Acne: a side-effect of masculinizing hormonal therapy in transgender patients.

BACKGROUND: Masculinizing hormonal treatment in transgender men has the potential to increase the level of androgens at end organs, including the pilosebaceous unit. Androgen-induced sebocyte growth and differentiation, sebum production and infundibular keratinization may underlie the development of acne vulgaris among patients receiving this therapy. OBJECTIVES: The aim of this article is to familiarize dermatologists with the sensitivities and challenges of treating acne in transgender male individuals. METHODS: This review article discusses the pathogenesis and treatment of acne in transgender men on testosterone therapy and highlights the unique considerations in treating this underserved patient population. RESULTS: Despite the incidence of treatment-related acne and the unique considerations in treating transgender men, studies addressing this topic among this patient population are limited. CONCLUSIONS: Generally, the standard guidelines for the treatment of acne can be followed in treating these patients; however, several medical, social and psychological factors should be considered.

Intra-amniotic digoxin for feticide between 21 and 30 weeks of gestation: a prospective study.

OBJECTIVE: Intra-amniotic injection of digoxin is a well-known method for feticide before inducing a termination of pregnancy (TOP) at 17-24 weeks of gestation. Information on its effectiveness when administered after 24 weeks of gestation is limited. This study evaluated the efficacy of intra-amniotic digoxin injection for inducing fetal demise within 18-24 hours, at 21-30 weeks of gestation, and its safety. DESIGN: Prospective cohort study. SETTING: Tertiary university medical centre. POPULATION: Women at 21-30 weeks of gestation with a singleton pregnancy, admitted for TOP. METHODS: Intra-amniotic injection of 2 mg of digoxin was performed 1 day before medical TOP. Fetal heart activity was evaluated by ultrasound for 18-24 hours after the injection. Serum digoxin level and maternal electrocardiogram (ECG) were evaluated 6, 10, and 20 hours after injection. MAIN OUTCOME MEASURE: Frequency of successful fetal demise. RESULTS: Fifty-nine women participated in the study. The mean gestational age was 24+2  weeks (range 21+0 -30+0 ), with 29 (49.2%) beyond 24+0  weeks of gestation. Fetal cardiac activity arrest was achieved in 55/59 cases (93.2%). Normal maternal ECG recordings were noted in all cases. Mean serum digoxin levels 6 and 10 hours after injection were in the therapeutic range (1.3 ± 0.7 ng/l and 1.24 ± 0.49 ng/l, respectively) and below the toxic level (2 ng/l). Extramural delivery following digoxin did not occur. There were no cases of chorioamnionitis. CONCLUSION: Intra-amniotic digoxin for feticide at 21-30 weeks of gestation in a singleton pregnancy appears effective and safe before TOP at advanced gestational ages. TWEETABLE ABSTRACT: This study shows that feticide by intra-amniotic digoxin injection at 21-30 weeks of gestation appears effective and safe.

Papular acantholytic dyskeratosis of the vulva associated with familial Hailey-Hailey disease.

Papular acantholytic dyskeratosis (PAD) of the vulva is a rare, chronic disorder first described in 1984. It presents in young women as white to skin-coloured smooth papules over the vulva, which are persistent but asymptomatic. Histologically, there is hyperkeratosis and focal parakeratosis with acantholytic and dyskeratotic cells forming corps ronds and grains, placing PAD within Ackerman's spectrum of focal acantholytic dyskeratoses with Hailey-Hailey disease (HHD) and Darier disease. There have been 17 previous reports of PAD of the vulva, to our knowledge. Only one demonstrated a familial pattern, and none of the cases was associated with a family history of HHD. This is the first report of PAD and HHD in a single family, suggesting that PAD and HHD lie on a spectrum of disease and are genetically linked.

First trimester human placental factors induce breast cancer cell autophagy.

