Disorders with Ophthalmic and Thoracic Involvement.

A variety of systemic conditions involve the thorax and the eyes. While subtle or nonspecific eye symptoms can be the initial clinical manifestation of some disorders, there can be additional manifestations in the thorax that lead to a specific diagnosis and affect patient outcomes. For instance, the initial clinical manifestation of Sjögren syndrome is dry eye or xerophthalmia; however, the presence of Sjögren lung disease represents a fourfold increase in mortality. Likewise, patients with acute sarcoidosis can initially present with pain and redness of the eye from uveitis in addition to fever and parotitis. Nearly 90% of patients with sarcoidosis have thoracic involvement, and the ophthalmologic symptoms can precede the thoracic symptoms by several years in some cases. Furthermore, a diagnosis made in one system can result in the screening of other organs as well as prompt genetic evaluation and examination of family members, such as in the setting of Marfan syndrome or Ehlers-Danlos syndrome. Multimodality imaging, particularly CT and MRI, plays a vital role in identification and characterization of these conditions. While it is helpful for ophthalmologists to be knowledgeable about these conditions and their associations so that they can order the pertinent radiologic studies, it is also important for radiologists to use the clues from ophthalmologic examination in addition to imaging findings to suggest a specific diagnosis. Systemic conditions with thoracic and ophthalmologic manifestations can be categorized as infectious, inflammatory, autoimmune, neoplastic, or hereditary in origin. The authors describe a spectrum of these conditions based on their underlying cause. ©RSNA, 2024.

Ureteroarterial fistula embolization by transradial approach: A case report.

Ureteroarterial fistula is a rare condition wherein a communication develops between a ureter and the common, internal, or external iliac artery. Localizing the fistula can be difficult, as cystoscopy, CT angiography, and conventional angiography have low sensitivity in identifying the fistula. Provocative maneuvers within the ureter, however, can aid in the visualization of fistulae on angiography. Prior reports of endovascular repair have utilized transfemoral access, which makes performing concurrent provocative maneuvers in the ureter challenging. We present a case of successful endovascular ureteroarterial fistula localization and embolization in an 80-year-old woman with recurrent gross hematuria by the transradial approach, aided by concurrent provocative maneuvers performed via cystoscopy. The transradial endovascular approach facilitated a multi-disciplinary joint procedure that resulted in effective treatment of the patient.

Urinary Catheter Management Approaches Among Women Undergoing Benign Gynecologic Surgery: A Randomized Trial.

OBJECTIVE: The objective of this study was to identify differences in voiding trial success rates between delayed (postoperative day 1) and day of surgery catheter removal ("fast track") among women undergoing benign gynecologic surgery. Rates of urinary tract infection, patient satisfaction, and lower urinary tract symptoms were compared between catheter management schemes. METHODS: Women undergoing benign gynecologic surgery were randomized to either "conventional" delayed urinary catheter care removal on postoperative day 1 or day of surgery catheter removal (fast track) 4 hours after surgery. Subjects were asked to complete a brief survey recording bladder function before and during their hospitalization and satisfaction with their catheter management. Subjects were contacted by phone 2 to 3 weeks after the index surgery to survey their bladder function including symptoms (eg, dysuria) or treatment indicative of a bladder infection. RESULTS: The median dwell time for Foley catheters in the "fast-track" group was 8.15 hours (SD = 375 minutes), whereas the median dwell time in the conventional group was 20.6 hours (SD = 265 minutes), which was significantly different (P < 0.001). Overall, 153 (93%) patients passed their voiding trial with significantly more patients passing their voiding trial in the conventional management group (P = 0.01). There was no difference in the Urogenital Distress Inventory scores at 2 weeks between catheter management cohorts (P = 0.81). CONCLUSIONS: Foley dwell time is significantly reduced in the fast-track cohort. Voiding trial failure is higher with same-day catheter removal but that rate of failure rate is low. Patient satisfaction, the Urogenital Distress Inventory score, and postoperative urinary tract infection rates are not significantly different between cohorts.

