PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect.

Parkin functions as a multipurpose E3 ubiquitin ligase, and Parkin loss of function is associated with both sporadic and familial Parkinson's disease (PD). We report that the Bin/Amphiphysin/Rvs (BAR) domain of protein interacting with PRKCA1 (PICK1) bound to the really interesting new gene 1 (RING1) domain of Parkin and potently inhibited the E3 ligase activity of Parkin by disrupting its interaction with UbcH7. Parkin translocated to damaged mitochondria and led to their degradation in neurons, whereas PICK1 robustly inhibited this process. PICK1 also impaired the protective function of Parkin against stresses in SH-SY5Y cells and neurons. The protein levels of several Parkin substrates were reduced in young PICK1-knockout mice, and these mice were resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated toxicity. Taken together, the results indicate that PICK1 is a potent inhibitor of Parkin, and the reduction of PICK1 enhances the protective effect of Parkin.

Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

AIMS: Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood-brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects. METHODS AND RESULTS: Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9. CONCLUSION: A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.

Endothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation.

Endothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress- or cofilin activation-driven cofilin rod formation. Here, we demonstrate that exposure to 100 nm ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nm IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 µm VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nm FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.

Exchange protein directly activated by cAMP (Epac) 1 plays an essential role in stress-induced exercise capacity by regulating PGC-1α and fatty acid metabolism in skeletal muscle.

Exchange protein directly activated by cAMP (Epac) mediates cAMP-mediated cell signal independent of protein kinase A (PKA). Mice lacking Epac1 displayed metabolic defect suggesting possible functional involvement of skeletal muscle and exercise capacity. Epac1 was highly expressed, but not Epac 2, in the extensor digitorum longus (EDL) and soleus muscles. The exercise significantly increased protein expression of Epac 1 in EDL and soleus muscle of wild-type (WT) mice. A global proteomics and pathway analyses revealed that Epac 1 deficiency mainly affected "the energy production and utilization" process in the skeletal muscle. We have tested their forced treadmill exercise tolerance. Epac1-/- mice exhibited significantly reduced exercise capacity in the forced treadmill exercise and lower number of type 1 fibers than WT mice. The basal protein level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was reduced in the Epac1-/- mice. Furthermore, increasing expression of PGC-1α by exercise was also significantly attenuated in the skeletal muscle of Epac1-/- mice. The expressions of downstream target genes of PGC-1α, which involved in uptake and oxidation of fatty acids, ERRα and PPARδ, and fatty acid content were lower in muscles of Epac1-/-, suggesting a role of Epac1 in forced treadmill exercise capacity by regulating PGC-1α pathway and lipid metabolism in skeletal muscle. Taken together, Epac1 plays an important role in exercise capacity by regulating PGC-1α and fatty acid metabolism in the skeletal muscle.

Systematic Review of Postfertilization Effects and Potential for Embryo Formation and Loss during the Use of Intrauterine Devices.

OBJECTIVES: This review sought to evaluate the evidence for embryo formation during intrauterine device (IUD) use, to articulate how often embryo loss occurs in well-designed studies, and to comment on other bodies of literature suggestive of postfertilization mechanisms of action of IUDs. METHODS: The MEDLINE, EMBASE, and Ovid databases were searched for English-language studies of markers of pregnancy in IUD users in May 2018. Studies of human chorionic gonadotropin (hCG) were subjected to quality assessment based on the US Preventive Services Task Force quality tool. Bias of studies assessing pregnancy in other ways was assessed on a study-to-study basis. RESULTS: In all, 1,073 studies were identified and 138 were read in detail. Twenty-three studies of ß-hCG, 4 studies of direct observation of embryos in fallopian tubes, 2 studies of pregnancy-specific binding globulin (PSBG), and 1 study of heat-shock protein 10 (Hsp10) or chaperonin 10 were included. In all studies considered together, 7.3 percent of IUD users had evidence of fertilization and pregnancy failure. In good-quality studies, 4.5 percent had evidence of fertilization and pregnancy failure. DISCUSSION: There are no randomized trials of embryo formation and loss in IUD users compared with noncontracepting controls. Studies of ß-hCG span a large spectrum of quality, but several good-quality studies exist, which support embryo formation and loss in IUD users. Evidence of embryos found in tubes is moderate and evidence of PSBG and Hsp10 elaboration was limited, but these are also concerning for embryo formation and loss. CONCLUSION: There is good-quality evidence of embryo formation and loss in IUD users. Studies are inconsistent, and the stated conclusions of several papers inaccurately diminish postfertilization evidence of embryo formation. To better assess the rate of embryo loss in IUD users compared with non-users, future research should include well-designed prospective trials and less subjective assessments of embryos in fallopian tubes. SUMMARY: A systematic review was carried out examining the English-language literature in the MEDLINE, EMBASE, and Ovid databases for evidence of embryo formation and loss during IUD use. In all, 1,073 studies were identified and 138 were read. There are no randomized trials and evidence ranges in quality, but evidence for the embryo formation and loss in 4.5 percent of IUD users exists in good-quality research. Further research is needed to compare embryo loss in IUD users to loss in controls.

Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke.

BACKGROUND: Endothelin-1 (ET-1) is synthesized and upregulated in astrocytes under stroke. We previously demonstrated that transgenic mice over-expressing astrocytic ET-1 (GET-1) displayed more severe neurological deficits characterized by a larger infarct after transient middle cerebral artery occlusion (tMCAO). ET-1 is a known vasoconstrictor, mitogenic, and a survival factor. However, it is unclear whether the observed severe brain damage in GET-1 mice post stroke is due to ET-1 dysregulation of neurogenesis by altering the stem cell niche. METHODS: Non-transgenic (Ntg) and GET-1 mice were subjected to tMCAO with 1 h occlusion followed by long-term reperfusion (from day 1 to day 28). Neurological function was assessed using a four-point scale method. Infarct area and volume were determined by 2,3,5-triphenyltetra-zolium chloride staining. Neural stem cell (NSC) proliferation and migration in subventricular zone (SVZ) were evaluated by immunofluorescence double labeling of bromodeoxyuridine (BrdU), Ki67 and Sox2, Nestin, and Doublecortin (DCX). NSC differentiation in SVZ was evaluated using the following immunofluorescence double immunostaining: BrdU and neuron-specific nuclear protein (NeuN), BrdU and glial fibrillary acidic protein (GFAP). Phospho-Stat3 (p-Stat3) expression detected by Western-blot and immunofluorescence staining. RESULTS: GET-1 mice displayed a more severe neurological deficit and larger infarct area after tMCAO injury. There was a significant increase of BrdU-labeled progenitor cell proliferation, which co-expressed with GFAP, at SVZ in the ipsilateral side of the GET-1 brain at 28 days after tMCAO. p-Stat3 expression was increased in both Ntg and GET-1 mice in the ischemia brain at 7 days after tMCAO. p-Stat3 expression was significantly upregulated in the ipsilateral side in the GET-1 brain than that in the Ntg brain at 7 days after tMCAO. Furthermore, GET-1 mice treated with AG490 (a JAK2/Stat3 inhibitor) sh owed a significant reduction in neurological deficit along with reduced infarct area and dwarfed astrocytic differentiation in the ipsilateral brain after tMCAO. CONCLUSIONS: The data indicate that astrocytic endothelin-1 overexpression promotes progenitor stem cell proliferation and astr ocytic differentiation via the Jak2/Stat3 pathway.

Systematic Review of Ovarian Activity and Potential for Embryo Formation and Loss during the Use of Hormonal Contraception.

