Quality of Life after Laparoscopic and Open Abdominal Myomectomy.

STUDY OBJECTIVE: To evaluate the baseline and postoperative changes in quality of life and symptom-severity scores in women undergoing laparoscopic or open abdominal myomectomy for symptomatic myomas. DESIGN: Prospective cohort study of patients choosing myomectomy for symptomatic uterine myomas. SETTING: Academic medical center. PATIENTS: A total of 143 women enrolled in the study. Of these, 80 women completed both a preoperative questionnaire and at least 1 postoperative questionnaire between 6 and 27 months after surgery. INTERVENTIONS: A total of 52 women had open abdominal myomectomy, and 28 had laparoscopic myomectomy between October 2014 and September 2017. MEASUREMENTS AND MAIN RESULTS: The results of the Uterine Fibroid Symptom and Health-Related Quality-of-Life Questionnaire were compared before and after laparoscopic or open myomectomy. Women undergoing open abdominal myomectomy had larger and more numerous myomas than women undergoing laparoscopic myomectomy. Baseline quality-of-life scores were less adversely affected for women having laparoscopic myomectomy (mean [standard deviation], 57 [24] laparoscopic vs 43 [19] open abdominal, p = .01). However, baseline symptom-severity scores were statistically similar (49 [22] for laparoscopic and 57 [20] for open abdominal, p = .08) approaches. Six to 12 months after surgery, both open abdominal and laparoscopic surgeries provided excellent and similar improvements in symptom-severity and quality of life (postoperative symptoms severity scores, mean [standard deviation], 20 [14] laparoscopic vs 13 [11] open abdominal, p = .24 and quality-of-life scores, mean [standard deviation], 91 [16] laparoscopic vs 88 [17] open abdominal, p = .49). These improvements were sustained for women who returned questionnaires up to 27 months of follow-up. CONCLUSION: Women with symptomatic myomas have a compromised quality of life, and they experience a similarly dramatic improvement in quality of life and decrease in symptom-severity after both laparoscopic and open abdominal myomectomies.

COVID-19 and postural tachycardia syndrome: a case series.

BACKGROUND: Postural tachycardia syndrome (PTS) is a novel identified sequela of COVID-19 infection. This observational study describes clinical presentation, testing, and treatment response in seven patients diagnosed with PTS following COVID-19 infection. CASE SUMMARY: A total of seven active patients (three collegiate athletes, one recreational athlete, two registered nurses, one hospitality employee), age 24 ± 6 years, and six females were followed for a mean of 152 ± 105 days after contracting COVID-19. Tilt table was performed to establish the diagnosis. The most common presenting symptoms were palpitations (7/7), dyspnoea (6/7), and gastrointestinal complaints (5/7). One patient required hospitalization for symptom management. The mean latency of PTS onset following COVID-19 was 21 ± 15 days. Electrocardiograms (ECGs) demonstrated sinus rhythm in all patients, one with resting sinus tachycardia. Echocardiogram demonstrated normal systolic and diastolic left ventricular function in all patients. On tilt table testing, baseline heart rate (HR) was 72 ± 12 with maximum HR reaching 136 ± 13. Six of seven patients failed to respond to supportive therapy alone, and two patients failed medical management with ivabradine, midodrine, and/or metoprolol. Of three severely symptomatic patients, two demonstrated some degree of clinical recovery with intravenous immunoglobulin (IVIG). DISCUSSION: This novel case series describes the development of PTS in the context of COVID-19 infection. Severity of symptoms and response to treatment was heterogeneous. Interestingly, patients were poorly responsive to traditional PTS treatments, but IVIG showed potential as a possible therapeutic strategy for refractory PTS in two patients, particularly following COVID-19 infection.

Massive cotyledenoid leiomyoma treated with uterine-conserving surgery.

