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Objective: To estimate the incidence of cystoscopy use at time of hysterectomy and its use to detect urinary tract injury.Methods: This was a retrospective cohort study in a tertiary care academic center of 1982 patients who underwent a hysterectomy for any indication (excluding obstetric) between January 2009 and December 2010. Medical records were reviewed for baseline and perioperative characteristics, cystoscopy use, and information about bladder or ureteral injury related to hysterectomy.Results: Two hundred fifty-one women (12.66%, 95% confidence interval [CI] 11.23-14.21%) underwent a cystoscopy at the time of hysterectomy with no reported complications resulting from the cystoscopy procedure. Cystoscopy was most frequently used by low-volume surgeons and in cases involving prolapse or vaginal mode of access. Fourteen patients (0.71%, 95% CI 0.39-1.19%) experienced bladder injury and five patients (0.25%, 95% CI 0.08-0.58%) sustained ureteral injury. None of these complications were detected by cystoscopy; cystoscopy was either normal at the time of hysterectomy or was omitted. The presence of adhesions was significantly associated with bladder injury at the time of hysterectomy (P=.006). Low-volume surgeon and laparoscopic or robotic mode of access were both significantly associated with ureteral injury (P=.023 and P=.042, respectively).Conclusions: Our data support selective rather than universal cystoscopy at the time of hysterectomy. [ABSTRACT FROM AUTHOR]

Objective: Prolonged labor is the commonest indication for intrapartum cesarean section, but definitions are inconsistent and some common definitions were recently found to overestimate the speed of physiological labor. The objective of this review is to establish an overview of synonyms and definitions used in the literature for prolonged labor, separated into first and second stages, and establish types of definitions used., Data Sources: A systematic search was conducted in PubMed, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier., Study Eligibility Criteria: All articles in English that (1) attempted to define prolonged labor, (2) included a definition of prolonged labor, or (3) included any synonym for prolonged labor, were included., Methods: Data on study design, year of publication, country or region of origin, synonyms used, definition of prolonged first and/or second stage, and origin of provided definition (if not primarily established by the study) were collected into a database., Results: In total, 3402 abstracts and 536 full-text papers were screened, and 232 papers were included. Our search established 53 synonyms for prolonged labor. Forty-three studies defined prolonged labor and 189 studies adopted a definition of prolonged labor. Definitions for prolonged first stage of labor were categorized into: time-based ( n =14), progress-based ( n =12), clinician-based ( n =5), or outcome-based ( n =4). For the 33 studies defining prolonged second stage, the majority of definitions ( n =25) were time-based, either based on total duration or duration of no descent of the presenting part., Conclusions: Despite efforts to arrive at uniform labor curves, there is still little uniformity in definitions of prolonged labor. Consensus on which definition to use is called for, in order to safely and respectfully allow physiological labor progress, ensure timely management, and assess and compare incidence of prolonged labor between settings., Competing Interests: The authors declare no conflict of interest, other than that some have contributed to included studies.1,2,88 SM is funded through a mid-career Scientist Award by the South African Medical Research Council., (© 2024 The Authors.)

Objective: To assess the incidence of severe maternal outcome (SMO), comprising maternal mortality (MM) and maternal near miss (MNM), in Metro East health district, Western Cape Province, South Africa between November 2014 and November 2015 and to identify associated determinants leading to SMO with the aim to improve maternity care., Methods: Region-wide population-based case-control study. Women were included in the study, if they were maternal deaths or met MNM criteria, both as defined by WHO. Characteristics of women with SMO were compared with those of a sample of women without SMO, matched for age and parity, taken from midwifery-led obstetrical units from two residential areas in Metro East, using multivariate regression analysis., Results: Incidence of SMO was 9.1 per 1000 live births, and incidence of MNM was 8.6 per 1000 live births. Main causes of SMO were obstetrical hemorrhage and hypertensive disorders. Factors associated with SMO were HIV (adjusted odds ratio [aOR] 24.8; 95% confidence interval [CI] 10.0-61.6), pre-eclampsia (aOR 17.5; 95% CI 7.9-38.7), birth by cesarean section (aOR 8.4; 95% CI 5.8-12.3), and chronic hypertension (aOR 2.4; 95% CI 1.1-5.1)., Conclusion: Evaluation of SMO incidence and associated determinants supports optimizing tailored guidelines in Metro-East health district to improve maternal health., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

The aim of this study was to evaluate the catheterisation regimes after a laparoscopic hysterectomy (LH) in Dutch hospitals and to assess the nurses' opinion on this topic. This was particularly relevant as no consensus exists on the best moment to remove a urinary catheter after an LH. All 89 Dutch hospitals were successfully contacted and provided information on their catheterisation regime after LH: 69 (77.5%) hospitals reported removing the catheter the next morning after the LH, while nine hospitals (10.1%) removed it directly at the end of the procedure. The other 11 hospitals had different policies (four hours, up to two days). Additionally, all nurses working in the gynaecology departments of the hospitals affiliated to Leiden University were asked to fill in a self-developed questionnaire. Of the 111 nurses who completed the questionnaire (response rate 81%), 90% was convinced that a direct removal was feasible and 78% would recommend it to a family member or friend. Impact Statement What is already known on this subject? Although an indwelling catheter is routinely placed during a hysterectomy, it is unclear what the best moment is to remove it after an LH specifically. To fully benefit from the advantages associated with this minimally invasive approach, postoperative catheter management, should be, amongst others, optimal and LH-specific. A few studies have demonstrated that the direct removal of urinary catheter after an uncomplicated LH is feasible, but the evidence is limited. What the results of this study add? While waiting for the results of the randomised trials, this present study provides insight into the nationwide catheterisation management after an LH. Despite the lack of consensus on the topic, catheterisation management was quite uniform in the Netherlands: most Dutch hospitals removed the urinary catheter one day after an LH. Yet, this was not in line with the opinion of the surveyed nurses, as the majority would recommend a direct removal. This is interesting as nurses are closely involved in the patients' postoperative care. What are the implications of these findings for clinical practice and/or further research? Although randomised trials are necessary to determine an optimal catheterisation management, the findings of this present study are valuable if a new urinary catheter regime has to be implemented.

