Donor Mesenchymal Stem Cells Program Bone Marrow, Altering Macrophages, and Suppressing Endometriosis in Mice.

Endometriosis is a chronic inflammatory gynecological disorder regulated by estrogen and characterized by the growth of endometrial tissue outside the uterus. We have previously demonstrated that mesenchymal stem cells (MSCs) contribute directly to endometriosis. Here, we investigated an indirect effect; we hypothesized that MSCs may also impact the bone marrow (BM) by regulating bone marrow-derived inflammatory cells. Endometriosis was induced in mice by transplanting uterine tissue into recipient mice followed by BM transplant. Control or MSC conditioned BM was injected retro-orbitally. Direct administration of MSCs outside of the setting of BM conditioning did not alter endometriosis. Coculture of an undifferentiated macrophage cell line with MSCs in vitro led to a reduction of M1 and increased M2 macrophages as determined by fluorescence-activated cell sorting and western blot. Conditioning of BM with MSCs and transplantation into a mouse model inhibited endometriotic lesion development and reduced lesion volume by sevenfold compared to BM transplant without MSCs conditioning. Immunohistochemistry and immunofluorescence showed that MSC conditioned BM reduced the infiltration of macrophages and neutrophils into endometriotic lesions by twofold and decreased the proportion of M1 compared to M2 macrophages, reducing inflammation and likely promoting tissue repair. Expression of several inflammatory markers measured by quantitative real-time polymerase chain reaction, including tumor necrosis factor alpha and CXCR4, was decreased in the conditioned BM. Donor MSCs were not detected in recipient BM or endometriotic lesions, suggesting that MSCs actively program the transplanted BM. Taken together, these data show that individual characteristics of BM have an unexpected role in the development of endometriosis. BM remodeling and alterations in the inflammatory response are also potential treatments for endometriosis. Identification of the molecular basis for BM programing by MSCs will lead to a better understanding of the immune system contribution to this disease and may lead to new therapeutic targets for endometriosis.

Uterine administration of C-X-C motif chemokine ligand 12 increases the pregnancy rates in mice with induced endometriosis.

OBJECTIVE: To study the effect of intrauterine injection of C-X-C motif chemokine ligand 12 (CXCL12), also known as a stem cell chemoattractant (stromal cell-derived factor 1), on fertility and endometrial receptivity in mice with endometriosis. DESIGN: Laboratory study. SETTING: Academic Medical Center. ANIMAL(S): Fifty-six mice underwent chemotherapy and bone marrow transplantation. Thirty-six of these mice underwent either surgery to induce endometriosis (n = 20) or sham surgery (n = 16). INTERVENTION(S): Injection of CXCL12 as a potential therapeutic agent to improve fertility in endometriosis. MAIN OUTCOME MEASURE(S): Pregnancy rate, bone marrow-derived cell (BMDC) recruitment and endometrial receptivity markers. RESULT(S): The mice with or without endometriosis received a single uterine injection of either CXCL12 or placebo. Uterine injection of CXCL12 increased the pregnancy rates in a mouse model of endometriosis. Mice were euthanized after delivery, and implantation markers homeobox A11, alpha-v beta-3 integrin, and progesterone receptor were analyzed by immunohistochemistry, whereas green fluorescent protein positive BMDC recruitment was quantified by immunohistochemistry and immunofluorescence. The sham surgery groups without endometriosis had the highest cumulative pregnancy rate (100%) regardless of CXCL12 treatment. The endometriosis group treated with placebo had the lowest pregnancy rate. An increased pregnancy rate was noted in the endometriosis group after treatment with CXCL12. There was also an increase in BMDC recruitment and endometrial expression of progesterone receptor and alpha-v beta-3 integrin in the endometriosis group that received CXCL12 compared with that in the endometriosis group that received placebo. CONCLUSION(S): Uterine injection of CXCL12 increased the pregnancy rates in a mouse model of endometriosis. These results suggest that CXCL12 has a potential role as a therapeutic agent in women with infertility related to endometriosis and potentially other endometrial receptivity defects.

Estimation of Excess Deaths Associated With the COVID-19 Pandemic in Istanbul, Turkey.

