Effect of chemical stabilizers of hypoxia-inducible factors on early lung development

Low oxygen stimulates pulmonary vascular development and airway branching and involves hypoxia-inducible factor (HIF). HIF is stable and initiates expression of angiogenic factors under hypoxia, whereas normoxia triggers hydroxylation of the HIF-1α subunit by prolyl hydroxylases (PHDs) and subsequent degradation. Herein, we investigated whether chemical stabilization of HIF-1α under normoxic (20% O2) conditions would stimulate vascular growth and branching morphogenesis in early lung explants. Tie2-LacZ (endothelial LacZ marker) mice were used for visualization of the vasculature. Embryonic day 11.5 (E11.5) lung buds were dissected and cultured in 20% O 2 in the absence or presence of cobalt chloride (CoCl2, a hypoxia mimetic), dimethyloxalylglycine (DMOG; a nonspecific inhibitor of PHDs), or desferrioxamine (DFO; an iron chelator). Vascularization was assessed by X-gal staining, and terminal buds were counted. The fine vascular network surrounding the developing lung buds seen in control explants disappeared in CoCl2- and DFO-treated explants. Also, epithelial branching was reduced in the explants treated with CoCl2 and DFO. In contrast, DMOG inhibited branching but stimulated vascularization. Both DFO and DMOG increased nuclear HIF-1α protein levels, whereas CoCl2 had no effect. Since HIF-1α induces VEGF expression, the effect of SU-5416, a potent VEGF receptor (VEGFR) blocker, on early lung development was also investigated. Inhibition of VEGFR2 signaling in explants maintained under hypoxic (2% O 2) conditions completely abolished vascularization and slightly decreased epithelial branching. Taken together, the data suggest that DMOG stabilization of HIF-1α during early development leads to a hypervascular lung and that airway branching proceeds without the vasculature, albeit at a slower rate

Alveolar capillary dysplasia: A logical approach to a fatal disease

Purpose: The aim of the study was to review the authors' experience with alveolar capillary dysplasia (ACD), a cause of persistent pulmonary hypertension of the neonate (PPHN) caused by decreased alveolar units, dilated anomalous pulmonary veins, thick-walled arterioles, and thickened interalveolar septa. Methods: The records of all neonates with ACD were reviewed from Children's Hospital, Columbus, Ohio, and Sophia's Children's Hospital, Rotterdam, The Netherlands. The clinical characteristics and pathological findings are discussed. Results: Eight neonates were diagnosed with ACD from 1994 to 2002. Twenty-five percent (2/8) experienced respiratory distress immediately after birth, whereas 75% (6/8) had normal Apgar scores but deteriorated 1.5 hours to 30 days after birth. All infants required conventional ventilation initially; 50% (4/8) were placed on high-frequency oscillating ventilation and 87% (7/8) on extracorporeal membrane oxygenation. A premorbid diagnosis was established in 3 patients by open lung biopsy. The diagnosis of ACD was confirmed at autopsy in all patients. Conclusions: ACD is a fatal disease that should be suspected in all neonates with respiratory failure and PPHN who fail conventional therapy. Prompt diagnosis helps to avoid prolongation of costly treatment modalities in a uniformly fatal disease. An algorithm is proposed in which neonates with PPHN who fail treatment with extracorporeal membrane oxygenation are managed by open lung biopsy

The effect of colpectomy on lower urinary tract function in transgender men

Background: In transgender men, effects of colpectomy on voiding function are unknown, except for the incidence rates of urinary tract infections and urinary retention. Aims: To provide insight into the effect of colpectomy on Lower Urinary Tract Function (LUTF) in transgender men. Methods: A retrospective chart review was conducted among transgender men who underwent colpectomy between January 2018 and October 2020. Primary outcomes were objective and subjective changes in voiding. Secondary outcomes were transurethral catheterization length and the need for clean intermittent self-catheterization (CISC). Results: Of 132 men, 89 (67%) underwent Robot-assisted Laparoscopic Colpectomy (RaLC) and 43 (33%) Vaginal Colpectomy (VC). Maximum flow rate on uroflowmetry decreased following RaLC (mean of 29.1 vs. 38.3 mL/s, p = 0.002) and VC (mean of 29.2 vs. 40.3 mL/s, p < 0.001) after a median of four months postoperatively. An increase in total International Prostate Symptom Score was seen more frequently following VC compared to RaLC. Subjective changes were indicated by 39%, more often by men who underwent VC, of which the majority improved during the first months postoperatively. Trial without catheter (TWOC) on the first postoperative day was more successful after RaLC (79/89, 89%) than VC (24/43, 56%). Secondary TWOC was successful in 22/132 (17%) patients after a median of eight days postoperatively. In 5/132 (4%) men (three VC and two RaLC), temporary CISC was necessary for a period ranging from 5 to 21 days. The last 2/132 (2%) men after RaLC were still performing CISC at end of follow-up. Eventually, 5% (two VC and four RaLC) had to refrain from genital gender-affirming surgery with urethral lengthening due to voiding dysfunction. Discussion: After colpectomy, most objective and subjective worsening in LUTF is of a temporary nature, however, 5% had to refrain from genital gender-affirming surgery with urethral lengthening due to persistent voiding dysfunction, despite the desire to void while standing