Background: To assess potential risks of new surgical procedures and devices before their introduction into daily practice, a prospective risk inventory (PRI) is a required step. This study assesses the applicability of the Health Failure Mode and Effects Analysis (HFMEA) as part of a PRI of new technology in minimally invasive gynecologic surgery., Methods: A reference case was defined of a patient with presumed benign leiomyoma undergoing a laparoscopic hysterectomy or myomectomy including in-bag power morcellation; however, pathology defined a stage I uterine leiomyosarcoma. Using in-bag morcellation as a template, a HFMEA was performed. All steps of the in-bag morcellation technique were identified. Next, the possible hazards of these steps were explored and possible measures to control these hazards were discussed., Results: Five main steps of the morcellation process were identified. For retrieval bags without openings to accommodate instruments inside the bag, 120 risks were identified. Of these risks, 67 should be eliminated. For containment bags with openings 131 risks were identified of which 68 should be eliminated. Of the 10 causes most at risk to cause spillage, two can be eliminated by using appropriate bag materials. Myomectomy appears to be more at risk for residual tissue spillage compared to total hysterectomy., Conclusion: The HFMEA has provided important new insights regarding potential weaknesses of the in-bag morcellation technique, particularly with respect to hazardous steps in the morcellation process as well as requirements that bags should meet. As such, this study has shown HFMEA to be a valuable method that identifies and quantifies potential hazards of new technology.

Introduction: Induction of labor is a common intervention. The objective was to investigate whether larger Foley catheter volumes for labor induction decrease the total time from induction to delivery., Material and Methods: Randomized controlled trials comparing larger single-balloon volumes (60-80 mL) during Foley catheter cervical ripening with usual volume (30 mL) in women undergoing labor induction were identified by searching electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) from inception through 2017. The primary outcome was mean time from induction to delivery in hours. Secondary outcomes included time from induction to vaginal delivery, delivery within 24 h, time to Foley expulsion, cesarean section, chorioamnionitis, epidural use, hemorrhage, meconium staining, and neonatal intensive care unit admission. Meta-analysis was performed using the random effects model of DerSimonian and Laird (PROSPERO CRD42017058885)., Results: Seven randomized controlled trials including 1432 singleton gestations were included in the systematic review. Women randomized to larger volumes of balloon had a significantly shorter time from induction to delivery (mean difference 1.97 h, 95% CI -3.88 to -0.06). There was no difference in cesarean section between groups (16 vs. 18%, relative risk 0.84, 95% CI 0.6-1.17). A larger balloon volume was associated with a nonsignificant decrease in time from induction to delivery in multiparous (mean difference 2.67 h, 95% CI -6.1 to 0.76) and nulliparous women (mean difference 1.82 h, 95% CI -4.16 to 0.53)., Conclusion: Balloon volumes larger than 30 mL during Foley catheter induction reduce total time to delivery by approximately 2 h., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: To compare uterine-sparing treatment options for fibroids in terms of reintervention risk and quality of life., Design: Systematic review and meta-analysis according to PRISMA guidelines., Setting: Not applicable., Patient(s): Women with uterine fibroids undergoing a uterine-sparing intervention., Interventions(s): Not applicable., Main Outcome Measure(s): 1) Reintervention risk after uterine-sparing treatment for fibroids after 12, 36, and 60 months; and 2) quality of life outcomes, based on validated questionnaires. Two separate analyses were performed for the procedures that used an abdominal approach (myomectomy, uterine artery embolization [UAE], artery ligation, high-intensity focused ultrasound [HIFU], laparoscopic radiofrequency ablation [RFA]) and for the procedures managing intracavitary fibroids (hysteroscopic approach, including hysteroscopic myomectomy and hysteroscopic RFA)., Result(s): There were 85 articles included for analysis, representing 17,789 women. Stratified by treatment options, reintervention risk after 60 months was 12.2% (95% confidence interval [CI] 5.2%-21.2%) for myomectomy, 14.4% (95% CI 9.8%-19.6%) for UAE, 53.9% (95% CI 47.2%-60.4%) for HIFU, and 7% (95% CI 4.8%-9.5%) for hysteroscopy. For the other treatment options, no studies were available at 60 months. For quality of life outcomes, symptoms improved after treatment for all options. The HIFU procedure had the least favorable outcomes., Conclusion(s): Despite the substantial heterogeneity of the study population, this meta-analysis provides valuable information on relative treatment efficacy of various uterine-sparing interventions for fibroids, which is relevant when counseling patients in daily practice. Furthermore, this study demonstrates that long-term data, particularly for the newest uterine-sparing interventions, are urgently needed., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Pelvic endometriosis is often mentioned as one of the variables influencing surgical outcomes of laparoscopic hysterectomy (LH). However, its additional surgical risks have not been well established. The aim of this study was to analyze to what extent concomitant endometriosis influences surgical outcomes of LH and to determine if it should be considered as case-mix variable., Results: A total of 2655 LH's were analyzed, of which 397 (15.0%) with concomitant endometriosis. For blood loss and operative time, no measurable association was found for stages I ( n  = 106) and II ( n  = 103) endometriosis compared to LH without endometriosis. LH with stages III ( n  = 93) and IV ( n  = 95) endometriosis were associated with more intra-operative blood loss ( p  = < .001) and a prolonged operative time ( p  = < .001) compared to LH without endometriosis. No significant association was found between endometriosis (all stages) and complications ( p  = .62)., Conclusions: The findings of our study have provided numeric support for the influence of concomitant endometriosis on surgical outcomes of LH, without bowel or bladder dissection. Only stages III and IV were associated with a longer operative time and more blood loss and should thus be considered as case-mix variables in future quality measurement tools., Competing Interests: The Institutional Review Board (IRB) of Leiden University Medical Centre, Leiden, the Netherlands reviewed the study and exempted it from IRB approval. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this retrospective study, formal consent is not required. This article does not contain any studies with animals performed by any of the authors.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The success of newly introduced surgical techniques is generally primarily assessed by surgical outcome measures. However, data on medical liability should concomitantly be used to evaluate provided care as they give a unique insight into substandard care from patient's point of view. The aim of this study was to analyze the number and type of medical claims after laparoscopic gynecologic procedures since the introduction of advanced laparoscopy two decades ago. Secondly, our objective was to identify trends and/or risk factors associated with these claims., Methods: To identify the claims, we searched the databases of the two largest medical liability mutual insurance companies in The Netherlands (MediRisk and Centramed), covering together 96% of the Dutch hospitals. All claims related to laparoscopic gynecologic surgery and filed between 1993 and 2015 were included., Results: A total of 133 claims met our inclusion criteria, of which 54 were accepted claims (41%) and 79 rejected (59%). The number of claims remained relatively constant over time. The majority of claims were filed for visceral and/or vascular injuries (82%), specifically to the bowel (40%) and ureters (20%). More than one-third of the injuries were entry related (38%) and 77% of the claims were filed after non-advanced procedures. A delay in diagnosing injuries was the primary reason for financial compensation (33%). The median sum paid to patients was €12,000 (500-848,689). In 90 claims, an attorney was defending the patient (83% for the accepted claims; 57% for the rejected claims)., Conclusion: The number of claims remained relatively constant during the study period. Most claims were provoked by bowel and ureter injuries. Delay in recognizing injuries was the most encountered reason for granting financial compensation. Entering the abdominal cavity during laparoscopy continues to be a potential dangerous step. As a result, gynecologists are recommended to thoroughly counsel patients undergoing any laparoscopic procedure, even regarding the risk of entry-related injuries.