The purpose of this review was to determine whether there is evidence that ovulation can occur in women using hormonal contraceptives and whether these drugs might inhibit implantation. We performed a systematic review of the published English-language literature from 1990 to the present which included studies on the hormonal milieu following egg release in women using any hormonal contraceptive method. High circulating estrogens and progestins in the follicular phase appear to induce dysfunctional ovulation, where follicular rupture occurs but is followed by low or absent corpus luteum production of progesterone. Hoogland scoring of ovulatory activity may inadvertently obscure the reality of ovum release by limiting the term "ovulation" to those instances where follicular rupture is followed by production of a threshold level of luteal progesterone, sufficient to sustain fertilization, implantation, and the end point of a positive ß-human chorionic gonadotropin. However, follicular ruptures and egg release with subsequent low progesterone output have been documented in women using hormonal contraception. In the absence of specific ovulation and fertilization markers, follicular rupture should be considered the best marker for egg release and potential fertilization. Women using hormonal contraceptives may produce more eggs than previously described by established criteria; moreover, suboptimal luteal progesterone production may be more likely than previously acknowledged, which may contribute to embryo loss. This information should be included in informed consent for women who are considering the use of hormonal contraception. SUMMARY: For this study, the authors looked at English-language research articles that focused on how hormonal birth control, such as the birth control pill, may affect very early human embryos. The authors found that abnormal ovulation, or release of an egg followed by abnormal hormone levels, may often occur in women using hormonal birth control. This may increase the number of very early human embryos who are lost before a pregnancy test becomes positive. For women who are thinking about using hormonal birth control, this is important information to consider.

Endometriosis in Hydatid Cysts of Morgagni: A Retrospective Cohort Study of Another Atypical Manifestation of Endometriosis.

STUDY OBJECTIVE: To report on the presence and rate of endometriosis in hydatid cysts of Morgagni found at the time of excision surgery for endometriosis and to describe any association of endometriosis in hydatid cysts of Morgagni with preoperative or operative factors. DESIGN: A retrospective cohort study (Canadian Task Force Classification II-2). SETTING: The Center for Endometriosis at Saint Louis University, a tertiary referral center for endometriosis. PATIENTS: Women who underwent optimal excision surgery for suspected endometriosis because of chronic pelvic pain and/or infertility and who also had hydatid cysts of Morgagni removed at the time of surgery when found. INTERVENTIONS: Preoperative and operative data were collected prospectively. MAIN OUTCOME MEASURES: The rate of endometriosis in hydatid cysts of Morgagni. Secondary measures included are the rate of hydatid cysts of Morgagni in patients with pelvic pain or infertility with and without endometriosis in the cysts. RESULTS: The overall prevalence of endometriosis in hydatid cysts of Morgagni was 11.3%. Patients with pelvic pain had a higher rate (although not statistically significant) of hydatid cysts of Morgagni compared with those without pain (21.1% vs 12.5 %, p = .54). Patients with infertility had a higher rate of hydatid cysts of Morgagni compared with those without infertility (38.1% vs 16.7%, p < .001), and there was a higher rate of endometriosis in the hydatid cysts of Morgagni in patients with infertility compared with those without (11.1% vs 0.0%, p < .001). CONCLUSIONS: This study is the first known report of endometriosis found within hydatid cysts of Morgagni. With a rate of 11.3% of cysts of Morgagni having endometriosis within them, this study supports a practice of removing hydatid cysts of Morgagni at the time of surgery in order to achieve optimal excision of endometriosis. The rates of hydatid cysts of Morgagni and of endometriosis found within hydatid cysts of Morgagni were higher in patients with infertility. Further studies are needed to evaluate whether excising cysts of Morgagni affects clinical outcomes.

Single-Use Energy Sources and Operating Room Time for Laparoscopic Hysterectomy: A Randomized Controlled Trial.

STUDY OBJECTIVES: To compare the intraoperative direct costs of a single-use energy device with reusable energy devices during laparoscopic hysterectomy. DESIGN: A randomized controlled trial (Canadian Task Force Classification I). SETTING: An academic hospital. PATIENTS: Forty-six women who underwent laparoscopic hysterectomy from March 2013 to September 2013. INTERVENTIONS: Each patient served as her own control. One side of the uterine attachments was desiccated and transected with the single-use device (Ligasure 5-mm Blunt Tip LF1537 with the Force Triad generator). The other side was desiccated and transected with reusable bipolar forceps (RoBi 5 mm), and transected with monopolar scissors using the same Covidien Force Triad generator. The instrument approach used was randomized to the attending physician who was always on the patient's left side. Resident physicians always operated on the patient's right side and used the converse instruments of the attending physician. MEASUREMENTS AND MAIN RESULTS: Start time was recorded at the utero-ovarian pedicle and end time was recorded after transection of the uterine artery on the same side. Costs included the single-use device; amortized costs of the generator, reusable instruments, and cords; cleaning and packaging of reusable instruments; and disposal of the single-use device. Operating room time was $94.14/min. We estimated that our single use-device cost $630.14 and had a total time savings of 6.7 min per case, or 3.35 min per side, which could justify the expense of the device. The single-use energy device had significant median time savings (-4.7 min per side, p < .001) and total intraoperative direct cost savings ($254.16 per case). CONCLUSIONS: A single-use energy device that both desiccates and cuts significantly reduced operating room time to justify its own cost, and it also reduced total intraoperative direct costs during laparoscopic hysterectomy in our institution. Operating room cost per minute varies between institutions and must be considered before generalizing our results.

Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop ß-cell dysfunction and metabolic syndrome.

Previously, exchange protein directly activated by cAMP 2 (Epac2) and PKA were known to play a role in glucose-stimulated insulin secretion (GSIS) by pancreatic ß cells. The present study shows that Epac1 mRNA is also expressed by ß cells. Therefore, we generated mice and embryonic stem (ES) cells with deletion of the Epac1 gene to define its role in ß-cell biology and metabolism. The homozygous Epac1-knockout (Epac1(-/-)) mice developed impaired glucose tolerance and GSIS with deranged islet cytoarchitecture, which was confirmed by isolated islets from adult Epac1(-/-) mice. Moreover, Epac1(-/-) mice developed more severe hyperglycemia with increased ß-cell apoptosis and insulitis after multiple low-dose streptozotocin (MLDS; 40 mg/kg) treatment than Epac1(+/+) mice. Interestingly, Epac1(-/-) mice also showed metabolic defects, including increased respiratory exchange ratio (RER) and plasma triglyceride (TG), and more severe diet-induced obesity with insulin resistance, which may contributed to ß-cell dysfunction. However, islets differentiated from Epac1(-/-) ES cells showed insulin secretion defect, reduced Glut2 and PDX-1 expression, and abolished GLP-1-stimulated PCNA induction, suggesting a role of Epac1 in ß-cell function. The current study provides in vitro and in vivo evidence that Epac1 has an important role in GSIS of ß cells and phenotype resembling metabolic syndrome.

Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis. RESULTS: The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood-brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ETA receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH. CONCLUSIONS: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

Transgenic mice over-expressing endothelial endothelin-1 show cognitive deficit with blood-brain barrier breakdown after transient ischemia with long-term reperfusion.

Increased level of endothelin-1 (ET-1), a potent vasoconstrictor, has been found in the cerebral spinal fluid (CSF) of patients with multi-infarction dementia, suggesting a possible role of ET-1 in cognitive deficit associated with stroke. Previously, we have reported that synthesis of ET-1 is induced in endothelial cells in hypoxic/ischemic conditions. Transgenic mice over-expressing endothelin-1 in endothelial cells (TET-1) developed systemic hypertension and showed more severe brain damage after transient ischemia. To further understand the significance of endothelial ET-1 in cognitive deficit, we subjected adult TET-1 mice to 30 min middle cerebral artery occlusion (MCAO) with 7 days reperfusion. At baseline, TET-1 mice showed similar locomotor activity, emotion and cognitive function compared to non-transgenic (NTg) mice. However, after 30 min MCAO and 7 days reperfusion, although the sensorimotor function measured by neurological scores was recovered in both genotypes, TET-1 mice showed increased anxiety-like behavior in the open field test and impaired spatial learning and reference memory in the Morris water maze. Parallel with these behavioral changes, TET-1 mice showed more severe brain damage with blood-brain-barrier breakdown (BBB), reactive astrogliosis, increased caspase-3, and increased peroxiredoxin 6 (Prx6) expressions around blood vessels in the ipsilateral hippocampus, compared to that of NTg mice, suggesting that ET-1 over-expression in the endothelial cells leads to more severe BBB breakdown and increased oxidative stress which may resulted in neuronal apoptosis and glial reactivity, which might contribute to the emotional changes and cognitive deficits after short-term ischemia with long-term reperfusion.