Nationwide salpingectomy rates for an indication of permanent contraception before and after published practice guidelines.

OBJECTIVE: To identify the nationwide rate of salpingectomy for permanent contraception before and after the January 2015 American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, Salpingectomy for Ovarian Cancer Prevention. STUDY DESIGN: Using ICD-9/10 diagnosis and procedure codes within the Vizient database, we identify permanent contraception procedures with and without salpingectomy, among females 18-50 years old between January 2013 and January 2017. Subject, hospital characteristics and costs information were recorded. To determine the changes in salpingectomy rates over time analysis was conducted using the Cochran-Armitage trend test and logistic regression models. RESULTS: A total of 211,312 women across 303 Vizient-member hospitals underwent a permanent contraception procedure over the study period. Of these, 174,930 subjects were selected from 160 hospitals that contributed data over the full 49-month period. Overall, 25,882 (14.8%) subjects underwent a salpingectomy for an indication of permanent contraception. Higher salpingectomy rates were identified among larger (p<.0001), teaching (p<.0001) hospitals versus smaller, non-teaching hospitals and in subjects with commercial/private payers (p<.0001). A lower salpingectomy rate was observed in Northeast hospitals (p<.0001). Median total hospital costs differed by $25 between permanent contraceptions performed with and without salpingectomy. The proportion of salpingectomies was <1% in January 2013 slowly rising to 20.6% in October 2015 and then 61.5% by January 2017 (p<.0001). During the pre-opinion period (Jan 2013-Dec 2014) the monthly increase in the odds of salpingectomy was 6% (OR 1.06, 95% CI 1.05, 1.06) compared to a monthly increase of 18% (OR 1.18, 95% CI 1.18, 1.18) during the post-opinion period (Jan 2015-Jan 2017). CONCLUSIONS: The nationwide rate of salpingectomies for permanent contraception has steadily increased among Vizient-member hospitals since the ACOG committee opinion. IMPLICATIONS: Salpingectomy as an approach to permanent contraception in the United States is increasing since the ACOG Committee Opinion with differing utilization rates by hospital type, region, size, and patient payer types. Physician behavior may be influenced by practice guidelines but other factors mitigate the effect.

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity.

Road to recovery after transvaginal surgery for urethral mesh perforation: evaluation of outcomes and subsequent procedures.

INTRODUCTION AND HYPOTHESIS: Urethral injury resulting from transvaginal mesh slings is a rare complication with an estimated incidence of <1%. Our objective was to review the surgical management and functional outcomes of women presenting with urethral mesh perforation following midurethral sling (MUS) placement. METHODS: This was a retrospective multicenter review of women who from January 2011 to March 2016 at two institutions underwent mesh sling excision for urethral perforation with Female Pelvic Medicine and Reconstructive Surgery fellowship-trained surgeons. Data comprising preoperative symptoms, operative details, and postoperative outcomes were collected by telephone (n 13) or based on their last follow-up appointment. RESULTS OBTAINED: Nineteen women underwent transvaginal sling excision for urethral mesh perforation. Eight (42%) patients had undergone previous sling revision surgery. Sixty percent of women had resolution of their pelvic pain postoperatively. At follow-up, 92% reported urinary incontinence (UI), and three had undergone five additional procedures for vaginal prolapse mesh exposure (n 1), incontinence (onabotulinum toxin injection n 1, rectus fascia autologous sling n 1), prolapse (colpopexy n 1), and pain (trigger-point injection n 1). Patient global impression of improvement data was available for 13 patients, of whom seven (54%) rated their postoperative condition as Very much better or Much better. CONCLUSIONS: The management of urethral mesh perforation is complex. Most women reported resolution of their pelvic pain and a high rate of satisfaction with their postoperative condition despite high rates of incontinence.