Purpose: Since the introduction of minimally invasive gynecologic surgery, the percentage of advanced laparoscopic procedures has greatly increased worldwide. It seems therefore, timely to standardize laparoscopic gynecologic care according to the principles of evidence-based medicine. With this goal in mind-the Dutch Society of Gynecological Endoscopic Surgery initiated in The Netherlands the development of a national guideline for laparoscopic hysterectomy (LH). This present article provides a summary of the main recommendations of the guideline., Methods: This guideline was developed following the Dutch guideline of medical specialists and in accordance with the AGREE II tool. Clinically important issues were firstly defined and translated into research questions. A literature search per topic was then conducted to identify relevant articles. The quality of the evidence of these articles was rated following the GRADE systematic. An expert panel consisting of 18 selected gynecologists was consulted to formulate best practice recommendations for each topic., Results: Ten topics were considered in this guideline, including amongst others, the different approaches for hysterectomy, advice regarding tissue extraction, pre-operative medical treatment and prevention of ureter injury. This work resulted in the development of a clinical practical guideline of LH with evidence- and expert-based recommendations. The guideline is currently being implemented in The Netherlands., Conclusion: A guideline for LH was developed. It gives an overview of best clinical practice recommendations. It serves to standardize care, provides guidance for daily practice and aims to guarantee the quality of LH at an (inter)national level.

Background: Since the introduction of minimally invasive surgery (MIS), concerns for patient safety are more often brought to the attention. Knowledge about and awareness of patient safety risk factors are crucial in order to improve and enhance the surgical team, the environment, and finally surgical performance. The aim of this study was to identify and quantify patient safety risk factors in laparoscopic hysterectomy and to determine their influence on surgical outcomes., Methods: A prospective multicenter study was conducted from April 2014 to January 2016, participating gynecologists registered their performed laparoscopic hysterectomies (LHs). If deemed necessary, gynecologists could fill out a checklist with validated patient safety risk factors. Association between procedures with and without an occurred risk factor(s) and the surgical outcomes (blood loss, operative time, and complications) were assessed, using multivariate logistic regression and generalized estimation equations., Results: Eighty-five gynecologists participated in the study, registering a total of 2237 LHs. For 627(28 %) procedures, the checklist was entered (in total 920 items). The most reported risk factors were related to the surgeon (19.6 %), the surgical team (14.4 %), technology (16.6 %), and the patient (26.8 %). The procedures where a risk factor was registered had significantly less favorable outcomes, higher complication rate (10.5 vs. 4.8 % (p = 0.002), longer operative time [114 vs. 95 min (p < 0.001)], and more blood loss [110 vs. 168 mL (p = 0.047)], which was mainly due to the technological and patient-related risk factors., Conclusion: Technological incidents are the most important and clinically relevant risk factors affecting surgical outcomes of LH. Future improvements of MIS need to focus on this. As awareness of safety risk factors in MIS is important, embedding of a safety risk factor checklist in registration systems will help surgeons to evaluate and improve their individual performance. This will inherently improve the surgical outcomes and thus patient safety.

Purpose: To assess the safety and effectiveness of LESS compared to conventional hysterectomy., Methods: The systematic review and meta-analysis was performed according to the MOOSE guideline, and quality of evidence was assessed using GRADE. Different databases were searched up to 4th of August 2016. Randomized controlled trials and cohort studies comparing LESS to the conventional laparoscopic hysterectomy were considered for inclusion., Results: Of the 668 unique articles, 23 were found relevant. We investigated safety by analyzing the complication rate and found no significant differences between both groups [OR 0.94 (0.61, 1.44), I 2  = 19%]. We assessed effectiveness by analyzing conversion risk, postoperative pain, and patient satisfaction. For conversion rates to laparotomy, no differences were identified [OR 1.60 (0.40, 6.38), I 2  = 45%]. In 3.5% of the cases in the LESS group, an additional port was needed during LESS. For postoperative pain scores and patient satisfaction, some of the included studies reported favorable results for LESS, but the clinical relevance was non-significant. Concerning secondary outcomes, only a difference in operative time was found in favor of the conventional group [MD 11.3 min (5.45-17.17), I 2  = 89%]. The quality of evidence for our primary outcomes was low or very low due to the study designs and lack of power for the specified outcomes. Therefore, caution is urged when interpreting the results., Conclusion: The single-port technique for benign hysterectomy is feasible, safe, and equally effective compared to the conventional technique. No clinically relevant advantages were identified, and as no data on cost effectiveness are available, there are currently not enough valid arguments to broadly implement LESS for hysterectomy.