Patient preferences of cosmesis for abdominal incisions in gynecologic surgery.

STUDY OBJECTIVE: To estimate patient preferences insofar as the cosmetic appeal of abdominal incisions used for hysterectomy. We hypothesized that the laparoendoscopic single-site surgery (LESS) incision would be preferred cosmetically to traditional multiport laparoscopic incisions and open abdominal incisions via Pfannenstiel, vertical midline, or horizontal mini-laparotomy. DESIGN: Prospective comparative study (Canadian Task Force classification II-2). SETTING: Two gynecology clinics at Duke University Medical Center in Durham, North Carolina. PATIENTS: Seventy-three women including 50 consecutive women from a private specialty clinic and 23 consecutive women from a resident indigent care clinic. INTERVENTIONS: A brief questionnaire was distributed that assessed preferences via ranking and by using a visual analog scale. Patients were also asked to rate the importance of 4 factors in their decision making: size, location, and number of incisions, and perceived recovery time. Descriptive statistics, t tests, Wilcoxon rank-sum tests, and χ(2) tests were used to compare continuous or categorical values. MEASUREMENTS AND MAIN RESULTS: Overall, the LESS incision was the most preferred incision according to most common choice and visual analog scale scores. In the private clinic, the LESS incision was preferred most often, with 53% of women (39/73) ranking it as their first choice. In the resident clinic, the horizontal mini-laparotomy incision was preferred most often, with 27% of women (20/73) ranking it their first choice. Neither the demographic factors nor any of the factors in decision making explained the difference between the clinics. CONCLUSION: The LESS incision was most preferred in this study. However, the horizontal mini-laparotomy incision and the traditional laparoscopic with low lateral incisions were also highly preferred. Patient perception of the "visibility" of abdominal incisions may be the distinguishing issue to explain the difference in the preferences between the clinics and the differences between the present study and previously published studies of cosmetic preferences.

A pilot feasibility multicenter study of patients after excision of endometriosis.

OBJECTIVE: To serve as a pilot feasibility study for a randomized study of excision versus ablation in the treatment of endometriosis by (1) estimating the magnitude of change in symptoms after excision only at multiple referral centers and (2) determining the proportion of women willing to participate in a randomized trial. METHODS: We performed a multicenter prospective study of women undergoing excision for endometriosis (Canadian Task Force class II-3) at Duke University Center for Endometriosis Research & Treatment (currently the Saint Louis University Center for Endometriosis), Center for Endometriosis Care, Northshore University Health System, Memorial University (Canada), and Florida Hospital. The study comprised 100 female patients, aged 18 to 55 years, with endometriosis-suspected pelvic pain. The intervention was laparoscopic excision only of the abnormal peritoneum suspicious for endometriosis. The main outcome measures were quality of life, pelvic pain, dysmenorrhea, dyspareunia, and bowel and bladder symptoms. RESULTS: The mean follow-up period was 8.5 months. Excision of endometriosis showed a significant reduction in all pain scores except bowel symptoms, as well as significant improvement in quality of life. Of the patients, 84% were willing to participate in a randomized study. CONCLUSIONS: Quality of life is a needed primary outcome for any randomized study comparing excision versus ablation. A multicenter comparative trial is feasible, although quality assurance would have to be addressed. Patients were willing to be randomized even at surgical referral centers.

Fertility after expanded polytetrafluoroethylene use after endometrioma cystectomy: a pilot study.

