Analysis of the relationship between age-related erythrocyte dysfunction and fatigue.

With the declining birth rates and aging societies in developed countries, the average age of the working population is increasing. Older people tend to get tired more easily, so prevention of fatigue is important to improve the quality of life for older workers. This study aimed to assess the mechanism of fatigue in older people, especially focused on relation between dysfunction of erythrocyte and fatigue. Total power (TP), which is the value of autonomic nerve activity, was measured as a value of fatigue and significantly decreased in workers with aging. As properties of senescent erythrocytes, the erythrocyte sedimentation rate and damaged erythrocytes population increased with aging and correlated with TP. These results suggested that the accumulation of damaged erythrocytes contributes to fatigue. Recent studies revealed that senescence-associated secretory phenotype (SASP), a phenomenon in which senescent cells secrete a variety of cytokines, affected hematopoiesis in bone marrow. We analyzed the effects of SASP factors on erythropoiesis and found that Interleukin -1α (IL-1α) suppressed erythrocyte differentiation of hematopoietic stem cells in vitro. We also showed that IL-1α levels in human blood and saliva increase with aging, suggesting the possibility that IL-1α level in saliva can be used to predict the decline in hematopoietic function.

Guideline for gynecological practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2023 edition.

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Applicability of the FDA-approved Immunohistochemical Panel for Identification of MMRd Phenotype in Uterine Endometrioid Carcinoma.

Recently, the US Food and Drug Administration (FDA) approved the Ventana MMR RxDx Panel as the first immunohistochemical companion diagnostic test for identification of tumors with mismatch repair (MMR) status. The aim of this study was to investigate the accuracy of this test in comparison with polymerase chain reaction (PCR)-based microsatellite instability (MSI) analysis. We assessed the MMR/MSI concordance rate in 140 cases of endometrioid carcinoma. MMR status was evaluated by immunohistochemistry (MMR-IHC), and MSI status was evaluated by PCR-based analysis (MSI-PCR). Potential molecular mechanisms responsible for MSH6 staining variations were also analyzed. Immunohistochemistry showed that 34 tumors (24.3%) were MMRd; these included 26 with combined MLH1/PMS2 loss, 2 with combined MSH2/MSH6 loss, and 6 with isolated MSH6 loss. Heterogeneous MSH6 loss was found in 10 tumors and was recognized only in tumors with combined MLH1/PMS2 loss. Eight of 10 tumors with heterogeneous MSH6 loss harbored MSH6 C8 tract instability, suggesting a secondary somatic event after MLH1/PMS2 loss. MSI-PCR revealed that 102 tumors were MSS, 4 were MSI-low, and 34 were MSI-high. Consequently, MMR-IHC and MSI-PCR showed perfect concordance (kappa=0.080, P <0.0001). However, 10 of the 34 MSI-high tumors, including the 6 tumors with isolated MSH6 loss, showed only minimal microsatellite shift by MSI-PCR, which may have been erroneously interpreted as MSS or MSI-low. On the basis of these findings, we consider that the FDA-approved immunohistochemical panel can detect MMR variations consistently and is more accurate than MSI-PCR for determining the applicability of immune checkpoint inhibitors for treatment of endometrioid carcinomas.

Effects of Intraoperative Opioid Administration on Postoperative Pain and Pain Threshold: A Randomized Controlled Study.

Fentanyl and short-acting remifentanil are often used in combination. We evaluated the effect of intraoperative opioid administration on postoperative pain and pain thresholds when the two drugs were used. Patients who underwent gynecological laparoscopic surgery were randomly assigned into two groups (15 patients each) to receive either sufficient (group A) or minimum (group B) fentanyl (maximum estimated effect site concentration: A: 7.86 ng/mL, B: 1.5 ng/mL). The estimated effect site concentration at the end of surgery was adjusted to the same level (1 ng/mL). Patients in both groups also received continuous intravenous remifentanil during surgery. The primary outcome was the pressure pain threshold, as evaluated by a pressure algometer 3 h postoperatively. The pressure pain threshold at 3 h postoperatively was 51.1% (95% CI: [44.4-57.8]) in group A and 56.6% [49.5-63.6] in group B, assuming a preoperative value of 100% (p = 0.298). There were no significant differences in pressure pain threshold and numeric rating scale scores between the groups after surgery. The pain threshold decreased significantly in both groups at 3 h postoperatively compared to preoperative values, and recovered at 24 h. Co-administration of both opioids caused hyperalgesia regardless of fentanyl dose.

Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in women with hydatidiform mole.

OBJECTIVE: To show soluble fms-like tyrosine kinase 1 (sFlt1) levels in sera from patients with hydatidiform mole, which is known to predispose women to severe early-onset preeclampsia. DESIGN: Comparative study. SETTING: University hospital and surrounding community hospitals. PATIENT(S): Seven women with pathologically diagnosed complete hydatidiform mole (mole group), 21 gestational- and maternal-age-matched women who did not develop any pregnant complication during their pregnancy (control group), and eight women who subsequently developed preeclampsia (preclinical preeclampsia group). INTERVENTION(S): Blood samples were taken before and after evacuations of hydatidiform mole. MAIN OUTCOME MEASURE(S): Concentrations of sFlt1 and free placental growth factor (PlGF) in serum were measured by ELISA. RESULT(S): Serum sFlt1 concentrations were significantly higher in the mole group compared with the control group and the preclinical preeclampsia group. In contrast, serum free PlGF concentrations were significantly lower in the mole group. In the mole group, there was a significant negative correlation between sFlt1 and PlGF serum concentrations. After the evacuation of hydatidiform mole, the level of serum sFlt1 decreased dramatically. CONCLUSION(S): Elevated levels of sFlt1 were noted in molar gestations and may play in a role in early-onset preeclampsia reported in such pregnancies.

Dioxin may promote inflammation-related development of endometriosis.

Laboratory and population-based studies suggest that exposure to environmental toxicants may be one of several triggers for the development of endometriosis. We discuss evidence that modulation of the endometrial endocrine-immune interface could mechanistically link toxicant exposure to the development of this disease.

Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

OBJECTIVE: To analyze endometrial progesterone receptor (PR) expression in women with endometriosis compared with disease-free women and to assess the impact of in vitro 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on PR isotype expression. DESIGN: Controlled laboratory study. SETTING: University medical center. PATIENT(S): Healthy volunteers and women with surgically diagnosed endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Analysis of in vivo PR-A and PR-B expression in endometrium from women with and without endometriosis. The impact of in vitro TCDD exposure on PR-B/PR-A ratio and cell-specific matrix metalloproteinase (MMP) expression was also determined. RESULT(S): The PR-B/PR-A ratio was lower in endometrial tissues from women with endometriosis compared with normal tissues. A similar ratio was induced in normal stromal cells cocultured with epithelial cells and exposed to TCDD. Disruption of stromal PR expression following TCDD exposure was associated with a failure of P-mediated down-regulation of both stromal-specific pro-MMP-3 and epithelial-specific pro-MMP-7. CONCLUSION(S): Our data suggest that reduced progesterone (P) sensitivity in the endometrium of women with endometriosis may be related to an altered pattern of PR expression. The ability of TCDD to selectively down-regulate stromal PR-B expression and increase MMP expression in both stromal and epithelial cells suggests that exposure to this toxin may negatively impact P-mediated cell-cell communication in the human endometrium.

Progesterone action in the human endometrium: induction of a unique tissue environment which limits matrix metalloproteinase (MMP) expression.

The endometrium is a unique adult tissue which, in the absence of pregnancy or disease, undergoes cyclic breakdown and regrowth approximately 400 times during a woman's reproductive life. The chances of reproductive success during each cycle depends on appropriate, cell-specific responses to steroids, including expression of matrix metalloproteinases (MMPs). Normal endometrial MMP regulation in response to either estrogen or progesterone requires additional, cell-specific interactions mediated by various growth factors and cytokines. During endometrial maturation, progesterone, retinoic acid and TGF-beta act cooperatively, providing a remarkable biological balance to regulate expression of MMPs in the highly steroid-sensitive endometrium. Exploring the regulatory actions of locally produced growth factors and cytokines on members of the MMP family and their inhibitors will allow a better understanding of the unique physiology of the human endometrium under the influence of progesterone.