Objectives: One of the methods used to induce labour is the placement of a transcervical Foley catheter (FC). The aim of this randomized controlled study was to assess in term pregnant women with an unfavourable cervix, whether there is a difference in efficacy between the two most commonly used insufflation volumes of FC (30mL and 60mL)., Study Design: Randomized controlled trial., Results: Women were randomized to induction of labour with a Foley catheter filled with 30mL or with 60mL. Primary outcome was delivery within eight hours after amniotomy. Secondary outcomes included the time interval between placement of the Foley and amniotomy, the mode of delivery, complications and neonatal outcomes. In total, 174 women (87 in each arm) were randomized. The number of deliveries within eight hours after amniotomy was not significantly different between the two groups (40.7% versus 48.83%, OR=0.71(CI; 0.39-1.3)). Sub-analysis showed that more multiparous women in the 60mL group delivered within eight hours (93.10% versus 65.22%, OR=7.2 (CI; 1.35-38.37)). For the nulliparous, the 30mL Foley catheter was associated with a higher caesarean section rate (31.75% versus 15.52% (OR 2.53; CI; 1.1-6.2)). The 60mL Foley catheter was also associated with a higher chance of spontaneous labour after placement (OR 2.35; CI; 1.1-5.1), a shorter time interval for cervical ripening (OR=4.5; CI: 1.2-16.7) and less blood loss. (p=0.002). The Foley catheter ruptured twelve times in the 60mL group whereas this did not happen once in the 30mL group. One case of umbilical cord prolapse was observed in the 60mL group. No differences in neonatal outcomes and patient satisfaction were seen., Conclusions: For our primary outcome, no difference was observed between the Foley catheter balloon filled with 60mL and the one filled with 30mL. Yet, a Foley catheter filled with 60mL was associated in multiparous women with a higher rate of deliveries within eight hours after amniotomy and in nulliparous with a significantly lower caesarean section rate. These latest findings should be interpreted with cautious as underpowered., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hysterectomies performed laparoscopically have greatly increased within the last few decades and even exceed the number of vaginal hysterectomies (VHs). This systematic review, conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines, compares surgical outcomes of total laparoscopic hysterectomy (TLH) and VH to evaluate which approach offers the most benefits. A literature search was performed in PubMed, Embase, and Web of Science for all relevant publications from January 2000 to February 2016. All randomized controlled trials and cohort studies for benign indication or low-grade malignancy comparing TLH with VH were considered for inclusion. From the literature search, 24 articles were found to be relevant and included in this review. The results of our meta-analysis showed no difference between the 2 groups for overall complications (OR 1.24 [.68, 2.28] for major complications; OR .83 [.53, 1.28] for minor complications), risk of ureter and bladder injuries (OR .81 [.34, 1.92]), intraoperative blood loss (mean difference [MD] -30 mL [-67.34, 7.60]), and length of hospital stay (-.61 days [-1.23, -.01]). VH was associated with a shorter operative time (MD 42 minute [29.34, 55.91]) and a lower rate of vaginal cuff dehiscence (OR 6.28 [2.38, 16.57]) and conversion to laparotomy (OR 3.89 [2.18, 6.95]). Although not significant, the costs of procedure were lower for VH (MD 3889.9 dollars [2120.3, 89 000]). Patients in the TLH group had lower postoperative visual analog scale scores (MD -1.08, [-1.74, -.42]) and required less analgesia during a shorter period of time (MD -.64 days, [-1.06, -.22]). Defining the best surgical approach is a dynamic process that requires frequent re-evaluation as techniques improve. Although TLH and VH result in similar outcomes, our meta-analysis showed that when both procedures are feasible, VH is currently still associated with greater benefits, such as shorter operative time, lower rate of vaginal dehiscence and conversion to laparotomy, and lower costs. Many factors influence the choice for surgical approach to hysterectomy, and shared decision-making is recommended., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

In the last decennia, the length of hospital stay of admitted patients has significantly decreased in all medical fields. As a result, postoperative recovery mainly takes place at home, inherently leading to new challenges. Here, two patients are being discussed for whom the postoperative period was substandard. To guarantee optimal quality of care in the home situation, the medical specialist and the general practitioner need to make the necessary arrangements. We would first of all recommend providing each discharged patient with specific, structured and individualised advices regarding postoperative recovery but also regarding alarm symptoms and logistics (e.g. who to call in case of emergency). Finally, we believe that, as (serious) complications are rare, it should be agreed on the fact that the responsible medical specialist is the coordinator of the postoperative period and the first contact point for postoperative patients.