OBJECTIVE: To describe and illustrate a massive cotyledenoid leiomyoma treated with uterine-conserving surgery. DESIGN: Case report. SETTING: Medical center. PATIENTS: A 39-year-old woman with a large abdominal mass and a magnetic resonance imaging scan showing a 28-cm multi-lobulated mass. INTERVENTIONS: Laparotomy and myomectomy. MAIN OUTCOME MEASURES: Recurrence and need for repeat surgery. RESULTS: No recurrence at 8 years of follow-up. CONCLUSIONS: Cotyledonoid leiomyomas are rare. These benign tumors may be suspected preoperatively based on MRI appearance. Frozen section suggests a benign process and uterine-conserving surgery may be successfully accomplished.

Indications for morcellation in gynecologic surgery.

PURPOSE OF REVIEW: Minimally invasive gynecologic procedures, in particular laparoscopic hysterectomy and myomectomy, often require tissue morcellation. RECENT FINDINGS: Whether morcellated or not, myometrial cells can be found in the abdomen and pelvis after either laparoscopic or open myomectomy. Following morcellation, careful inspection for and removal of tissue fragments and copious irrigation and suctioning of fluid can remove residual tissue and cells without the use of containment bags. The dogma of not 'cutting-through' cancer is not correct for many surgical specialties and irrelevant with regards to leiomyosarcoma (LMS) and minimally invasive gynecologic surgery. Eliminating residual disease in the pelvis and abdomen should be the goal of myomectomy or hysterectomy. SUMMARY: Morcellation of excised tissue is necessary for many women with symptomatic fibroids who choose to undergo laparoscopic myomectomy or hysterectomy. LMS is an uncommon disease, with a poor prognosis due to early hematogenous metastasis to lung, bone and liver. Preoperatively, it is often difficult to differentiate from benign fibroids. LMS has a high propensity for local recurrence despite performance of total hysterectomy. Efforts to remove all tissue and cells from the pelvis and abdomen should be the goal of minimally invasive surgery with morcellation.

Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton.

Vitamin C, or ascorbic acid, both tightens the endothelial permeability barrier in basal cells and also prevents barrier leak induced by inflammatory agents. Barrier tightening by ascorbate in basal endothelial cells requires nitric oxide derived from activation of nitric oxide synthase. Although ascorbate did not affect cyclic AMP levels in our previous study, there remains a question of whether it might activate downstream cyclic AMP-dependent pathways. In this work, we found in both primary and immortalized cultured endothelial cells that ascorbate tightened the endothelial permeability barrier by ∼30%. In human umbilical vein endothelial cells, this occurred at what are likely physiologic intracellular ascorbate concentrations. In so doing, ascorbate decreased measures of oxidative stress and also flattened the cells to increase cell-to-cell contact. Inhibition of downstream cyclic AMP-dependent proteins via protein kinase A did not prevent ascorbate from tightening the endothelial permeability barrier, whereas inhibition of Epac1 did block the ascorbate effect. Although Epac1 was required, its mediator Rap1 was not activated. Furthermore, ascorbate acutely stabilized microtubules during depolymerization induced by colchicine and nocodazole. Over several days in culture, ascorbate also increased the amount of stable acetylated α-tubulin. Microtubule stabilization was further suggested by the finding that ascorbate increased the amount of Epac1 bound to α-tubulin. These results suggest that physiologic ascorbate concentrations tighten the endothelial permeability barrier in unstimulated cells by stabilizing microtubules in a manner downstream of cyclic AMP that might be due both to increasing nitric oxide availability and to scavenging of reactive oxygen or nitrogen species.

Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability.

Vascular endothelial growth factor (VEGF) increases endothelial barrier permeability, an effect that may contribute to macular edema in diabetic retinopathy. Since vitamin C, or ascorbic acid, can tighten the endothelial permeability barrier, we examined whether it could prevent the increase in permeability due to VEGF in human umbilical vein endothelial cells (HUVECs). As previously observed, VEGF increased HUVEC permeability to radiolabeled inulin within 60 min in a concentration-dependent manner. Loading the cells with increasing concentrations of ascorbate progressively prevented the leakage caused by 100 ng/ml VEGF, with a significant inhibition at 13 µM and complete inhibition at 50 µM. Loading cells with 100 µM ascorbate also decreased the basal generation of reactive oxygen species and prevented the increase caused by both 100 ng/ml VEGF. VEGF treatment decreased intracellular ascorbate by 25%, thus linking ascorbate oxidation to its prevention of VEGF-induced barrier leakage. The latter was blocked by treating the cells with 60 µM L-NAME (but not D-NAME) as well as by 30 µM sepiapterin, a precursor of tetrahydrobiopterin that is required for proper function of endothelial nitric oxide synthase (eNOS). These findings suggest that VEGF-induced barrier leakage uncouples eNOS. Ascorbate inhibition of the VEGF effect could thus be due either to scavenging superoxide or to peroxynitrite generated by the uncoupled eNOS, or more likely to its ability to recycle tetrahydrobiopterin, thus avoiding enzyme uncoupling in the first place. Ascorbate prevention of VEGF-induced increases in endothelial permeability opens the possibility that its repletion could benefit diabetic macular edema.