Fractional CO2 laser of the vagina for genitourinary syndrome of menopause: Is the out-of-pocket cost worth the outcome of treatment?

OBJECTIVES: The purpose of this study is to assess patient's satisfaction treatment outcomes and out-of-pocket expense for the fractional CO2 laser (SmartXide) in the treatment of genitourinary symptoms of menopause (GSM). MATERIALS AND METHODS: A multicenter retrospective cohort study of patients who completed a course of three vaginal treatments with the SmartXide11 Fractional CO2 laser. Patients contacted via telephone and asked to participate in questionnaires to evaluate for adverse outcomes since last treatment, symptom severity before and after treatment, patient satisfaction with treatment, patient satisfaction with out-of-pocket expense, and sexual function. RESULTS: Of the 368 patients contacted, 122 agreed to be interviewed. No patients reported seeking emergent medical treatment. Patient reported vaginal dryness significantly improved following treatment (P < 0.05). The frequency of intercourse increased from "once a month" to "few times a month" (P < 0.001). The vast majority of patients reported being satisfied with their treatment results (86%) and with the cost of treatment (78%). Satisfaction with the out-of-pocket expense did not correlate with household income (P = 0.07). CONCLUSION: The SmartXide Fractional CO2 laser is a safe and efficacious treatment for GSM. This treatment is associated with a high level of patient satisfaction with both treatment results and out-of-pocket expense. Lasers Surg. Med. 49:882-885, 2017. © 2017 Wiley Periodicals, Inc.

Anterior compartment prolapse: what's new?

PURPOSE OF REVIEW: The purpose of this review is to summarize the treatment options for anterior compartment prolapse, describe the role that apical suspension plays in the correction of anterior vaginal wall prolapse, and assess the risks and benefits of biologic and synthetic graft use in anterior compartment repair. RECENT FINDINGS: In 2016, The Cochrane Review published a review of 37 trials including 4023 participants finding that compared to native tissue repair, the use of synthetic mesh resulted in reduced symptomatic prolapse recurrence, anatomic recurrence, and repeat prolapse surgery. There was insufficient evidence regarding quality of life improvement or the use of biologic grafts. Of note the differences between native tissue and mesh kit repairs were not large. SUMMARY: A strong consideration should be on the correction of apical prolapse when present; isolated anterior wall repairs should be pursued with caution. The surgeon may consider the use of augmenting materials in their repair of anterior vaginal wall prolapse, although the available evidence is not strongly supportive of their use given potential risks.

Lasers for pelvic floor dysfunctions: is there evidence?

PURPOSE OF REVIEW: The purpose of this review is to discuss the available energy sources used in the vaginal canal that are currently being promoted for certain pelvic floor conditions and explore the body of peer-reviewed literature supporting their use. RECENT FINDINGS: The majority of research has focused on the use of fractional CO2 laser treatment for genitourinary syndrome of menopause (GSM). Most of these studies are nonrandomized prospective studies, but their data consistently shows an improvement in symptoms without significant side effects. SUMMARY: Vaginal laser treatment for GSM is of particular interest to gynecologists as it provides patients with a history of estrogen receptor positive breast cancer, thromboembolic event, or other contraindication to hormone therapy, an effective treatment option. Currently, we are in the early stages of scientific investigation into the use of lasers in the treatment of pelvic floor dysfunction, but the emerging data is encouraging. The existing data is limited to mostly observational studies with additional quality randomized controlled trials and sham studies needed to ensure that physicians are providing the optimum evidence-based treatments to their patients. At the present time there is insufficient data to promote these therapies for stress incontinence, vaginal tightening, or other pelvic floor abnormalities.

ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation.

Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest - and, in the absence of p53, non-apoptotic cell death - redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition.

Titin stiffness modifies the force-generating region of muscle sarcomeres.