Background: The current health care system has an urgent need for tools to measure quality. A wide range of quality indicators have been developed in an attempt to differentiate between high-quality and low-quality health care processes. However, one of the main issues of currently used indicators is the lack of case-mix correction and improvement possibilities. Case-mix is defined as specific (patient) characteristics that are known to potentially affect (surgical) outcome. If these characteristics are not taken into consideration, comparisons of outcome among health care providers may not be valid., Objective: The objective of the study was to develop and test a quality assessment tool for laparoscopic hysterectomy, which can serve as a new outcome quality indicator., Study Design: This is a prospective, international, multicenter implementation study. A web-based application was developed with 3 main goals: (1) to measure the surgeon's performance using 3 primary outcomes (blood loss, operative time, and complications); (2) to provide immediate individual feedback using cumulative observed-minus-expected graphs; and (3) to detect consistently suboptimal performance after correcting for case-mix characteristics. All gynecologists who perform laparoscopic hysterectomies were requested to register their procedures in the application. A patient safety risk factor checklist was used by the surgeon for reflection. Thereafter a prospective implementation study was performed, and the application was tested using a survey that included the System Usability Scale., Results: A total of 2066 laparoscopic hysterectomies were registered by 81 gynecologists. Mean operative time was 100 ± 39 minutes, blood loss 127 ± 163 mL, and the complication rate 6.1%. The overall survey response rate was 75%, and the mean System Usability Scale was 76.5 ± 13.6, which indicates that the application was good to excellent. The majority of surgeons reported that the application made them more aware of their performance, the outcomes, and patient safety, and they noted that the application provided motivation for improving future performance., Conclusion: We report the development and test of a real-time, dynamic, quality assessment tool for measuring individual surgical outcome for laparoscopic hysterectomy. Importantly, this tool provides opportunities for improving surgical performance. Our study provides a foundation for helping clinicians develop evidence-based quality indicators for other surgical procedures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.ajog.2016.07.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal, (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To report the surgical outcomes of laparoscopic myomectomy (LM) and abdominal myomectomy (AM) at a high-volume tertiary care hospital, to evaluate the risk of conversion during LM, and to analyze the associated risk factors., Design: Retrospective cohort study (Canadian Task Force classification II)., Patients: All patients who underwent LM and AM in a tertiary academic center in Boston, Massachusetts between 2009 and 2012., Intervention: Medical records were reviewed for baseline characteristics and perioperative outcomes. Robot-assisted laparoscopy was considered a subtype of LM., Results: A total of 966 patients underwent myomectomy during the study period, including 731 LM cases (75.67%) and 235 AM cases (24.33%). Compared with patients undergoing LM, those undergoing AM had more myomas removed and heavier specimens (mean number of myomas, 12.60 vs 3.54, p ≤ .001; mean weight, 592.75 g vs 263.4 g, p ≤ .001). Conversion was necessary in 8 LM cases (1.09%). All conversions were reactive in nature and were associated with greater blood loss (mean, 1381.25 vs 167.95 mL; p ≤ .001) and longer hospital stay (mean, 3.13 vs 0.55 days; p ≤ .001) compared with cases without conversion. Factors associated with conversion included both the number and the weight of myomas removed (mean number, 9.75 vs 3.48, p = .003; mean weight, 667.9 vs 259.25 g, p = .015), especially with myomas weighing >500 g (odds ratio = 8.551; p = .005)., Conclusion: The risk of conversion for LM was low (1.09%) in this cohort, and was associated both with the number and the weight of myomas removed. LM is a feasible approach for surgical management of myomas in the majority of cases; however, when myomas are expected to weigh >500 g, it may be prudent to consider referring those cases to specialized centers with highly experienced teams., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

The assessment of surgical quality is complex, and an adequate case-mix correction is missing in currently applied quality indicators. The purpose of this study is to give an overview of all studies mentioning statistically significant associations between patient characteristics and surgical outcomes for laparoscopic hysterectomy (LH). Additionally, we identified a set of potential case-mix characteristics for LH. This systematic review was conducted according to the Meta-Analysis of Observational Studies in Epidemiology guidelines. We searched PubMed and EMBASE from January 1, 2000 to August 1, 2015. All articles describing statistically significant associations between patient characteristics and adverse outcomes of LH for benign indications were included. Primary outcomes were blood loss, operative time, conversion, and complications. The methodologic quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The included articles were summed per predictor and surgical outcome. Three sets of case-mix characteristics were determined, stratified by different levels of evidence. Eighty-five of 1549 identified studies were considered eligible. Uterine weight and body mass index (BMI) were the most mentioned predictors (described, respectively, 83 and 45 times) in high quality studies. For longer operative time and higher blood loss, uterine weight ≥ 250 to 300 g and ≥500 g and BMI ≥ 30 kg/m(2) dominated as predictors. Previous operations, adhesions, and higher age were also considered as predictors for longer operative time. For complications and conversions, the patient characteristics varied widely, and uterine weight, BMI, previous operations, adhesions, and age predominated. Studies of high methodologic quality indicated uterine weight and BMI as relevant case-mix characteristics for all surgical outcomes. For future development of quality indicators of LH and to compare surgical outcomes adequately, a case-mix correction is suggested for at least uterine weight and BMI. A potential case-mix correction for adhesions and previous operations can be considered. For both surgeons and patients it is valuable to be aware of potential factors predicting adverse outcomes and to anticipate this. Finally, to benchmark clinical outcomes at an international level, it is of the utmost importance to introduce uniform outcome definitions., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Objective: To assess features of power morcellators (blade diameter, circular vs oscillating cutting, blade rotation speed, experience level) regarding their effect on the amount of tissue spill. In addition, the amount of tissue spill after the initial two-thirds and final one-third of the morcellated specimen was evaluated., Design: In vitro study (Canadian Task Force classification II-2)., Setting: Laparoscopic skills lab of an academic hospital., Patients: Not applicable., Intervention: Power morcellation of beef tongue specimens., Measurements and Main Results: Twenty-four trials were performed. Morcellation was performed in 2 phases (phase 1: initial two-thirds of the total tissue; phase 2: last one-third of the tissue). With larger blade diameter a decline was observed in both the weight of the spilled particles (phase 1) and the number of spilled particles (phases 1 and 2 and both combined) (weight phase 1: 6.5 g vs 6.3 g vs 2.2 g for 12.5 mm vs 15 mm vs 20 mm, respectively, p = .04; number particles: phase 1, 10.2 vs 7.2 vs 2.7, p = .01; phase 2, 22.9 vs 19.0 vs 8.9, p = .02; total, 34.7 vs 26.2 vs 11.6, p = .01). Also, spinning of the tissue mass due to torque applied by the rotating blade occurred later when blade size increased, and the size of the spilled particles was larger (weight of morcellated tissue at onset of torque: 136 g vs 198 g vs 222 g, p = .07; size: .6 g vs .9 g vs .8 g, p = .1). In the oscillation mode there was less total spill (6.8 g/100 g vs 21.3 g/100 g, p = .01, for oscillation and circular cutting, respectively)., Conclusion: The present study demonstrates that less spill is created by power morcellators with an oscillating blade and/or a large diameter (≥20 mm). Furthermore, when using a large-diameter blade the spilled particles are larger, and less morcellation repetitions are needed. By combining these features with currently introduced contained morcellation, the safety of the morcellation process with respect to tissue spill can be further improved., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood., Methods: We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin-embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments., Results: PTEN was significantly lost in both endometriosis and invasive tumour tissues, while oestrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2 and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p ⩽ 0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodelling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker Wilms' tumour protein 1 (WT1) in OCCC, while endometriotic tissues showed significant co-expression of WT1 and ER., Conclusions: Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic programme for lineage-specific transformation of endometriosis to OCCC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hysterectomy is still one of the most frequently performed gynaecological procedures. The use of the laparoscopic approach has increased over recent years and a shift in indication has been observed. However, not every clinic or gynaecologist is able to provide laparoscopic hysterectomy for more challenging patients. Therefore, referral to an expert centre is of the highest importance in order to offer the patient the least invasive approach to hysterectomy. The advantages of the laparoscopic approach have become more evident over recent years. The widespread introduction of minimally invasive surgery means that surgeons are encountering new challenges, such as the rapid introduction of new instruments, the absolute increased incidence of rare complications and the provision of post-operative counselling on recovery. Maintaining knowledge of these matters is essential in order to secure the quality of care.

