Abstract Study question Are there genetic mutations which may lead to recurrent failures of assisted reproductive technology? Summary answer In this study, some genes were found to be candidates for causing repeated ART failures. What is known already Although reproductive aging is one of the greatest hindrances to successful pregnancy, many patients remain infertile, enduring recurrent ART failures, and approximately 20% of infertility is idiopathic. At present, the mutation of 8 genes, PADI6, NLRP2, TLE6, NLRP5, BTG4, KHDC3L, REC114 and OOEP has been reported to cause early embryonic arrest, while the mutation of PATL2 with GV stage arrest; TUBB8 and TRIP13 with failure of polar body extrusion; PANX1 with oocyte death; ZP1, ZP2, ZP3 with empty follicle syndrome; WEE2, TLE6 and CDC20 with fertilization failure have been found. Study design, size, duration Between January and October 2021, at Hanabusa Women’s Clinic, 25 infertile women, who experienced IVF / ICSI failure more than 5 times, with blastocyst formation rates of less than 10%, were recruited, after informed consent was obtained. 10 staff members of Hanabusa Women’s Clinic who conceived and delivered naturally were compared as normal controls. Participants/materials, setting, methods Genomic DNA was extracted from whole blood and genomic DNA samples were subjected to whole exome sequencing. High impact variants with allele frequencies of ≦0.20 in the 1000 Genome EAS, which were not found in the control subjects, were selected. Data from the Human Genetic Variation Database (HGVD) was used for the Hardy-Weinberg equation (HWE) to evaluate possible candidates for recurrent ART failures caused by genetic mutations. Main results and the role of chance High impact homozygous variants were detected in 57 genes among the study subjects of infertile women, but not among the control subjects. Among these 57 genes, significant differences in the allele frequencies between 8.3KJPN and the patients were detected in ADAM33 (p = 0.009), CEP89 (p = 0.012), CRIPAK (p < 0.001), LGALS9B (p < 0.001), PDZRN3 (p = 0.001), RAET1E (p = 0.007) and SPATA31A3 (p = 0.045). The HWE of each gene was calculated based on the data from HGVD. Among the 57 genes mentioned above, significantly lower HWE was detected in patients as compared to the HGVD in ADAM33 (p < 0.001), CEP89 (p = 0.033), MICA (p < 0.001), OR2T29 (p = 0.003), OR52J3 (p = 0.0497), RABL2A (p < 0.001), RNF17 (p = 0.0499), SPATA31C1 (p = 0.030) and WWTR1 (p < 0.001). Having identified one of the piRNA pathway genes, RNF17, which had significantly reduced HWE, the localization of RNF17 in the primordial follicle was examined. Immunofluorescent staining showed that RNF17 was sporadically localized in the cytoplasm of primordial follicles. Limitations, reasons for caution The sample size of this study was relatively small, and precise information such as age, gender in the database used in this study did not match that of the study patients, thus, the interpretation of the results is limited and further research is required to confirm our findings. Wider implications of the findings Among abovementioned genes, one of the piRNA pathway genes, RNF17, and one of the Hippo signal pathway genes, WWER1, were the most likely causes of repeated ART failures. The findings may provide potential diagnostic markers for patients with recurrent ART failures, helping us understand the genetic basis of female infertility. Trial registration number Not applicable
The effects of maternal exercise on pregnant women and fetal well-being are largely unknown. Forty-eight pregnant women between 16 and 39 weeks' gestation were exercised on a bicycle ergometer. We studied the oxygen consumption, blood pressure, maternal and fetal heart rate (FHR) at rest, during and after the exercise. The mean maternal heart rate and blood pressure were increased to 166.1 +/- 12.2/min (mean +/- S.D., n = 48) and 161.1 +/- 20.1/82.7 +/- 15.2 mmHg, respectively, at maximal exercise. The absolute oxygen consumption (1/min) was increased with advancing pregnancy at rest and maximal exercise, but the functional oxygen consumption (ml/kg/min) was not changed during pregnancy. The mean FHR was increased about 4 and 9 bpm in the 2nd and 3rd trimesters, respectively. Abnormal FHR patterns after the exercise were observed in 8 cases (16.7%), mild tachycardia: 6 cases, deceleration: 2 cases. Increasing the maternal heart rate at maximal exercise, increased the frequency of the abnormal FHR pattern. When the maternal heart rate was below 160/min, there was no abnormal FHR pattern. These results suggest that several medical checks should be done not only for the mother but also for her fetus during exercise and the maternal heart rate should not exceed 160/min.
Combined chemotherapy with cisplatin was performed in patients with advanced esophageal cancer. Two types of administration schedule were used: method I (three-drug combination of cisplatin, bleomycin and methotrexate) and method II (combination of cisplatin, peplomycin and methotrexate). Of 16 cases, 6 (37.5%) showed partial remission. With regard to the method of administration, the response rate for method I was 33%, and that for method II was 43%. Nausea (84%), vomiting (56%), loss of appetite (94%), malaise (75%) and alopecia (25%) were observed as side effects. Nausea and vomiting were ameliorated by use of metoclopramide. In bloodchemistry, anemia (87%), leukopenia (56%), thrombopenia (31%) and increase of BUN (63%) were observed. However, these changes were ameliorated by hydration or blood transfusion. Combined chemotherapy with CDDP should be a more useful future treatment for esophageal cancer.
Effects of i.v. bolus administration of verapamil (10-300 micrograms/kg) and nitroglycerin (0.01-30 micrograms/kg) on coronary and systemic hemodynamics were studied in chronically instrumented conscious dogs. Verapamil in a dose of 10 micrograms/kg dilated the large epicardial coronary artery, increased the coronary blood flow and heart rate and decreased the aortic pressure. A reduction of left ventricular dP/dt was observed when over 30 micrograms/kg of verapamil was administered. Nitroglycerin in a dose of 0.01 micrograms/kg dilated the large epicardial coronary artery. Other variables such as coronary blood flow, aortic pressure and heart rate were influenced when over 0.1 micrograms/kg of nitroglycerin was given. The effects of these drugs on coronary and systemic hemodynamics were augmented when incremental doses were given. Duration of the increases in coronary diameter and coronary blood flow persisted longer after verapamil than after nitroglycerin. To estimate the changes in coronary diameter, independent of flow change, the effects of verapamil (100 micrograms/kg) and nitroglycerin (20 micrograms/kg) on the large epicardial coronary artery were reexamined when the coronary blood flow was maintained constant using a cuff occluder. The extent of coronary artery dilation, unaffected by coronary blood flow, was 62% with verapamil and 100% with nitroglycerin. Thus, although nitroglycerin preferentially and flow-independently dilates the large epicardial coronary artery, dilation of the large epicardial coronary artery after verapamil is augmented by the process of flow-induced arterial relaxation.
