Mayer-Rokitansky-Küster-Hauser syndrome patients' interest, expectations and demands concerning uterus transplantation.

OBJECTIVE: To better understand patients' conditions and expectations before starting a uterus transplantation (UTx) program for women suffering from Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome). METHOD: A web-based survey was conducted among MRKH patients via the French national association network from March to August 2020. The questionnaire comprised twenty-eight questions about their desire for parenthood, their condition's characteristics and previous reconstructive procedures, opinions and knowledge about UTx. RESULTS: Among the 148 participants, 88 % reported a desire for parenthood, and 61 % opted for UTx as their first choice to reach this aim. The possibility of bearing a child and having the same genetic heritage were the main motivations. Once informed about the usual course of an UTx protocol, only 13 % of the participants changed their mind and 3 out of 4 of them opted for UT. CONCLUSION: Uterus transplantation seems to be the first option to reach motherhood in patients suffering from MRKH syndrome. The development of UTx programs could meet the demands of this already well-informed population.

Paget's disease of the vulva: A challenge for the gynaecologist.

Paget's disease of the vulva is a rare form of extramammary Paget's disease mainly affecting postmenopausal women. Its pathophysiology remains largely unknown. Up to fairly recently, the only treatment for this disease was surgery, often mutilating the vulva, with significant psychosexual repercussions without the assurance of complete therapeutic efficacy. New therapeutic approaches -topical treatments, radiotherapy or chemotherapy- have emerged in recent years but lack consensual guidelines. We present a literature review of the recent results published in this field.

Vulvar intraepithelial neoplasia: Classification, epidemiology, diagnosis, and management.

Vulvar intraepithelial neoplasia (VIN) is classified into two entities: differentiated (dVIN) and vulvar high-grade squamous intraepithelial lesions (vH-SIL). dVIN is a premalignant lesion that develops on an existing vulvar lesion such as lichen sclerosus, while vH-SIL is associated with HPV infection. The two entities differ in terms of pathophysiology, background, prognosis, and management. The incidence of VIN in young women is rising and recurrence is common, even after radical surgery, which can cause significant disfigurement. Alternative strategies include topical treatments, ablation, and a watch-and-wait approach. There is currently no consensus on how these lesions should be managed. We review the literature in this field.

Inhibition of VRAC by c-Src tyrosine kinase targeted to caveolae is mediated by the Src homology domains.

We used the whole cell patch-clamp technique in calf pulmonary endothelial (CPAE) cells to investigate the effect of wild-type and mutant c-Src tyrosine kinase on I(Cl,swell), the swelling-induced Cl- current through volume-regulated anion channels (VRAC). Transient transfection of wild-type c-Src in CPAE cells did not significantly affect I(Cl,swell). However, transfection of c-Src with a Ser3Cys mutation that introduces a dual acylation signal and targets c-Src to lipid rafts and caveolae strongly repressed hypotonicity-induced I(Cl,swell) in CPAE cells. Kinase activity was dispensable for the inhibition of I(Cl,swell), since kinase-deficient c-Src Ser3Cys either with an inactivating point mutation in the kinase domain or with the entire kinase domain deleted still suppressed VRAC activity. Again, the Ser3Cys mutation was required to obtain maximal inhibition by the kinase-deleted c-Src. In contrast, the inhibitory effect was completely lost when the Src homology domains 2 and 3 were deleted in c-Src. We therefore conclude that c-Src-mediated inhibition of VRAC requires compartmentalization of c-Src to caveolae and that the Src homology domains 2 and/or 3 are necessary and sufficient for inhibition.

Cellular function and control of volume-regulated anion channels.

Restoration of cell volume after cell swelling in mammalian cells is achieved by the loss of solutes (K+, Cl-, and organic osmolytes) and the subsequent osmotically driven efflux of water. This process is generally known as regulatory volume decrease (RVD). One pathway for the swelling induced loss of Cl- (and also organic osmolytes) during RVD is the volume-regulated anion channel (VRAC). In this review, we discuss the physiological role and cellular control of VRAC. We will first highlight evidence that VRAC is more than a volume regulator and that it participates in other fundamental cellular processes such as cell proliferation and apoptosis. The second part concentrates on the Rho/Rho kinase/myosin phosphorylation cascade and on compartmentalization in caveolae as modulators of the signal transduction cascade that controls VRAC gating in vascular endothelial cells.

Myosin light chain phosphorylation-dependent modulation of volume-regulated anion channels in macrovascular endothelium.

The Rho/Rho-associated kinase (ROK) pathway has been shown to modulate volume-regulated anion channels (VRAC) in cultured calf pulmonary artery endothelial (CPAE) cells. Since Rho/ROK can increase myosin light chain phosphorylation, we have now studied the effects of inhibitors of myosin light chain kinase (MLCK) or myosin light chain phosphatase (MLCP) on VRAC in CPAE. Application of ML-9, an MLCK inhibitor, inhibited VRAC, both when applied extracellularly or when dialyzed into the cell. A similar inhibitory effect was obtained by dialyzing the cells with AV25, a specific MLCK inhibitory peptide. Conversely, NIPP1(191-210), an MLCP inhibitory peptide, potentiated the activation of VRAC by a 25% hypotonic stimulus. These data indicate that activation of VRAC is modulated by MLC phosphorylation.