Introduction: Pregnancy rates after the placement of expanded polytetrafluoroethylene (ePTFE, trade name Gore-Tex®) for adhesion prevention following cystectomy of endometriomas ≥3 cm and excision of endometriosis were analyzed in this pilot study. Methods: A prospective cohort study was performed at a single tertiary care center. 56 women qualified for the study and underwent surgery. Expanded polytetrafluoroethylene placement around affected ovaries was self-selected. Inclusion criteria for analysis were pathology-confirmed endometrioma ≥3 cm, no hysterectomy at time of surgery, ≥1 year of postoperative survey completion, and absence of strategies to avoid pregnancy. 18 women in the ePTFE group and 11 women in the control group met inclusion criteria for analysis. 16 of the 18 women in the ePTFE group and 7 of the 11 women in the control group were affected by infertility. Absolute pregnancy rates and cumulative 4-year pregnancy rates, which are based on survival analysis using lifetables and adjust for varying follow-up times, were calculated for all women as well as for women with infertility only. Results: High cumulative 4-year pregnancy rates were observed for women with expanded polytetrafluoroethylene compared to women without (85% vs. 65%, p = 0.69). High cumulative 4-year pregnancy rates for women with infertility prior to surgery were observed for women with expanded polytetrafluoroethylene compared to women without (83% vs. 33%, p = 0.89). Discussion: There are consistent trends, although not statistically significant, seen in pregnancy rates for women with ePTFE compared to women without, particularly in those with a history of infertility prior to ePTFE use. This is the first study examining how adhesion prevention strategy targeting the adnexa during surgery for endometriosis affects pregnancy rates. The trend towards increased pregnancy rates with expanded polytetrafluoroethylene use, particularly in patients with a history of infertility, is promising and warrants further study with larger groups.

Nuclear factor of activated T cells 5 deficiency increases the severity of neuronal cell death in ischemic injury.

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in regulating several genes that are thought to be neuroprotective in ischemic injury. Because of the embryonic lethality of NFAT5 knockout (NFAT5(-/-)) mice, the heterozygous (NFAT5(+/-)) mice were used to study the in vivo role of NFAT5 in hypoxia/ischemia (H/I) condition. The NFAT5(+/-) mice exhibited more severe neurological deficits, larger infarct area and edema formation associated with increased aquaporin 4 expressions in the brain. Under in vitro H/I condition, increased apoptotic cell death was found in NFAT5(-/-) neurons. Moreover, SMIT, a downstream to NFAT5, was upregulated in NFAT5(+/+) neurons, while the SMIT level could not be upregulated in NFAT5(-/-) neurons under H/I condition. The elevation of reactive oxygen species generation in NFAT5(-/-) neurons under H/I condition further confirmed that NFAT5(-/-) neurons were more susceptible to oxidative stress. The present study demonstrated that activation of NFAT5 and its downstream SMIT induction is important in protecting neurons from ischemia-induced oxidative stress.

The Evaluation and Treatment of Cervical Factor Infertility a Medical-Moral Analysis.

The current approach to infertility of assisted reproductive technology (ART) completely misses and then bypasses the evaluation and treatment of cervical factor infertility. In contrast, the Creighton Model Fertility Care System (CrMS), a method of fertility awareness that has the unique ability to quantify cervical mucus observations, and natural procreative technology (NaProTECHNOLOGY or NPT) directly evaluate and treat cervical factor infertility. The ART treatment of choice for cervical factor infertility--intrauterine insemination (IUI)--is also morally disparate from the NPT treatment protocol: while the latter genuinely assists the infertile couple's act of sexual union to achieve its natural end of pregnancy, IUI replaces the natural act, depriving human conception of the one context worthy of the dignity of human life and procreation, a reciprocal self-gifting act of love between husband and wife. A renewed interest and focus on the direct evaluation and treatment of cervical factor infertility is needed.

Deficiency of exchange protein directly activated by cAMP (EPAC)-1 in mice augments glucose intolerance, inflammation, and gut dysbiosis associated with Western diet.

