Follicle inhibition at the primordial stage without increasing apoptosis, with a combination of everolimus, verapamil.

The aim of the present study was to test whether inhibition of ovarian primordial follicles and subsequent activation can be achieved by transient mTOR inhibition. In this preclinical investigation, forty-five female immature Wistar rats were randomized in 5 groups. The control group received subcutaneous saline injections. The other groups received Everolimus, Everolimus plus Verapamil, Everolimus plus Fisetin, and Fisetin alone. Primary and secondary outcomes were measured in the left ovary after a treatment period of 8 weeks. Ten days later, animals received 35 IU FSH for 4 days and 35 IU of hCG on the 5th day. The same parameters were examined in the right ovary. AMH, estradiol, and progesterone levels were assessed at the end of both interventions. Significantly, more primordial and less atretic follicles were observed in the Everolimus plus Verapamil group. AMH and progesterone levels were substantially lower in the Everolimus group. Interestingly, after ovarian stimulation higher levels of AMH and progesterone were observed in the Everolimus plus Verapamil group. Immunoblot analysis of ovarian extracts revealed that the administration of Everolimus led to a significant reduction in the mTORC1-mediated phosphorylation of the 70-kDa ribosomal protein S6 kinase 1. This decrease was reversed in the presence of FSH after stopping drug administration. The expression of the anti-apoptotic molecule Bcl2 as well as of LC3-II and ATG12 was increased after removal of the Everolimus plus Verapamil combination, indicating reduced apoptosis and increased autophagy, whereas the levels of the proliferation marker PCNA in the granulosa cells were elevated, consistent with initiation of follicular growth.Thus, the combination of Everolimus plus Verapamil is capable of increasing the number of competent primordial follicles while reducing atresia.

Caplacizumab in pediatric immune thrombotic thrombocytopenic purpura: the UK TTP Registry experience.

ABSTRACT: Pediatric thrombotic thrombocytopenic purpura (TTP) is an ultrarare disease. Immune TTP (iTTP) is driven by anti-ADAMTS13 autoantibodies causing an imbalanced von Willebrand factor (VWF):ADAMTS13 axis, and rarer still in children, but potentially life-threatening. Caplacizumab is licensed for iTTP treatment in adults and adolescents aged ≥12 years who weigh ≥40 kg. There is a need to clarify whether caplacizumab can be used in younger children. We retrospectively described caplacizumab use in 16 patients under 18 years of age from the UK TTP Registry, including 4 children aged <12 years. For patients weighing <40 kg (n = 3), caplacizumab was dosed at 5 mg once dailyThe youngest patient was 33 months old at diagnosis. Plasma exchange (PEX) was used in 15 patients, with a median of 5 exchanges required before platelet count normalization (range, 2-9). One patient was managed without PEX. All patients achieved normalization of platelet count (median, 5.5 days; range, 3-28) and ADAMTS13 activity (median, 35 days; range, 8-149), with a median hospital admission of 11 days (range, 5-26). There were no refractory patients. One patient relapsed 9 months after presentation. Bleeding requiring VWF supplementation and reduction of caplacizumab use occurred in 1 patient with severe epistaxis, with no significant intracranial or gastrointestinal bleeding. We demonstrated the efficacy and safety of caplacizumab in the pediatric population, which is synonymous with the adult trial data: primarily, reduction of PEX compared with the precaplacizumab era. This has implications for the intensification and duration of admission, particularly relevant in pediatric care.

Inguinal endometriosis: A systematic review.

Inguinal endometriosis is a very rare entity with uncertain pathophysiology, that poses several diagnostic and therapeutic challenges. This study aimed to summarize published literature on the diagnosis and treatment of this condition. Thus, a systematic literature search was conducted in PubMed/MEDLINE, Scopus and the Cochrane Library. An effort was made to numerically analyze all parameters included in case reports and retrospective analyses, as well. The typical and atypical features of this condition, investigations used, type of treatment and histopathology were recorded. More specifications about the surgical treatment, such as operations previously performed, type of surgery and treatment after surgery have been acknowledged. Other sites of endometriosis, the presence of pelvic endometriosis and the follow-up and recurrence have been also documented. Overall, the search yielded 61 eligible studies including 133 cases of inguinal endometriosis. The typical clinical presentation includes a unilateral inguinal mass, with or without catamenial pain. Transabdominal or transvaginal ultrasound was typically used as the first line method of diagnosis. Groin incision and exploratory surgery was the treatment indicated by the majority of the authors, while excision of part of the round ligament was reported in about half of the cases. Chemotherapy and radiotherapy were initiated in cases of coexisting endometriosis-related neoplasia. Inguinal recurrence or malignant transformation was rarely reported. The treatment of inguinal endometriosis is surgical and a long-term follow-up is needed. More research is needed on the effectiveness of suppressive hormonal therapy, recurrence rate and its relationship with endometriosis-associated malignancies.

Pathways Involved in Premature Ovarian Failure: A Systematic Review of Experimental Studies.

Premature ovarian failure (POF), which may be undetectable for a long time, is associated with impaired fertility. The mechanisms involved in the pathogenesis of POF as well as the concomitant treatments are still unclear. Although many data exist, mainly produced by the study of transgenic animals under various experimental conditions, they remain fragmented. A systematic review of the pathways involved in premature ovarian failure was conducted. Data extraction was performed from experimental studies until 2019. The molecular processes and their correlation with the follicular developmental stage have been described. Furthermore, the effects in other cells, such as oocytes, granulosa and theca cells have been reported. An overall estimation was conducted.