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

What is the Future of Open Intraperitoneal Power-Morcellation of Fibroids?

In November 2014, the Food and Drug Administration (FDA) calculated that for every 498 women having surgery for presumed fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). The FDA issued a safety communication warning against the use of laparoscopic morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids. This communication was prompted by concern that if a patient had an occult LMS, the morcellator might spread tumor cells within the peritoneal cavity. We submit that the FDA directive was based on a flawed and misleading analysis. More rigorous evidence estimates the prevalence of LMS among women operated upon for presumed uterine fibroids at approximately one in 2000 women, significantly lower than the FDA's estimate. In addition, there is no reliable evidence that morcellation influences survival or that power-morcellation is inferior to vaginal or mini-lap morcellation with a scalpel. Recent publication shows that open surgery carries more risk for women when compared with minimally invasive surgery. Although the possibility of occult LMS should be considered by women and their gynecologists, we suggest that current morcellation techniques be continued for women who wish to benefit from minimally invasive surgery. Investigation into new and, hopefully, better morcellating devices may make the procedure safer for women.

Management of Hemorrhage During Gynecologic Surgery.

Surgical blood loss of >1000 mL or blood loss that requires a blood transfusion usually defines intraoperative hemorrhage. Intraoperative hemorrhage has been reported in 1% to 2% of hysterectomy studies. Cardiovascular instability with significant hypotension often results from a loss of 30% to 40% of the patient's blood volume and >40% blood loss is life threatening. Preparation, planning, and practicing for a massive hemorrhage is essential for all surgeons and gynecologic operating room teams. Emergency steps should be written and posted in the operating room and rehearsed quarterly.

Intracellular Ascorbate Prevents Endothelial Barrier Permeabilization by Thrombin.

Intracellular ascorbate (vitamin C) has previously been shown to tighten the endothelial barrier and maintain barrier integrity during acute inflammation in vitro. However, the downstream effectors of ascorbate in the regulation of endothelial permeability remain unclear. In this study, we evaluated ascorbate as a mediator of thrombin-induced barrier permeabilization in human umbilical vein endothelial cells and their immortalized hybridoma line, EA.hy926. We found that the vitamin fully prevented increased permeability to the polysaccharide inulin by thrombin in a dose-dependent manner, and it took effect both before and after subjection to thrombin. Thrombin exposure consumed intracellular ascorbate but not the endogenous antioxidant GSH. Likewise, the antioxidants dithiothreitol and tempol did not reverse permeabilization. We identified a novel role for ascorbate in preserving cAMP during thrombin stimulation, resulting in two downstream effects. First, ascorbate maintained the cortical actin cytoskeleton in a Rap1- and Rac1-dependent manner, thus preserving stable adherens junctions between adjacent cells. Second, ascorbate prevented actin polymerization and formation of stress fibers by reducing the activation of RhoA and phosphorylation of myosin light chain. Although ascorbate and thrombin both required calcium for their respective effects, ascorbate did not prevent thrombin permeabilization by obstructing calcium influx. However, preservation of cAMP by ascorbate was found to depend on both the production of nitric oxide by endothelial nitric-oxide synthase, which ascorbate is known to activate, and the subsequent generation cGMP by guanylate cyclase. Together, these data implicate ascorbate in the prevention of inflammatory endothelial barrier permeabilization and explain the underlying signaling mechanism.

Ascorbic acid transport in brain microvascular pericytes.