Study Objective: To compare closure times, cuff healing, and postoperative dyspareunia between barbed and traditional sutures during laparoscopic total hysterectomy., Design: A randomized clinical trial (Canadian Task Force classification I)., Setting: A university hospital., Patients: Sixty-three women undergoing total laparoscopic hysterectomy., Interventions: Total laparoscopic hysterectomy was performed using standard techniques. The vaginal cuff closure method was randomized to barbed suture (Quill; Angiotech Pharmaceuticals, Inc., Vancouver, Canada) or standard suture (Vicryl; Ethicon Inc., Somerville, NJ). The time required for cuff closure was documented. Patients were examined postoperatively to assess cuff healing, and a standardized sexual function questionnaire was administered preoperatively and at 3 months postoperatively., Measurements and Main Results: The mean vaginal cuff closure time was 10.4 minutes versus 9.6 minutes in the barbed versus standard suture group (p = .51). Cuff healing appeared similar between the 2 groups. Rates of dyspareunia, partner dyspareunia, and sexual function were similar in both groups at 3 months postoperatively. Vaginal cuff closure times were significantly faster among attendings compared with residents/fellows (7.1 vs. 12.8 minutes, respectively; p < .0001). The study was designed to have a statistical power of 80% to detect a difference of 5 minutes in cuff closure time between the 2 groups (α level of 0.05)., Conclusion: Laparoscopic vaginal cuff closure times are similar when using barbed sutures and braided sutures., (Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the use of venous thromboembolism (VTE) prophylaxis for laparoscopic surgery among members of the Society of Gynecologic Oncology (SGO)., Methods: A 23-item questionnaire was sent to all working/eligible SGO member e-mail addresses (n = 1356). Data were collected and analyzed using descriptive statistics. χ2 was used to determine differences in responses between groups., Results: Of the 287 (21.2%) responding SGO members, most (61.3%) estimated the risk of VTE for laparoscopic surgery between 1% and 2%. Most (51.2%) of respondents did not routinely use preoperative pharmacoprophylaxis, and most discontinued prophylaxis upon hospital discharge, regardless of benign (73.5%) or malignant (53.3%) pathology. Combination prophylaxis was preferred for procedures in the setting of intermediate- (50.2%) or high-complexity (78%), malignancy (70.7%), obesity (71.4%), multiple medical comorbidities (76%), or the elderly (64.5%). When compared with respondents of greater surgical volume, respondents who performed less than 5 laparoscopic cases per month were more likely to use sequential compression devices alone in the setting of malignancy (52.6%, P = 0.025). The omission of VTE prophylaxis was rare and varied depending on the patient scenario (0.7%-3.5%). When compared with younger respondents, those who were 61 to 70 years old more frequently omitted VTE prophylaxis in the setting of low-complexity procedures (22.2%, P = 0.003), obesity (11.1%, P = 0.021), multiple medical comorbidities (11.1%, P = 0.008), and the elderly (11.1%, P = 0.009)., Conclusions: Among SGO members, the preferred method of VTE prophylaxis during laparoscopic surgery for several high-risk patient scenarios was combination prophylaxis. The use versus nonuse and the preferred method of VTE prophylaxis were influenced by respondent age and surgical volume.

Brain-specific angiogenesis inhibitor 1 (BAI1), an orphan G protein-coupled receptor-type seven transmembrane protein, was recently found mutated or silenced in multiple human cancers and can interfere with tumor growth when overexpressed. Yet, little is known about its regulation and the molecular mechanisms through which this novel tumor suppressor exerts its anti-cancer effects. Here, we demonstrate that the N terminus of BAI1 is cleaved extracellularly to generate a truncated receptor and a 40-kDa fragment (Vasculostatin-40) that inhibits angiogenesis. We demonstrate that this novel proteolytic processing event depends on a two-step cascade of protease activation: proprotein convertases, primarily furin, activate latent matrix metalloproteinase-14, which then directly cleaves BAI1 to release the bioactive fragment. These findings significantly augment our knowledge of BAI1 by showing a novel post-translational mechanism regulating BAI1 activity through cancer-associated proteases, have important implications for BAI1 function and regulation, and present novel opportunities for therapy of cancer and other vascular diseases.

Objective: To compare cellular composition (fibroblasts vs. smooth muscle cells) and proliferation in uterine healing wounds after application of barbed compared with standard suture in a sheep model., Design: Randomized trial (Canadian Task Force classification I) using each animal as its own control., Setting: Certified animal research facility. Population or sample. 23 non-pregnant ewes., Methods: A myometrial incision was created with the harmonic scalpel in each horn of the bicornuate uterus. The incisions were randomly allocated to be closed using either polyglactin 210 (Vicryl®) or barbed suture. Three months later, uterine tissues were collected, fixed and used for determination of cellular composition and proliferation using histochemistry (Masson trichrome staining) and immunohistochemistry (staining of smooth muscle cell actin and Ki67, a marker of proliferating cells) followed by image analysis., Main Outcome Measures: Evaluation and comparison of the cellular composition and proliferation of uterine wounds after application of barbed vs. standard suture., Results: The ratio between connective tissue elements and smooth muscle cells, expression of smooth muscle cell actin and labeling index were similar in wounds after application of barbed compared with standard suture, but were different (p < 0.0001-0.05) in wounds than in non-wounded areas in uterus., Conclusion: Both barbed and standard sutures had similar effects on cellular composition and proliferation of uterine wounds in an animal model., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

The introduction of laparoscopy to gynecologic surgery has allowed for both innovative advancements and new challenges in the field. As the complexity of laparoscopically approached gynecologic cases continues to increase, it is imperative for surgeons to be aware of the risk of ureteral injury. Although rare, ureteral complications with gynecologic surgery may be quite morbid; therefore, knowledge about their prevention, diagnosis, and management is of the utmost importance.

