No abstract

Polycystic ovary syndrome, characterized by hyperandrogenism and chronic anovulation, is frequently associated with insulin resistance. Ample evidence implicates a role for insulin in the genesis of ovarian hyperandrogenism. The objective of this study was to begin to define the intracellular signaling pathway(s) that mediates insulin regulation of 17alpha-hydroxylase activity in human ovarian theca cells. Third-passage theca cells, isolated from the ovaries of regularly cycling premenopausal women, were used. Insulin alone had no effect on 17alpha-hydroxylase activity or CYP17 mRNA expression but required costimulation with forskolin. At the insulin concentration used (10 ng/ml), a neutralizing antibody to the insulin receptor (but not an antibody to the type I IGF receptor) blocked the insulin stimulation of 17alpha-hydroxylase activity, demonstrating that the effects were mediated by the insulin receptor. Insulin stimulated both phosphatidylinositol-3-kinase (PI3-kinase) and extracellular signal-regulated kinase-1/2 (MAPK) pathways. Specific inhibition of MAPK kinase (MEK) with PD98059 or I0126 did not decrease the 17alpha-hydroxylase activity stimulated by forskolin or forskolin plus insulin. In contrast, the PI3-kinase inhibitor LY294002 completely blocked insulin-stimulated 17alpha-hydroxylase activity. Our data demonstrate that insulin stimulates PI3-kinase and extracellular signal-regulated kinase-1/2 activities in human theca cells, but only PI3-kinase mediates the insulin augmentation of forskolin-stimulated 17alpha-hydroxylase activity.

No abstract

ClinicalTrials.gov, NCT01760954 and NCT02143713.

Background Natural orifice translumenal endoscopic surgery (NOTES) has moved quickly from preclinical investigation to clinical implementation. However, several major technical problems limit clinical NOTES including safe access, retraction and dissection of the gallbladder, and clipping of key structures. This study aimed to identify challenges and develop solutions for NOTES during the initial clinical experience. Methods Under an Institutional Review Board (IRB)-approved protocol, patients consented to a natural orifice operation for removal of either the gallbladder or the appendix via either the vagina or the stomach using a single umbilical trocar for safety and assistance. Results Nine transvaginal cholecystectomies, one transgastric appendectomy, and one transvaginal appendectomy have been completed to date. All but one patient were discharged on postoperative day 1 as per protocol. No complications occurred. ConclusionThe limited initial evidence from this study demonstrates that NOTES is feasible and safe. The addition of an umbilical trocar is a bridge allowing safe performance of NOTES procedures until better instruments become available. The addition of a flexible long grasper through the vagina and a flexible operating platform through the stomach has enabled the performance of NOTES in a safe and easily reproducible manner. The use of a uterine manipulator has facilitated visualization of the cul de sac in women with a uterus to allow for safe transvaginal access.

Endometriosis may exert a profound negative influence on the lives of individuals with the disorder, adversely affecting quality of life, participation in daily and social activities, physical and sexual functioning, relationships, educational and work productivity, mental health, and well-being. Over the course of a lifetime, these daily challenges may translate into limitations in achieving life goals such as pursuing or completing educational opportunities; making career choices or advancing in a chosen career; forming stable, fulfilling relationships; or starting a family, all of which ultimately alter one's life trajectory. The potential for endometriosis to impact the life course is considerable, as symptom onset generally occurs at a time of life (menarche through menopause, adolescence through middle age) when multiple life-changing and trajectory-defining decisions are made. Using a lifecourse approach, we examine how the known effects of endometriosis on life-domain satisfaction may impact health and well-being across the life course of affected individuals. We provide a quasi-systematic, narrative review of the literature as well as expert opinion on recommendations for clinical management and future research directions.

The responses of single‐channel currents to capsaicin were recorded using the giga‐seal patch‐clamp technique in cell‐attached and excised (inside‐out/outside‐out) patches from embryonic rat dorsal root ganglion (DRG) neurones in culture and in Xenopus oocytes heterologously expressing the rat vanilloid receptor (rVR1). Native and cloned vanilloid receptor (VR)‐mediated currents exhibited outward rectification. In both the DRG neurones and oocytes expressing VR1, the chord conductances at −60 and +60 mV were ≈50 and ≈100 pS, respectively. At positive potentials, the channel exhibited a single conductance state. In contrast, at negative potentials, brief sojourns to subconductance states were apparent. The probability of the channel being open (Po) was dependent on the transmembrane voltage and the patch configuration (i.e. cell‐attached vs. excised). In both DRG neurones and oocytes, the Po was greater at positive (+60 mV) than at negative (‐60 mV) potentials. In cell‐attached patches, the Po was approximately twofold higher, regardless of the applied potential. Most likely, the outward rectification observed in whole‐cell currents is due to the voltage dependence of single‐channel conductance and Po. The open‐time distributions of single‐channel currents recorded from native and cloned VRs in the presence of low agonist concentrations (0.01‐0.03 μm) were best fitted with three exponential components. The closed‐time distributions were best fitted by five exponential components. At higher concentrations (0.5‐1 μm), an additional component was required to fit the open‐time distribution, and the number of exponential components needed to fit the closed‐time distributions was reduced to two. The overall mean open time at +60 mV was ≈4 ms, compared to ≈1.2 ms at −60 mV. However, the overall mean closed time was not voltage dependent. There were no significant differences between the native and cloned receptors. A comparison of single‐channel properties of native and heterologously expressed VR channels indicates that expression of the rVR1 subunit alone can account for the single‐channel behaviour of the majority of the native VRs. These results suggest that either native VRs are made up of VR1 subunits, or the incorporation of subunits other than VR1 does not influence the functional properties.

Plasma BDNF is a potentially useful clinical marker of endometriosis that is superior to NGF, NT4/5, CA-125, and CRP.