The contractile units of striated muscle, the sarcomeres, comprise the thick (myosin) and thin (actin) filaments mediating active contraction and the titin filaments determining "passive" elasticity. We hypothesized that titin may be more active in muscle contraction by directly modulating thick-filament properties. We used single-myofibril mechanical measurements and atomic force microscopy of individual sarcomeres to quantify the effects of sarcomere strain and titin spring length on both the inter-filament lattice spacing and the lateral stiffness of the actin-myosin overlap zone (A-band). We found that strain reduced the lattice spacing similarly in sarcomeres with stiff (rabbit psoas) or compliant titin (rabbit diaphragm), but increased A-band lateral stiffness much more in psoas than in diaphragm. The strain-induced alterations in A-band stiffness that occur independently of lattice spacing effects may be due to titin stiffness-sensing by A-band proteins. This mechanosensitivity could play a role in the physiologically important phenomenon of length-dependent activation of striated muscle.

Rectal perforation at the time of vaginal mesh placement and subsequent abdominal mesh removal.

INTRODUCTION: We present an uncommon complication of vaginally placed synthetic prolapse mesh and demonstrate repair of rectal mesh perforation. METHODS: A 41-year-old was referred with multiple complaints following rectocele repair using a posterior vaginal mesh kit 5 months earlier. In the immediate postoperative period, she experienced severe pain radiating down her right leg, pelvic pain, dyspareunia, dyschezia, diarrhea, and new onset fecal incontinence. Our examination revealed tight, tender mesh arms palpable at the vaginal apex with no evidence of erosion or rectovaginal fistula. Rectal examination revealed intrarectal mesh traversing the rectal lumen 6 cm from the anal verge. Pelvic MRI demonstrated a possible rectovaginal fistula with inflammation surrounding the right sciatic nerve plexus. The patient underwent exploratory laparotomy, removal of the mesh, primary repair of two perforating rectal defects and diverting loop ileostomy. Postoperatively she experienced immediate improvement in pain and later underwent successful take-down of her ileostomy. She did well with improvement of bowel function, continence of feces, improvement of pain, and no recurrence of prolapse. CONCLUSION: Our video shows an abdominal approach for mesh removal and repair of rectal mesh injury occurring from vaginal mesh placement. We discuss the rationale for the abdominal approach and review techniques for proper placement of posterior vaginal mesh.

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.

RATIONALE: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique ß-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function. OBJECTIVE: Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation. METHODS AND RESULTS: By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts. CONCLUSIONS: Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.

Carcinoid syndrome and perioperative anesthetic considerations.

Carcinoid tumors are uncommon, slow-growing neoplasms. These tumors are capable of secreting numerous bioactive substances, which results in significant potential challenges in the management of patients afflicted with carcinoid syndrome. Over the past two decades, both surgical and medical therapeutic options have broadened, resulting in improved outcomes. The pathophysiology, clinical signs and symptoms, diagnosis, treatment options, and perioperative management, including anesthetic considerations, of carcinoid syndrome are presented.

Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells significantly increases 4-hydroxytamoxifen-induced apoptosis.

Previously, we reported a strong association of the high activity SULT1A1*1 allele and overall survival of patients receiving tamoxifen therapy, indicating that sulfation of 4-hydroxytamoxifen (4-OHT) via SULT1A1 may contribute to the therapeutic efficacy of tamoxifen treatment. In most, but not all cases, sulfation is considered to be an elimination pathway; therefore we sought to define the biological mechanism by which increased sulfation of tamoxifen could provide a therapeutic benefit. We compared the antiproliferative and apoptotic responses between MCF7-SULT1A1 expressing cells and control MCF7 pcDNA3 cells when treated with 4-OHT. We observed a greater than 30% decrease in cell proliferation in MCF7-SULT1A1 expressing cells at physiological concentrations of 4-OHT, and significant cell death in SULT1A1-expressing cells treated with 2µM 4-OHT for 48 hours compared to control cells (p<0.05). Within 24 hours of drug treatment, an 80% increase in apoptosis in SULT1A1-expressing cells was apparent when compared to similarly treated cells that did not express SULT1A1. We also observed an increase in endonuclease G, the primary endonuclease expressed in ER-dependent breast cancer cells, which participates in caspaseindependent apoptosis. These data confirm that SULT1A1-mediated biotransformation of 4-OHT is important in the efficacy of 4-OHT cytotoxicity in breast tumors, and reveals a potential role for sulfated metabolites in the efficacy of tamoxifen therapy.

