAO-A in chicks.

Norepinephrine does not alter NPY and POMC mRNA expression in neonatal chicks.

Norepinephrine (NE), synthesized in both the central and peripheral nervous system, is involved in food intake regulation of both mammals and chickens. Neuropeptide Y (NPY), a potent orexigenic peptide, is colocalized with NE neurons in the central and peripheral nervous system, suggesting an interaction. Proopiomelanocortin (POMC) is the precursor of alpha-melanocyte stimulating hormone, a potent anorexigenic peptide synthesized in the hypothalamus. In this study, two experiments were conducted to examine the effect of intracerebroventricular (ICV) injection of NE on appetite mediators in neonatal chicks (Gallus gallus). Experiment 1 was done to confirm the effect of centrally administered NE (0, 25, 50, and 100 microg) on food intake following a 3h fast, and to determine the change in NPY mRNA expression in the central nervous system (CNS). In Experiment 2, chicks fed ad libitum were treated ICV with NE (50 microg) to determine if changes occurred in brain NPY and POMC mRNA levels. In Experiment 1, the ICV injection of NE dose-dependently reduced food intake, but there was no change in NPY mRNA expression in the CNS. In Experiment 2, there was no significant change in NPY and POMC mRNA expression between the control and NE-treated group, indicating that ICV injection of NE may not be associated with changes in NPY or POMC gene expression.

[Marked effect of combination chemotherapy with tegafur-gimeracil-oteracil potassium and gemcitabine on a suspected case of pancreas cancer or gallbladder cancer metastasis to bone: further diagnosis of disseminated carcinomatosa of bone marrow recurrence after the 23 years of gastric cancer operation by autopsy findings].

A 70-year-old woman who underwent proximal gastrectomy for gastric cancer (poorly-differentiated adenocarcinoma) of Stage IIIB at age 46 visited our hospital April 2004 because of exacerbated pain by movement in the buttocks since November 2003. She showed multiple bone metastasis by CT (computerized tomography). Pancreas cancer or gallbladder cancer was suspected by CT, and a high tumor marker score (CA19-9 18,625 U/mL, DUPAN-II 15,000 U/ mL elevations were acknowledged). Although her symptoms were severe with performance status (PS) 4, she was administered combination chemotherapy with gemcitabine and cisplatin. After 2 cycle therapy, her PS was improved to 2, but the tumor markers had elevated. So we changed the chemotherapy menu to S-1 and gemcitabine. Her tumor markers lowered and PS was improved to 1. There was a remarkable response to this chemotherapy, and the result of CT and bone scintigraphy suggested that her bone metastasis was improved. Because of hematologic relapse due to DIC at 1 year after the first treatment, she was readmitted to our hospital and later died. The autopsical result revealed recurrence of gastric cancer 23 years post-operatively.

[ case of autoimmune pancreatitis with various extrapancreatic fibrosclerosis followed by malignant diseases].

We experienced a rare case of autoimmune pancreatitis with sclerosing cholangitis, retroperitoneal fibrosis and interstitial pneumonia. The patient was a 68-year old man and had abnormal liver function with jaundice. We performed endoscopic retrograde cholangiopancreatography (ERCP) and needle biopsy of the liver and pancreas. We obtained histological findings such as dense infiltration of plasma cells and lymphocytes and remarkable fibrosis and diagnosed AIP. The patient received treatment by prednisolone and thereafter developed bladder cancer and gastric cancer. He has been followed up for 4.5 years with no recurrence.

Striosome-based map of the mouse striatum that is conformable to both cortical afferent topography and uneven distributions of dopamine D1 and D2 receptor-expressing cells.

The striatum is critically involved in execution of appropriate behaviors, but its internal structures remain unmapped due to its unique structural organization, leading to ambiguity when interpreting heterogeneous properties of striatal neurons that differ by location. We focused on site-specific diversity of striosomes/matrix compartmentalization to draw the striatum map. Five types of striosomes were discriminated according to diverse immunoreactivities for the µ-opioid receptor, substance P (SP) and enkephalin, and each type occupied a particular domain inside the striatum. Furthermore, there was an additional domain lacking striosomes. This striosome-free space was located at the dorsolateral region and received afferents preferentially from the primary motor and sensory cortices, whereas the striosome-rich part received afferents from associational/limbic cortices, with topography inside both innervations. The proportion of dopamine D1 receptor-expressing, presumptive striatonigral neurons was approximately 70% in SP-positive striosomes, 40% in SP-deficient striosomes, 30% in the striosome-free space, and 50% in the matrix. In contrast, the proportion of D2 receptor-expressing, presumptive striatopallidal neurons was complementary to that of D1 receptor-expressing cells, indicating a close relationship between the map and the direct and indirect parallel circuitry. Finally, the most caudal part of the striatum lacked compartmentalization and consisted of three lamina characterized by intense and mutually exclusive immunoreactivities for SP and enkephalin. This tri-laminar part also received specific afferents from the cortex. The newly obtained map will facilitate broad fields of research in the basal ganglia with higher resolution of the three-dimensional anatomy of the striatum.

Intracerebroventricular injection of orexin-A stimulates monoamine metabolism but not HPA axis in neonatal chicks.

We investigated the effects of intracerebroventricular (ICV) injection of orexin-A on plasma corticosterone (CORT) concentration and brain monoamine metabolism to clarify the mechanism by which ICV orexin-A induced arousal in chicks. In Experiment 1, plasma CORT concentrations were measured as an indicator of hypothalamic-pituitary-adrenal (HPA) axis activity. There was no significant difference in CORT concentration between the control and orexin-A administered groups. In Experiment 2, the concentrations of monoamines (norepinephrine, dopamine and serotonin), their metabolites, and their metabolic turnover rates in the telencephalon, mesencephalon, and diencephalon were investigated. All metabolic turnover rates studied were increased at all brain sites after ICV orexin-A injection. In conclusion, the HPA axis does not appear to be involved in arousal-inducing mechanisms of orexin-A in neonatal chicks; however, several monoaminergic systems do.