Angiogenesis is a critical physiologic process that is appropriated during tumorigenesis. Little is known about how this process is specifically regulated in the brain. Brain angiogenesis inhibitor-1 (BAI1) is a brain-predominant seven-transmembrane protein that contains five antiangiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa antiangiogenic factor called vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on the intracranial growth of malignant gliomas and further study its antitumor mechanism. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong proangiogenic stimulus mediated by the oncoprotein epidermal growth factor receptor variant III (EGFRvIII). This tumor-suppressive effect is accompanied by a decrease in tumor vascular density, suggesting a potent antiangiogenic effect in the brain. Second, and consistent with this interpretation, we find that treatment with Vstat120 reduces the migration of cultured microvascular endothelial cells in vitro and inhibits corneal angiogenesis in vivo. Third, we show that these antivascular effects critically depend on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting the role of Vstat120 TSRs in mediating these effects. These results advance the understanding of brain-specific angiogenic regulation, and suggest that Vstat120 has therapeutic potential in the treatment of brain tumors and other intracerebral vasculopathies.

Pathologic angiogenesis has emerged as an important therapeutic target in several major diseases. Zebrafish offer the potential for high-throughput drug discovery in a whole vertebrate system. We developed the first quantitative, automated assay for antiangiogenic compound identification using zebrafish embryos. This assay uses transgenic zebrafish with fluorescent blood vessels to facilitate image analysis. We developed methods for automated drugging and imaging of zebrafish in 384-well plates and developed a custom algorithm to quantify the number of angiogenic blood vessels in zebrafish. The assay was used to screen the LOPAC1280 compound library for antiangiogenic compounds. Two known antiangiogenic compounds, SU4312 and AG1478, were identified as hits. Additionally, one compound with no previously known antiangiogenic activity, indirubin-3'-monoxime (IRO), was identified. We showed that each of the hit compounds had dose-dependent antiangiogenic activity in zebrafish. The IC(50) of SU4312, AG1478, and IRO in the zebrafish angiogenesis assay was 1.8, 8.5, and 0.31 micromol/L, respectively. IRO had the highest potency of the hit compounds. Moreover, IRO inhibited human umbilical vein endothelial cell tube formation and proliferation (IC(50) of 6.5 and 0.36 micromol/L, respectively). It is therefore the first antiangiogenic compound discovered initially in a zebrafish assay that also has demonstrable activity in human endothelial cell-based angiogenesis assays.

There is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4-treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations.

The commercially available Jak2 inhibitor, alpha-cyano-3,4-dihydroxy-N-benzylcinnamide (AG490), has been used extensively to study Jak2 kinase function. While alpha-cyano-3,4-dihydroxy-N-benzylcinnamide is a potent Jak2 inhibitor, it can inhibit a number of other kinase signaling pathways as well. To circumvent this problem, we sought to identify novel small molecule inhibitors of Jak2 tyrosine kinase activity. For this, we constructed a homology model of the Jak2 kinase domain and identified solvent accessible pockets on the surface of the structure. Using the DOCK program, we tested 6451 compounds of known chemical structure in silico for their ability to interact with a pocket positioned adjacent to the activation loop. We attained the top seven scoring compounds from the National Cancer Institute and tested their ability to inhibit Jak2 autophosphorylation in vitro. Using Western blot analysis, we found that one of the compounds, 1,2,3,4,5,6-hexabromocyclohexane, was able to potently, and directly, inhibit Jak2 autophosphorylation. Characterization of this compound revealed that it inhibits Jak2 tyrosine autophosphorylation in both a time- and concentration-dependent manner. It greatly reduced growth hormone-mediated Jak2 autophosphorylation but did not block autophosphorylation of the epidermal growth factor receptor. Furthermore, doses as high as 100 muM were not toxic to cells as measured by their ability to exclude propidium iodide. As such, we believe that this compound could serve as a lead compound for a new generation of Jak2 inhibitors and, perhaps, be useful in elucidating the mechanisms of Jak2 kinase function.

Angiotensin II is a well-known vasoactive peptide, but it can also act as a potent growth factor, partially through activation of the tyrosine kinase Jak2. Activated Jak2 tyrosine phosphorylates and activates members of the Signal Transducers and Activators of Transcription (STAT) family of cytoplasmic transcription factors. Recently, we demonstrated that tryptophan 1020 and glutamic acid 1024 within the Jak2 activation loop are required for Jak2 tyrosine kinase activity. Here, we sought to elucidate the requirement of glutamic acid 1024 for Jak2 function. Using molecular modeling algorithms of the Jak2 kinase domain, we identified a putative interaction between glutamic acid 1024 and an arginine at position 1113. We generated a series of charge-based substitution mutations at position 1113 and found that conversion of arginine 1113 to glutamic acid, alanine, or lysine prevented Jak2 autophosphorylation. Furthermore, mutation of arginine 1113 prevented the following angiotensin II-dependent processes from occurring: (1) Jak2 tyrosine phosphorylation, (2) Jak2/AT1receptor co-association, (3) STAT1 recruitment to the Jak2/AT1receptor complex, (4) STAT1 tyrosine phosphorylation, and (5) STAT-mediated gene expression. We determined that the interaction between glutamic acid 1024 and arginine 1113 consists of two distinct hydrogen bonds. We conclude that these hydrogen bond interactions are critical for Jak2 kinase function and subsequent angiotensin II-dependent activation of the Jak/STAT signaling pathway.