Background and Objectives: The official number of daily cases and deaths are the most prominent indicators used to plan actions against the COVID-19 pandemic but are insufficient to see the real impact. Official numbers vary due to testing policy, reporting methods, etc. Therefore, critical interventions are likely to lose their effectiveness and better-standardized indicators like excess deaths/mortality are needed. In this study, excess deaths in Istanbul were examined and a web-based monitor was developed. Methods: Daily all-cause deaths data between January 1, 2015- November 11, 2021 in Istanbul is used to estimate the excess deaths. Compared to the pre-pandemic period, the % increase in the number of deaths was calculated as the ratio of excess deaths to expected deaths (P-Scores). The ratio of excess deaths to official figures (T) was also examined. Results: The total number of official and excess deaths in Istanbul are 24.218 and 37.514, respectively. The ratio of excess deaths to official deaths is 1.55. During the first three death waves, maximum P-Scores were 71.8, 129.0, and 116.3% respectively. Conclusion: Excess mortality in Istanbul is close to the peak scores in Europe. 38.47% of total excess deaths could be considered as underreported or indirect deaths. To re-optimize the non-pharmaceutical interventions there is a need to monitor the real impact beyond the official figures. In this study, such a monitoring tool was created for Istanbul. The excess deaths are more reliable than official figures and it can be used as a gold standard to estimate the impact more precisely.

In vitro fertilization and preimplantation genetic diagnosis outcomes in mosaic Turner's syndrome: A retrospective cohort study from a single referral center experience.

BACKGROUND: Patients with mosaic Turner syndrome who have normal phenotype and pubertal development may be diagnosed based on karyotype examination which is performed due to recurrent abortion or recurrent implantation failure; but according to the literature review, reproductive and obstetric consequences of these cases are based on case reports. There are contradictory publications on this subject recommending pre-implantation genetic testing (PGT) may be a solution to reduce the high risk for the fetus and perform normal embryo transfer. AIM: In this study, our aim was to evaluate the results of in vitro fertilization and preimplantation genetic diagnosis in patients with low-grade and high-grade mosaic Turner syndrome. METHODS: We collected data of patients between 2012 and 2018 from a single center retrospectively. The study analyzed 36 mosaic Turner syndrome patients, of whom, 10 patients were evaluated as high, 26 patients were evaluated as low-grade mosaic pattern for Turner syndrome. RESULTS: Mean age (35,46±0,87 vs. 36,2 ± 1,85) body mass index (25,26±0,74 vs. 30,8 ± 0,63) baseline follicle stimulating hormone (5,73±0,74 vs. 6,70±1,17) basal luteinizing hormone (4,78±0,43 vs. 4,92±0,99) were similar between two groups. In the high-grade mosaic Turner Syndrome patients, duration of stimulation (7,60±0,16 vs. 8,0 ± 0,28, p<0,001), total gonadotrophin dose (1540,0 ± 165,12 vs. 2046,15± 111,47, p<0,001) and the number of normal karyotype embryos was statistically significantly higher (1,58±0,17 vs. 2,00±0,55, p<0,001). The Pregnancy rates in the low-grade and high-grade mosaic Turner syndrome patients' cycles were 30,8% versus 30%, (p = 0.76) respectively. IVF results were also evaluated by the presence of triploidy were accompanying Turner syndrome or not. In the presence of one or 2 X chromosomes, none of the included in the study could achieve live birth. The most common abnormality in the embryos was monosomy and trisomy of the chromosome13. In 30% of the cases, there were 2 or 3 abnormalities present together. In embryos with 2 abnormal chromosomes, the most common 2 abnormalities were monosomy 13 and trisomy 21, while trisomy 13, trisomy X and monosomy 18 were found in 3 or more abnormalities, respectively. CONCLUSION: In vitro fertilization and Preimplantation genetic diagnose should be considered in the infertility treatment of the patient with mosaic Turner Syndrome.

Nowcasting and Forecasting the Spread of COVID-19 and Healthcare Demand in Turkey, a Modeling Study.

Background: This study aims to estimate the total number of infected people, evaluate the effects of NPIs on the healthcare system, and predict the expected number of cases, deaths, hospitalizations due to COVID-19 in Turkey. Methods: This study was carried out according to three dimensions. In the first, the actual number of infected people was estimated. In the second, the expected total numbers of infected people, deaths, hospitalizations have been predicted in the case of no intervention. In the third, the distribution of the expected number of infected people and deaths, and ICU and non-ICU bed needs over time has been predicted via a SEIR-based simulator (TURKSAS) in four scenarios. Results: According to the number of deaths, the estimated number of infected people in Turkey on March 21 was 123,030. In the case of no intervention the expected number of infected people is 72,091,595 and deaths is 445,956, the attack rate is 88.1%, and the mortality ratio is 0.54%. The ICU bed capacity in Turkey is expected to be exceeded by 4.4-fold and non-ICU bed capacity by 3.21-fold. In the second and third scenarios compliance with NPIs makes a difference of 94,303 expected deaths. In both scenarios, the predicted peak value of occupied ICU and non-ICU beds remains below Turkey's capacity. Discussion: Predictions show that around 16 million people can be prevented from being infected and 94,000 deaths can be prevented by full compliance with the measures taken. Modeling epidemics and establishing decision support systems is an important requirement.