The effect of colpectomy on lower urinary tract function in transgender men

Background: In transgender men, effects of colpectomy on voiding function are unknown, except for the incidence rates of urinary tract infections and urinary retention. Aims: To provide insight into the effect of colpectomy on Lower Urinary Tract Function (LUTF) in transgender men. Methods: A retrospective chart review was conducted among transgender men who underwent colpectomy between January 2018 and October 2020. Primary outcomes were objective and subjective changes in voiding. Secondary outcomes were transurethral catheterization length and the need for clean intermittent self-catheterization (CISC). Results: Of 132 men, 89 (67%) underwent Robot-assisted Laparoscopic Colpectomy (RaLC) and 43 (33%) Vaginal Colpectomy (VC). Maximum flow rate on uroflowmetry decreased following RaLC (mean of 29.1 vs. 38.3 mL/s, p = 0.002) and VC (mean of 29.2 vs. 40.3 mL/s, p < 0.001) after a median of four months postoperatively. An increase in total International Prostate Symptom Score was seen more frequently following VC compared to RaLC. Subjective changes were indicated by 39%, more often by men who underwent VC, of which the majority improved during the first months postoperatively. Trial without catheter (TWOC) on the first postoperative day was more successful after RaLC (79/89, 89%) than VC (24/43, 56%). Secondary TWOC was successful in 22/132 (17%) patients after a median of eight days postoperatively. In 5/132 (4%) men (three VC and two RaLC), temporary CISC was necessary for a period ranging from 5 to 21 days. The last 2/132 (2%) men after RaLC were still performing CISC at end of follow-up. Eventually, 5% (two VC and four RaLC) had to refrain from genital gender-affirming surgery with urethral lengthening due to voiding dysfunction. Discussion: After colpectomy, most objective and subjective worsening in LUTF is of a temporary nature, however, 5% had to refrain from genital gender-affirming surgery with urethral lengthening due to persistent voiding dysfunction, despite the desire to void while standing

Perineal Cyst in Transgender Men: A Rare Complication Following Gender Affirming Surgery - A Case Series and Literature Overview

INTRODUCTION: Genital gender affirming surgery (gGAS) is usually the final stage in the medical transition for transgender men and consists of creating a neophallus and neo-scrotum, with or without urethral lengthening(UL). To reduce the complication risks of UL, a mandatory colpectomy is performed prior to UL. Colpectomy is considered a complex surgery, which may lead to various perioperative complications. There are few long-term complications reported. AIM: To describe the clinical presentation and management of 3 consecutive transgender men presenting with a perineal cyst following gGAS. METHODS: After obtaining informed consent all clinical data was collected, including medical history, current symptoms, imaging, as well as surgery and histological outcomes. Furthermore, a literature search was performed. MAIN OUTCOME MEASURE: To hypothesize the aetiology of the perineal cyst based on current published literature. RESULTS: Three otherwise healthy transgender men, ages 26-46 with a similar medical history, presented with a perineal cyst several months or years following colpectomy and gGAS with UL. All patients underwent surgery to remove the cyst. Several theories regarding aetiology of this perineal cyst are discussed in this report. CONCLUSION: There remain several gaps in our knowledge regarding the aetiology and management of this perineal cyst. Therefore, further research is necessary. Asseler JD, Ronkes BL, Groenman FA, et al. Perineal Cyst in Transgender Men: A Rare Complication Following Gender Affirming Surgery - A Case Series and Literature Overview. J Sex Med 2021;XX:XXX-XXX