In vascular smooth muscle cells, Jak2 tyrosine kinase becomes activated in response to oxidative stress in the form of hydrogen peroxide. Although it has been postulated that hydrogen peroxide-induced Jak2 activation promotes cell survival, this has never been tested. We therefore examined the role that Jak2 plays in vascular smooth muscle cell apoptosis following hydrogen peroxide treatment. Here, we report that Jak2 tyrosine kinase activation by hydrogen peroxide is required for apoptosis of vascular smooth muscle cells. Upon treatment of primary rat aortic smooth muscle cells with hydrogen peroxide, we observed laddering of genomic DNA and nuclear condensation, both hallmarks of apoptotic cells. However, apoptosis was prevented by either the expression of a dominant negative Jak2 protein or by the Jak2 pharmacological inhibitor AG490. Moreover, expression of the proapoptotic Bax protein was induced following hydrogen peroxide treatment. Again, expression of a dominant negative Jak2 protein or treatment of cells with AG490 prevented this Bax induction. Following Bax induction by hydrogen peroxide, mitochondrial membrane integrity was compromised, and caspase-9 became activated. In contrast, in cells expressing a Jak2 dominant negative we observed that mitochondrial membrane integrity was preserved, and no caspase-9 activation occurred. These data demonstrate that the activation of Jak2 tyrosine kinase by hydrogen peroxide is essential for apoptosis of vascular smooth muscle cells. Furthermore, this report identifies Jak2 as a potential therapeutic target in vascular diseases in which vascular smooth muscle cell apoptosis contributes to pathological progression.

Previous work has shown that inhibition of Jak2 via the pharmacological compound AG490 blocks the angiotensin II (Ang II)-dependent activation of ERK2, thereby suggesting an essential role of Jak2 in ERK activation. However, recent studies have thrown into question the specificity of AG490 and therefore the role of Jak2 in ERK activation. To address this, we reconstituted an Ang II signaling system in a Jak2-/-cell line and measured the ability of Ang II to activate ERK2 in these cells. Controls for this study were the same cells expressing Jak2 via the addition of a Jak2 expression plasmid. In the cells expressing Jak2, Ang II induced a marked increase in ERK2 activity as measured by Western blot analysis and in vitro kinase assays. ERK2 activity returned to basal levels within 30 min. However, in the cells lacking Jak2, Ang II treatment resulted in ERK2 activation that did not return to basal levels until 120 min after ligand addition. Analysis of phosphatase gene expression revealed that Ang II induced mitogen-activated protein kinase phosphatase 1 (MKP-1) expression in cells expressing Jak2 but failed to induce MKP-1 expression in cells lacking Jak2. Therefore, our results suggest that Jak2 is not required for Ang II-induced ERK2 activation. Rather Jak2 is required for Ang II-induced ERK2 inactivation via induction of MKP-1 gene expression.

Discovered roughly 10 yr ago, Jak2 tyrosine kinase has emerged as a critical molecule in mammalian development, physiology, and disease. Here, we review the early history of Jak2 and its role in health and disease. We will also review its critical role in mediating cytokine-dependent signal transduction. Additionally, more recent work demonstrating the importance of Jak2 in G protein-coupled receptor and tyrosine kinase growth factor receptor signal transduction will be discussed. The cellular and biochemical mechanisms by which Jak2 tyrosine kinase is activated and regulated within the cell also will be reviewed. Finally, structure-function and pharmacological-based studies that identified structural motifs and amino acids within Jak2 that are critical for its function will be examined. By reviewing the biology of Jak2 tyrosine kinase at the molecular, cellular, and physiological levels, we hope to advance the understanding of how a single gene can have such a profound impact on development, physiology, and disease.

Jak2 is a member of the Janus family of tyrosine kinases and is known to be activated by a wide variety of ligands. Here, we sought to identify amino acid residues within Jak2 that are essential for its activation. We provide evidence that glutamic acid 1046 (E1046) is one such residue. Using molecular modeling algorithms of the Jak2 kinase domain, we identified a putative molecular interaction between E1046 and tryptophan 1020 (W1020). Conversion of E1046 to either arginine (E 1046R), alanine (E1046A), aspartic acid (E1046D) or glutamine (E1046Q) abolished Jak2 kinase activity as measured by autophosphorylation assays. Conversion of W1020 to glycine (W1020G) similarly abolished Jak2 kinase activity. Finally, we tested the ability of the E1046R mutant to activate the Jak/STAT signaling pathway in a ligand-dependent signaling system. The ability of angiotensin II to activate the Jak/STAT signaling pathway in cells expressing the E1046R mutant was severely compromised as measured by reduced (1) Jak2 autophosphorylation (2) Jak2 kinase activity (3) AT1/Jak2 co-association (4) Stat1 tyrosine phosphorylation and (5) angiotensin Il-mediated gene transcription. Thus, these studies demonstrate for the first time, the critical role of E1046 in mediating Jak2 activation and its subsequent downstream signaling events.

Weanling Fischer 344/N (F344) rats and the first filial hybrid of C57BL/6 x C3H (B6C3F1) mice and retired breeders from the parental stocks of these strains were monitored over a 5-yr-period by examining the histopathology of selected organs and comparing those results to viral and mycoplasmal serology and the intestinal tract bacterial flora of each animal on an individual basis. Serology gave no evidence of viral infection, but Mycoplasma arthriditis antibodies were detected. Reactivity of serum of adult C57BL/6 female mice with control cells or media (tissue culture, TC) was seen in a significant number of mice. TC reactivity correlated positively with lymphoid perivascular infiltrates, predominantly of the lungs, suggesting an allergic response in development of the lesions. Other lesions of note consisted of Harderian gland inflammation of rats, focal necrotizing lesions of the liver of both species, and thickening of the pleura and adjacent pulmonary interstitium of weanling rats. Embolization of bacteria from the gastrointestinal tract to the liver was considered a possible cause of the liver necrosis in both species. Although lesions of the lung and Harderian gland of the rats are similar to those caused by known viral agents, the cause of the latter could not be determined as these animals were negative for viral antibodies and the former was considered to be related to incomplete pulmonary development in the young rat. Features differentiating the lesions observed in animals of this survey from those caused by viral infection are discussed.