Intracellular vitamin C, or ascorbic acid, has been shown to prevent the apoptosis of cultured vascular pericytes under simulated diabetic conditions. We sought to determine the mechanism by which ascorbate is transported into pericytes prior to exerting this protective effect. Measuring intracellular ascorbate, we found that pericytes display a linear uptake over 30 min and an apparent transport Km of 21 µM, both of which are consistent with activity of the Sodium-dependent Vitamin C Transporter 2 (SVCT2). Uptake of both radiolabeled and unlabeled ascorbate was prevented by inhibiting SVCT2 activity, but not by inhibiting the activity of GLUT-type glucose transporters, which import dehydroascorbate to also generate intracellular ascorbate. Likewise, uptake of dehydroascorbate was prevented with the inhibition of GLUTs, but not by inhibiting the SVCT2, indicating substrate specificity of both transporters. Finally, presence of the SVCT2 in pericytes was confirmed by western blot analysis, and immunocytochemistry was used to localize it to the plasma membrane and intracellular sites. Together, these data clarify previous inconsistencies in the literature, implicate SVCT2 as the pericyte ascorbate transporter, and show that pericytes are capable of concentrating intracellular ascorbate against a gradient in an energy- and sodium-dependent fashion.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

Survival and growth patterns of white spruce (Picea glauca [Moench] Voss) rangewide provenances and their implications for climate change adaptation.

Intraspecific assisted migration (ISAM) through seed transfer during artificial forest regeneration has been suggested as an adaptation strategy to enhance forest resilience and productivity under future climate. In this study, we assessed the risks and benefits of ISAM in white spruce based on long-term and multilocation, rangewide provenance test data. Our results indicate that the adaptive capacity and growth potential of white spruce varied considerably among 245 range-wide provenances sampled across North America; however, the results revealed that local populations could be outperformed by nonlocal ones. Provenances originating from south-central Ontario and southwestern Québec, Canada, close to the southern edge of the species' natural distribution, demonstrated superior growth in more northerly environments compared with local populations and performed much better than populations from western Canada and Alaska, United States. During the 19-28 years between planting and measurement, the southern provenances have not been more susceptible to freezing damage compared with local populations, indicating they have the potential to be used now for the reforestation of more northerly planting sites; based on changing temperature, these seed sources potentially could maintain or increase white spruce productivity at or above historical levels at northern sites. A universal response function (URF), which uses climatic variables to predict provenance performance across field trials, indicated a relatively weak relationship between provenance performance and the climate at provenance origin. Consequently, the URF from this study did not provide information useful to ISAM. The ecological and economic importance of conserving white spruce genetic resources in south-central Ontario and southwestern Québec for use in ISAM is discussed.

Ascorbic acid prevents high glucose-induced apoptosis in human brain pericytes.

High glucose concentrations due to diabetes increase apoptosis of vascular pericytes, impairing vascular regulation and weakening vessels, especially in brain and retina. We sought to determine whether vitamin C, or ascorbic acid, could prevent such high glucose-induced increases in pericyte apoptosis. Culture of human microvascular brain pericytes at 25 mM compared to 5mM glucose increased apoptosis measured as the appearance of cleaved caspase 3. Loading the cells with ascorbate during culture decreased apoptosis, both at 5 and 25 mM glucose. High glucose-induced apoptosis was due largely to activation of the receptor for advanced glycation end products (RAGE), since it was prevented by specific RAGE inhibition. Culture of pericytes for 24h with RAGE agonists also increased apoptosis, which was completely prevented by inclusion of 100 µM ascorbate. Ascorbate also prevented RAGE agonist-induced apoptosis measured as annexin V binding in human retinal pericytes, a cell type with relevance to diabetic retinopathy. RAGE agonists decreased intracellular ascorbate and GSH in brain pericytes. Despite this evidence of increased oxidative stress, ascorbate prevention of RAGE-induced apoptosis was not mimicked by several antioxidants. These results show that ascorbate prevents pericyte apoptosis due RAGE activation. Although RAGE activation decreases intracellular ascorbate and GSH, the prevention of apoptosis by ascorbate may involve effects beyond its function as an antioxidant.