Tissue Engineering Neovagina for Vaginoplasty in Mayer-Rokitansky-Küster-Hauser Syndrome and Gender Dysphoria Patients: A Systematic Review

Background: Vaginoplasty is a surgical solution to multiple disorders, including Mayer-Rokitansky-Küster-Hauser syndrome and male-to-female gender dysphoria. Using nonvaginal tissues for these reconstructions is associated with many complications, and autologous vaginal tissue may not be sufficient. The potential of tissue engineering for vaginoplasty was studied through a systematic bibliography search. Cell types, biomaterials, and signaling factors were analyzed by investigating advantages, disadvantages, complications, and research quantity. Search Methods: A systematic search was performed in Medline, EMBASE, Web of Science, and Scopus until March 8, 2022. Term combinations for tissue engineering, guided tissue regeneration, regenerative medicine, and tissue scaffold were applied, together with vaginoplasty and neovagina. The snowball method was performed on references and a Google Scholar search on the first 200 hits. Original research articles on human and/or animal subjects that met the inclusion (reconstruction of vaginal tissue and tissue engineering method) and no exclusion criteria (not available as full text; written in foreign language; nonoriginal study article; genital surgery other than neovaginal reconstruction; and vaginal reconstruction with autologous or allogenic tissue without tissue engineering or scaffold) were assessed. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, the Newcastle-Ottawa Scale, and the Gold Standard Publication Checklist were used to evaluate article quality and bias. Outcomes: A total of 31 out of 1569 articles were included. Data extraction was based on cell origin and type, biomaterial nature and composition, host species, number of hosts and controls, neovaginal size, replacement fraction, and signaling factors. An overview of used tissue engineering methods for neovaginal formation was created, showing high variance of cell types, biomaterials, and signaling factors and the same topics were rarely covered multiple times. Autologous vaginal cells and extracellular matrix-based biomaterials showed preferential properties, and stem cells carry potential. However, quality confirmation of orthotopic cell-seeded acellular vaginal matrix by clinical trials is needed as well as exploration of signaling factors for vaginoplasty. Impact statement General article quality was weak to sufficient due to unreported cofounders and incomplete animal study descriptions. Article quality and heterogenicity made identification of optimal cell types, biomaterials, or signaling factors unreliable. However, trends showed that autologous cells prevent complications and compatibility issues such as healthy cell destruction, whereas stem cells prevent cross talk (interference of signaling pathways by signals from other cell types) and rejection (but need confirmation testing beyond animal trials). Natural (orthotopic) extracellular matrix biomaterials have great preferential properties that encourage future research, and signaling factors for vascularization are important for tissue engineering of full-sized neovagina