Technical pentabromodiphenyl ether and hexabromocyclododecane as activators of the pregnane-X-receptor (PXR).

Technical pentabrominated diphenyl ether (pentaBDE mix) is a mixture of polybrominated diphenyl ethers (PBDEs) which has been widely used as a flame retardant. Since its ban in several countries it has been replaced by other brominated flame retardants such as hexabromocyclododecane (HBCD). Both certain PBDE congeners and HBCD are present in environmental and human samples reflecting their persistent and bioaccumulative properties. PentaBDE mix and HBCD have recently been found to induce cytochrome P450 (CYP) 3 enzymes in rat liver. In this study we tested both technical pentaBDE mix and HBCD for their potency to induce CYP3A enzymes in rat hepatocytes in primary culture, and in rat H4IIE and human HepG2 hepatoma cells. In rat hepatocytes, HBCD was a more effective CYP3A1 inducer than pentaBDE mix, being less effective, however, than the prototype inducer dexamethasone. In human HepG2 cells, both compounds and the prototype inducer rifampicin were about equally effective. In contrast, in HepG2 cells, HBCD failed to induce luciferin-PFBE dealkylase, a common catalytic activity of a number of CYP3A enzymes, possibly reflecting enzyme inhibition. A significant induction of catalytic activity was observed in rat hepatocytes with both compounds. Analysis of a XREM-driven reporter gene activity in transfected cells confirmed that both compounds act as agonists of the human and rat pregnane-X-receptor, which was detectable in all cell types used.

Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs.

The sarcomeric titin springs influence myocardial distensibility and passive stiffness. Titin isoform composition and protein kinase (PK)A-dependent titin phosphorylation are variables contributing to diastolic heart function. However, diastolic tone, relaxation speed, and left ventricular extensibility are also altered by PKG activation. We used back-phosphorylation assays to determine whether PKG can phosphorylate titin and affect titin-based stiffness in skinned myofibers and isolated myofibrils. PKG in the presence of 8-pCPT-cGMP (cGMP) phosphorylated the 2 main cardiac titin isoforms, N2BA and N2B, in human and canine left ventricles. In human myofibers/myofibrils dephosphorylated before mechanical analysis, passive stiffness dropped 10% to 20% on application of cGMP-PKG. Autoradiography and anti-phosphoserine blotting of recombinant human I-band titin domains established that PKG phosphorylates the N2-B and N2-A domains of titin. Using site-directed mutagenesis, serine residue S469 near the COOH terminus of the cardiac N2-B-unique sequence (N2-Bus) was identified as a PKG and PKA phosphorylation site. To address the mechanism of the PKG effect on titin stiffness, single-molecule atomic force microscopy force-extension experiments were performed on engineered N2-Bus-containing constructs. The presence of cGMP-PKG increased the bending rigidity of the N2-Bus to a degree that explained the overall PKG-mediated decrease in cardiomyofibrillar stiffness. Thus, the mechanically relevant site of PKG-induced titin phosphorylation is most likely in the N2-Bus; phosphorylation of other titin sites could affect protein-protein interactions. The results suggest that reducing titin stiffness by PKG-dependent phosphorylation of the N2-Bus can benefit diastolic function. Failing human hearts revealed a deficit for basal titin phosphorylation compared to donor hearts, which may contribute to diastolic dysfunction in heart failure.