Placental factors, progesterone included, facilitate breast cancer cell line (BCCL) motility and thus may contribute to the advanced breast cancer found during pregnancy. Cancer and placental implantations are similar; the last is accompanied by extravillous trophoblast cell invasion and autophagy which are interlinked. We aimed to analyze the effect of first trimester human placenta on BCCL autophagy. BCCLs (MCF-7/T47D) were cultured with placental explants (60 h) or placental supernatants (24 h). Following cultures, BCCLs were sorted out for RNA/protein extraction. RNA served for microarray/qPCR (BNIP3) and protein for Western blot (HIF1α, LC3BII) analyses. Inhibitors were added to the placenta-MCF-7 coculture or placental supernatants (autophagy inhibitor-3MA, progesterone receptor (PR) inhibitor-RU486, and HIF1α inhibitor-Vitexin) in order to evaluate their effects on BCCL motility and LC3BII/HIF1α expression. LC3BII (an autophagy marker) expression was elevated in BCCLs following placental explant coculture and exposure to placental supernatants. The autophagy inhibitor (3MA) repressed the placenta-induced MCF-7/T47D migration, establishing a connection between BCCL autophagy and migration. Microarray analysis of MCF-7 following placenta-MCF-7 coculture showed that "HIF1α pathway," a known autophagy facilitator, was significantly manipulated. Indeed, placental factors elevated HIF1α and its target BNIP3 in the BCCLs, verifying array results. Lastly, PR inhibitor reduced HIF1α expression and both PR and HIF1α inhibitors reduced MCF-7 LC3BII expression and motility, suggesting involvement of the PR-HIF1α axis in the autophagy process. Placental factors induced BCCL autophagy that is interlinked to their motility. This suggests that autophagy-related molecules may serve as targets for therapy in pregnancy-associated breast cancer.

The effect of heat shock protein 27 on extravillous trophoblast differentiation and on eukaryotic translation initiation factor 4E expression.

Heat shock protein (HSP27) is expressed in human placentae. Previously, we showed that HSP27 is expressed in the villous cell column of first trimester placental explants and in extravillous trophoblast (EVT) cells. EVT differentiation is accompanied by increased motility, matrix metalloproteinase (MMP) activity, decreased proliferation and expression of specific markers such as HLAG and CD9. HSP27 regulates cell apoptosis, migration, protein stability and the availability of eukaryotic translation initiation factors, such as eukaryotic translation initiation factor 4E (eIF4E). eIF4E supports trophoblast cell proliferation and survival. We wanted to explore the effect of HSP27 silencing on trophoblast cell phenotype, EVT markers and eIF4E expression and regulators [4E-binding protein (4E-BP1) and MAP kinase-interacting kinase (MNK1)]. This study evaluated the effect of HSP27 siRNA on placental explant and HTR-8/SVneo migration, MMP activity/mRNA, cell death, cell cycle, HLAG/CD9 levels, and eIF4E and its regulators' total and phosphorylated levels. Furthermore, we evaluated HSP27 levels in placentae exposed to ribavirin, which triggers EVT differentiation. We found that HSP27 silencing increased cell death in HTR-8/SVneo and placental explants. Furthermore, it reduced HTR-8/SVneo migration and EVT outgrowth from the explants (P < 0.05), MMP2 activity and expression of EVT markers HLAG and CD9 (in placental explants and HTR-8/SVneo, respectively, P < 0.05). Induction of EVT differentiation by ribavirin elevated HSP27 levels. Finally, HSP27 silencing in both HTR-8/SVneo and placental explants reduced eIF4E levels (33 and 28%, respectively, P < 0.05) and the levels of its regulators 4E-BP1 and MNK1 (37 and 32%, respectively, done on HTR-8/SVneo only), but not their phosphorylated forms. Altogether, our results suggest that HSP27 contributes to EVT cell differentiation.

Hormone-dependent placental manipulation of breast cancer cell migration.