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

BACKGROUND: Adenomyosis commonly occurs with abnormal uterine bleeding (AUB) and is associated with subfertility and a higher miscarriage rate. Recent evidence showed abnormal vascularization in the endometrium in patients with adenomyosis, suggesting a role of angiogenesis in the pathophysiology of AUB and subfertility in adenomyosis and providing a possible treatment target. OBJECTIVE AND RATIONALE: We hypothesized that the level of abnormal vascularization and expression of angiogenic markers is increased in the ectopic and eutopic endometrium of adenomyosis patients in comparison with the endometrium of control patients. This was investigated through a search of the literature. SEARCH METHODS: A systematic search was performed in PubMed and Embase until February 2019. Combinations of terms for angiogenesis and adenomyosis were applied as well as AUB, subfertility or anti-angiogenic therapy. The main search was limited to clinical studies carried out on premenopausal women. Original research articles focusing on markers of angiogenesis in the endometrium of patients with adenomyosis were included. Studies in which no comparison was made to control patients or which were not published in a peer-reviewed journal were excluded. A second search was performed to explore the therapeutic potential of targeting angiogenesis in adenomyosis. This search also included preclinical studies. OUTCOMES: A total of 20 articles out of 1669 hits met our selection criteria. The mean vascular density (MVD) was studied by quantification of CD31, CD34, von Willebrand Factor (vWF) or factor-VIII-antibody-stained microvessels in seven studies. All these studies reported a significantly increased MVD in ectopic endometrium, and out of the six articles that took it into account, four studies reported a significantly increased MVD in eutopic endometrium compared with control endometrium. Five articles showed a significantly higher vascular endothelial growth factor expression in ectopic endometrium and three articles in eutopic endometrium compared with control endometrium. The vascular and pro-angiogenic markers α-smooth muscle actin, endoglin, S100A13, vimentin, matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, tissue factor (TF), DJ-1, phosphorylated mammalian target of rapamycin, activin A, folli- and myostatin, CD41, SLIT, roundabout 1 (ROBO1), cyclooxygenase-2, lysophosphatidic acid (LPA) 1,4-5, phospho signal transducer and activator of transcription 3 (pSTAT3), interleukin (IL)-6, IL-22 and transforming growth factor-β1 were increased in ectopic endometrium, and the markers S100A13, MMP-2 and -9, TF, follistatin, myostatin, ROBO1, LPA1 and 4-5, pSTAT3, IL-6 and IL-22 were increased in eutopic endometrium, compared with control endometrium. The anti-angiogenic markers E-cadherin, eukaryotic translation initiation factor 3 subunit and gene associated with retinoic-interferon-induced mortality 19 were decreased in ectopic endometrium and IL-10 in eutopic endometrium, compared with control endometrium. The staining level of vWF and two pro-angiogenic markers (NF-κB nuclear p65 and TF) correlated with AUB in patients with adenomyosis. We found no studies that investigated the possible relationship between markers of angiogenesis and subfertility in adenomyosis patients. Nine articles reported on direct or indirect targeting of angiogenesis in adenomyosis-either by testing hormonal therapy or herbal compounds in clinical studies or by testing angiogenesis inhibitors in preclinical studies. However, there are no clinical studies on the effectiveness of such therapy for adenomyosis-related AUB or subfertility. WIDER IMPLICATIONS: The results are in agreement with our hypothesis that increased angiogenesis is present in the endometrium of patients with adenomyosis compared with the endometrium of control patients. It is likely that increased angiogenesis leads to fragile and more permeable vessels resulting in adenomyosis-related AUB and possibly subfertility. While this association has not sufficiently been studied yet, our results encourage future studies to investigate the exact role of angiogenesis in the etiology of adenomyosis and related AUB or subfertility in women with adenomyosis in order to design curative or preventive therapeutic strategies

Tissue Engineering Neovagina for Vaginoplasty in MRKHS and GD patients - a systematic review

BACKGROUND: Vaginoplasty is a surgical solution to multiple disorders, including Mayer-Rokitansky-Küster-Hauser syndrome and Male-to-Female gender dysphoria. Using non-vaginal tissues for these reconstructions is associated with many complications and autologous vaginal tissue may not be sufficient. The potential of tissue engineering for vaginoplasty was studied through a systematic bibliography search. Cell type, biomaterial and signalling factors were analyzed by investigating advantages, disadvantages, complications and research quantity. SEARCH METHODS: A systematic search was performed in Medline, EMBASE, Web of Science and Scopus until March 8, 2022. Term combinations for tissue engineering, guided tissue regeneration, regenerative medicine and tissue scaffold were applied, together with vaginoplasty and neovagina. The snowball method on references and a Google Scholar search on the first 200 hits were performed. Original studies on human and/or animal subjects, that met the inclusion (reconstruction of vaginal tissue; tissue engineering method) and no exclusion criteria (not available as full text; written in foreign language; non-original study article; genital surgery other than neovagina reconstruction; vaginal reconstruction with autologous or allogenic tissue without tissue engineering or scaffold) were assessed. The STROBE checklist, Newcastle Ottawa Scale and Gold Standard Publication Checklist were used to evaluate article quality and bias. OUTCOMES: A total of 31 out of 1569 articles were included. Data extraction was based on cell origin and type, biomaterial nature and composition, host specy, number of hosts and controls, neovagina size, replacement fraction and signalling factors. An overview of used tissue engineering methods for neovagina formation was created, showing high variance of cell type, biomaterial and signalling factors and topics were rarely covered multiple times. Autologous vaginal cells and Extracellular Matrix-based biomaterials showed preferential properties and stem cells carry potential. However, quality confirmation of orthotopic cell-seeded Acellular Vaginal Matrix by clinical trials is needed as well as exploration of signalling factors for vaginoplasty. IMPACT STATEMENT: Autologous cells prevent complications and compatibility issues like healthy cell destruction, whereas stem cells prevent cross-talk and rejection (but need confirmation testing beyond animal trials). Natural (orthotopic) ECM biomaterials have great preferential properties that encourage future research and signalling factors for vascularization are important for tissue engineering full-size neovagina