BACKGROUND: Gut microbiota (GM) dysregulation, known as dysbiosis, has been proposed as a crucial driver of obesity associated with "Western" diet (WD) consumption. Gut dysbiosis is associated with increased gut permeability, inflammation, and insulin resistance. However, host metabolic pathways implicated in the pathophysiology of gut dysbiosis are still elusive. Exchange protein directly activated by cAMP (Epac) plays a critical role in cell-cell junction formation and insulin secretion. Here, we used homozygous Epac1-knockout (Epac1-/-), Epac2-knockout (Epac2-/-), and wild-type (WT) mice to investigate the role of Epac proteins in mediating gut dysbiosis, gut permeability, and inflammation after WD feeding. RESULTS: The 16S rRNA gene sequencing of fecal DNA showed that the baseline GM of Epac2-/-, but not Epac1-/-, mice was represented by a significantly higher Firmicutes to Bacteroidetes ratio and significant alterations in several taxa compared to WT mice, suggesting that Epac2-/- mice had gut dysbiosis under physiological conditions. However, an 8-week WD led to a similar gut microbiome imbalance in mice regardless of genotype. While Epac1 deficiency modestly exacerbated the WD-induced GM dysbiosis, the WD-fed Epac2-/- mice had a more significant increase in gut permeability than corresponding WT mice. After WD feeding, Epac1-/-, but not Epac2-/-, mice had significantly higher mRNA levels of tumor necrosis factor-alpha (TNF-α) and F4/80 in the epididymal white adipose tissue (EWAT), increased circulating lipocalin-2 protein and more severe glucose intolerance, suggesting greater inflammation and insulin resistance in WD-fed Epac1-/- mice than corresponding WT mice. Consistently, Epac1 protein expression was significantly reduced in the EWAT of WD-fed WT and Epac2-/- mice. CONCLUSION: Despite significantly dysregulated baseline GM and a more pronounced increase in gut permeability upon WD feeding, WD-fed Epac2-/- mice did not exhibit more severe inflammation and glucose intolerance than corresponding WT mice. These findings suggest that the role of gut dysbiosis in mediating WD-associated obesity may be context-dependent. On the contrary, we demonstrate that deficiency of host signaling protein, Epac1, drives inflammation and glucose intolerance which are the hallmarks of WD-induced obesity. Video abstract.

Cystoscopic findings in women with minimal and maximal lower urinary tract symptoms.

BACKGROUND: Glomerulations are not specific for interstitial cystitis/bladder pain syndrome (IC/BPS). Controversy exists about whether cystoscopic findings differ between patients with and without lower urinary tract symptoms. We sought to compare the prevalence of cystoscopic findings in women with "no or minimal" urinary symptoms to those with a "high" symptom burden. METHODS: This is a secondary analysis of a prospective cohort study performed at a University Educational Facility. Participants in this study were part of a larger prospective study, in which female patients scheduled to undergo routine gynecologic procedures were all consented for cystoscopy with hydrodistension (CWHD). We defined the "minimally symptomatic group" as those with ≤1 on each of the O'Leary/Sant Interstitial Cystitis Symptom Index (ICSI) subscores and without history of IC/BPS. The "highly symptomatic" cohort of women had composite ICSI score ≥12 and a Burning/Pain subscore of 4 or 5. All were non-smokers. RESULTS: A total of 84 women underwent CWHD, with 33 having minimal symptoms and 51 being highly symptomatic. The two groups were not statistically different when assessing for 'any glomerulations' compared to 'no glomerulations.' However, minimally symptomatic women had an eight-fold lower prevalence of significant glomerulations than highly symptomatic women (3.0% minimally symptomatic vs. 23.5% highly symptomatic, P<0.05.). CONCLUSIONS: Extensive glomerulations (≥10 in 3 or 4 quadrants) are rare in women with minimal urinary symptoms. These findings contrast with prior limited prospective data which quoted similar incidence of glomerulations in IC/BPS patients and asymptomatic patients. This study highlights the importance of evaluating objective evidence on CWHD and merits further investigation as part of the ongoing conversation regarding the definition of bladder health and pathology.

Laparo-endoscopic single site hysterectomy in gynecologic surgery.

Laparo-endoscopic single site (LESS) surgery has recently gained broader acceptance as a less-invasive approach to traditional multi-port laparoscopic procedures. LESS hysterectomy represents the gynecologic surgeon's progression toward this goal of performing minimally invasive hysterectomy procedures through increasingly fewer incisions. Although this procedure offers improved cosmesis and potentially decreased post-operative pain, there are also many challenges to adoption of this surgical procedure. LESS hysterectomy is associated with a steep learning curve and the need for the gynecologic surgeon to adopt new technologies and develop a new set of surgical skills. Following the basic principles of LESS surgery is essential for the gynecologic surgeon to safely and efficiently adopt this surgical procedure. Advances in surgical instrumentation will continue to allow surgeons to perform increasingly complex LESS surgical procedures in the future.