BACKGROUND: Breast cancer during pregnancy is often more advanced than in non-pregnant women. Nevertheless, no case of metastasis inside the placenta has been reported. Previously, we showed that placental-explants eliminated breast cancer cells from their surroundings, due to cell-death and elevated migration. Our objective was to find the underlying mechanisms of these phenomena. METHODS AND RESULTS: Our model contained Michigan Cancer Foundation 7 (MCF7) or T47D cells co-cultured with and without human placental explants. Microarray analysis, validated by quantitative PCR, of MCF7 following their placental co-culture suggested activation of estrogen (E(2)) signaling. As extensive cross-talk exists between E(2) and progesterone, their involvement in mediating placental effects on breast cancer cells was tested. Indeed, addition of E(2) and progesterone receptor (ER and PR) inhibitors to the co-culture system reduced cancer cell motility, yet did not alter cell-cycle or death. E(2) and progesterone concentrations in placental media were found to be similar to those of early pregnancy blood levels. Interestingly, placental-breast cancer co-culture media contained lower progesterone (P < 0.05) and higher E(2) (200%, P < 0.05) levels than placentae cultured separately. Placental supernatant and E(2) and progesterone at placental levels were sufficient to increase MCF7 and T47D migration and invasion (P < 0.05), yet did not alter MCF7 cell-cycle or death. Furthermore, placental supernatant elevated p38 and Jun N-terminal kinase (JNK) phosphorylation in both cell lines (P < 0.05). Inhibitors of JNK, ER and PR reversed MCF7 and T47D motility induced by the placenta, suggesting their involvement. CONCLUSIONS: We suggest that E(2) and progesterone contribute to cell migration away from placental areas. We hypothesize that they may increase metastatic spread to other organs in pregnancy.

Breast cancer characteristics are modified by first trimester human placenta: in vitro co-culture study.

BACKGROUND: Pregnant women with breast cancer present with a more advanced disease compared with non-pregnant women. Nevertheless, breast cancer metastasis to the placenta is rare. Trophoblast/tumor implantations share the same biochemical mediators, while only the first is stringently controlled. We hypothesized that the same mechanisms that affect/restrain placental implantation may inhibit metastatic growth in the placenta. We aimed to analyze the effects of human placenta on breast cancer cells. METHODS: First trimester human placental explants were co-cultured with MCF-7/T47D-eGFP tagged cells. Following culture, placenta/cancer cells/both were fixed, paraffin embedded and sliced for immunohistochemical analysis or sorted by their eGFP expression for future analysis. The tested parameters were: proliferation (immunohistochemistry)/cell cycle (FACS), apoptosis (immunohistochemistry/FACS), cell count/adhesion/distribution around the placenta (cell sorter, visual observation and counting), matrix metalloproteinase activity (zymogram) and estrogen receptor (ER) expression (western blotting, immunohistochemistry). RESULTS: Reduced breast cancer cell numbers (45%↓, 48%↓ for MCF-7/T47D, respectively, P < 0.05) were observed near the placenta. The placenta elevated MCF-7 sub-G1 phase and modestly elevated apoptosis (3-17%↑ for T47D/MCF-7, respectively, P < 0.05). Our findings demonstrate breast cancer cell migration from the placenta as: (i) T47D/MCF-7 cells changed their morphology to that of motile cells; (ii) elevated MMPs activity was found in the co-culture; (iii) placental soluble factors detached breast cancer cells; and (4) the placenta reduced MCF-7/T47D cells' ER expression (a characteristic of motile cells). CONCLUSIONS: MCF-7/T47D cells are eliminated from the placental surroundings. Analyzing the causes of these phenomena may suggest biological pathways for this event and raise new therapeutic targets.

Lichenoid vulvar disease: A review.

Vulvar dermatoses are common, potentially debilitating conditions that can be seen by a variety of medical specialists. Lichenoid vulvar diseases, namely lichen sclerosus (LS), lichen planus (LP), and lichen simplex chronicus (LSC), can all negatively impact patients' quality of life and LS and LP also have an association with squamous cell carcinoma. It is essential that dermatologists are familiar with the unique features of each of these conditions to ensure the appropriate management and follow up. Herein, we provide an update on the epidemiology, clinical presentation, histopathology, and treatment of patients with vulvar LS, LP, and LSC.

Dilatation of bronchial stenoses due to sarcoidosis using a flexible fiberoptic bronchoscope.

Stenosis of the trachea and bronchi can complicate many diseases and lead to significant pulmonary complaints. Unfortunately, steroids rarely yield satisfactory results in reversing symptoms. We describe six patients with symptomatic airway stenosis from sarcoidosis, all of whom were refractory to steroid therapy. By using a Fogarty embolectomy catheter inserted through the inner channel of a flexible bronchoscope, we were able to dilate the stenotic areas under direct vision. Patients had significant subjective improvement following dilatation and no significant complications occurred. We believe this technique represents an improvement on previously described methods because it can easily access the upper lobes and more distal segments and can be performed at the bedside.

Placental site trophoblastic tumors (trophoblastic pseudotumors): pathology and clinical importance.

Placental site trophoblastic tumor (PSTT), which can be regarded as a subtype of gestational trophoblastic neoplasia is discussed. The histopathological features include trophoblastic proliferation without the typical organization of the bilamelar cyto and syncytiotrophoblastic villus. Ultrastructural investigation has demonstrated a clone structural relationship between the infiltrating cells and those of the trophoblastic components of the normal human placenta. Clinical management should be based on the complete surgical resection of the mass and a follow-up by measuring the serum levels of beta-human chorionic gonadotropin fractions.

Effect of saline irrigation flow rate on temperature profile during cooled radiofrequency ablation.

INTRODUCTION: Cooled radiofrequency ablation has been developed clinically for the treatment of ventricular tachycardia. Although clinical studies employ a constant saline flow rate for cooling, we hypothesized that varying the flow rates might optimize the temperature profile at depth. METHODS: In excised ovine left ventricle, we compared the temperature profile from a catheter tip electrode thermocouple to those placed at depths of 0.0 mm, 1.0 mm, and 2.0 mm. We compared the following settings: 20 Watts without flow, 20 Watts with 0.3 cc/sec flow, 20 Watts with 0.5cc/sec flow, and 70C surface temperature without flow (temperature control). RESULTS: The temperatures decreased from 77.5 +/-10.5 degrees C, 91.7+/-6.3 degrees C, 65.5 +/- 11.8 degrees C, and 52.5 +/- 11.8 degrees C at 20W without saline irrigation at the tip, 0.0mm, 1.0mm, and 2.0 mm, respectively, to 33.0+/-1.4 degrees C, 63.4 +/- 7.0 degrees C, 57.1+/-5.8 degrees C, 49.9+/-5.8 degrees C+ at 20W with 0.5 ml/sec flow (*p<0.01, +p = 0.09). The lesion volumes were 79.6mm3 for 20W without flow, 64.1 mm3 for 20W with 0.3 ml/sec flow, 47.5 mm3 for 20W with 0.5 ml/sec flow, and 28.6 mm3 for temperature control. CONCLUSIONS: We conclude that 1) the temperature profile greatly depends upon the rate of saline flow for cooling; 2) at high flow rates, the 0.0 mm and 1.0 mm temperatures are similar; 3) even at high irrigation rates, lesion size is greater than for temperature control; 4) the tip temperature significantly underestimates the surface temperature and improved methods of measuring temperature are needed.

Combined radiofrequency ablation-cooling catheter for reversible cryothermal mapping and ablation.

Reversible cryothermal mapping of cardiac arrhythmias has been performed intraoperatively. However, a steerable cooling catheter for reversible mapping has not yet been developed. We therefore developed and tested a cooling system consisting of a -15 degrees C hypertonic saline reservoir and a 7F steerable catheter also capable of radiofrequency (RF) ablation. Using excised ovine hearts placed in a 37 degrees C circulating saline bath, we measured the temperatures at depths of 0 mm, 1 mm, and 2 mm. The temperature after 90 seconds of cooling was 16.5 +/- 2.1 degrees C at 0 mm compared to 23.9 +/- 4.1 degrees C at 1 mm and 31.1 +/- 3.9 degrees C at 2 mm depth (p < 0.01). These data suggest that a 7F steerable combined RF ablation-cooling catheter may achieve temperatures suitable for mapping arrhythmias such as atrial tachycardias and right ventricular outflow tract tachycardias. Further enhancements to achieve lower temperatures at depth may be needed to reversibly map other arrhythmias such as left ventricular tachycardias.

Third-trimester uterine rupture after prostaglandin E2 use for labor induction.

Prostaglandin E2 is a powerful oxytoxic agent that reliably initiates labor, even in the presence of an unripened cervix. The very low incidence of obstetric and neonatal side effects contributes to its universal use. Only nine cases of uterine rupture during the third trimester of pregnancy after application of various prostaglandin E2 preparations have been reported in English. Although uterine rupture after prostaglandin administration is a very rare complication, no prostaglandin compound seems to be exempt from it.

Plasma levels of atrial natriuretic peptide and digoxin-like immunoreactive substances in intermittent peritoneal dialysis.

Plasma atrial natriuretic peptide (ANP) and digoxin-like immunoreactive substances (DLIS) levels were assayed in 10 patients on intermittent peritoneal dialysis (IPD) before and after a 12 hour dialysis session. Ultrafiltration volumes and blood pressures, pre and post dialysis were recorded. Left atrial diameter (LAD), as determined by M-mode echocardiography was measured prior to and at the end of each dialysis session. Ten age matched patients on hemodialysis (HD) served as controls. Predialysis plasma ANP was significantly higher in HD as compared to IPD patients and dialysis resulted in a significant decrease of plasma ANP in IPD and HD patients (37.9 +/- 28.0 to 23.1 +/- 28.5 and 201.9 +/- 110.7 to 117.0 +/- 75.6 pg/ml, respectively, p less than 0.05). Ultrafiltration volumes in IPD averaged 1840 +/- 645 ml/dialysis. The corresponding decrease in body weight in HD was 2000 +/- 220 g. Total DLIS levels in IPD and HD did not change with dialysis. LAD decrease significantly post dialysis (41.3 +/- 5.0 to 38.6 +/- 5.7 cm, p less than 0.001). Calculated ANP clearance during IPD was 5.6 +/- 3.9 ml/min. Plasma ANP correlated significantly with ultrafiltration volumes and LAD. It thus appears that ANP is sensitive to volume status in dialysed patients. Its dialysance, in IPD, approaches that of other middle molecules. Under the conditions tested ANP does not influence DLIS levels.

Differentiation between major and milder acute mental stress by means of the leukocyte adhesiveness/aggregation test.

Following previous observations that the adhesive state of white blood cells in the peripheral blood increases during stress, we examined 645 volunteers in various conditions of anticipatory anxiety. The volunteer subjects included 465 controls in whom stress was related solely to impending venipuncture, 149 persons under moderate stress (students before delivering a graded lecture, patients before dental treatment, etc), as well as 31 individuals under major stress (eg, before induction of anesthesia in the operating room). The respective values of aggregated leukocytes in the peripheral blood were 5.2 +/- 3.8, 6 +/- 4.2, and 19.3 +/- 9.3% of aggregated cells, with a significant difference (p < .0001) between the third and the other two groups. In both discriminant analysis and multiple regression, the leukocyte adhesiveness/aggregation test (LAAT) was shown to be superior to the white blood cell count for the detection of major stress. The LAAT had a sensitivity of 0.8, compared with only 0.35 for leukocyte count for that purpose. We concluded that the LAAT could be a powerful tool for the diagnosis of major acute mental stress and for discrimination between conditions causing major stress and those conditions that are less stressful.

The involvement of eukaryotic translation initiation factor 4E in extravillous trophoblast cell function.

UNLABELLED: Extravillous trophoblast cells (EVT) are major players in placental implantation. They differentiate in the villous cell column, invade to the uterus and remodel the uterine spiral arteries. Trophoblast and tumor cells have similar invasion mechanisms, share similar biochemical mediators (e.g. c-myc, MMP9) and growth-factors (e.g. VEGF). The mRNA of these proteins has extremely structured 5-UTR and their translation is highly dependent on eukaryotic-translation-initiation-factor-4E (eIF4E). Cancer cells have elevated eIF4E and are more vulnerable to its silencing than normal cells. We speculated that like cancer, trophoblast function is highly eIF4E dependent. OBJECTIVE: Analyze eIF4E involvement in EVT differentiation and function. STUDY DESIGN: EIF4E levels were assessed in first-trimester human placentae and in placental explants before and after EVT differentiation. The effect of eIF4E knockdown (siRNA, ribavirin) on the phenotype of placental explant and EVT cell lines (HTR-8/SVNEO) was evaluated. Tested parameters included eIF4E and its target levels, migration, invasion, cell death, cell cycle and cell count. RESULTS: High eIF4E levels were found in cytotrophoblast and especially EVT cells during their differentiation in the villi, compared to other placental cell types. EIF4E silencing increased cell death and cell cycle arrest in placental explants and HTR-8/SVNEO cells. Although it induced EVT outgrowth in the placental explants, it reduced HTR-8/SVNEO motility, reflecting the importance of using ex vivo models that include an intact placental microenvironment in its original architecture. CONCLUSIONS: Our results suggest that eIF4E prevents final EVT differentiation and supports placental cell proliferation and survival. A balance between cell proliferation and differentiation is crucial for placental development and implantation.

Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression.

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.