RESUMEN
BACKGROUND: Previous studies present mixed evidence on the relationship between psychiatric comorbidities and genital gender-affirming surgery (GGAS) in individuals with gender incongruence (GI). AIM: This research aims to investigate the psychiatric comorbidity rates post-GGAS in the GI population-namely, depressive disorders, anxiety disorders, posttraumatic stress disorders, substance abuse disorder, and suicidality. METHODS: Based on the TriNetX health care database, an international database with >250 million patients, a cross-sectional study was executed comparing psychiatric comorbidity rates among cases of GI with and without GGAS. Individuals were matched for demographic and health-related variables, which included history of cardiovascular disease, diabetes, and obesity. OUTCOMES: The main focus was to establish the rates and changes in psychiatric comorbidities following GGAS. RESULTS: Among individuals with GI, the study identified 4061 with GGAS and 100 097 without. At 1 year post-GGAS, there was a significant decrease in depression (odds ratio [OR], 0.748; 95% CI, 0.672-0.833; P < .0001), anxiety (OR, 0.730; 95% CI, 0.658-0.810; P < .0001), substance use disorder (OR, 0.730; 95% CI, 0.658-0.810; P < .0001), and suicidality (OR, 0.530; 95% CI, 0.425-0.661; P < .0001), and these reductions were maintained or improved on at 5 years, including posttraumatic stress disorder (OR, 0.831; 95% CI, 0.704-0.981; P = .028). CLINICAL IMPLICATIONS: The findings indicate that GGAS may play a crucial role in diminishing psychiatric comorbidities among individuals with GI. STRENGTHS AND LIMITATIONS: This is the largest known study to evaluate the effect of GGAS on psychiatric comorbidities in the GI population, offering robust evidence. The reliance on the precision of CPT and ICD-10 codes for data extraction poses a limitation due to potential coding inaccuracies. CONCLUSION: The evidence suggests a significant association between GGAS and reduced psychiatric comorbidities in individuals with GI.
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Disforia de Género , Trastornos Mentales , Cirugía de Reasignación de Sexo , Trastornos Mentales/epidemiología , Disforia de Género/epidemiología , Disforia de Género/psicología , Disforia de Género/cirugía , Humanos , Estudios Transversales , Masculino , Femenino , Adulto , Adulto JovenRESUMEN
Bipolar disorder is a mood disorder resulting in episodes of either mania or hypomania. The episodes can manifest themselves as a period of abnormally and persistently elevated mood, abnormally and persistently increased activity or energy, distractibility, insomnia, grandiosity, flight of ideas, increased activity, pressured speech, and racing thoughts. Neurosyphilis is a progression of syphilis infection involving the brain, meninges, or spinal cord. The interaction between bipolar disorder and neurosyphilis has not been extensively studied, but it has been theorized that neurosyphilis can exacerbate mood disorders. This case study details a patient with concurrent late-onset bipolar disorder and neurosyphilis and how the discontinuation of bipolar medication resulted in an acute manic episode. In addition, this case underscores the importance of differentiating the presenting symptoms between bipolar disorder and neurosyphilis.
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The N-nitroso-trischloroethylurea (NTCU)-induced mouse model of squamous lung carcinoma recapitulates human disease from premalignant dysplasia through invasive tumors, making it suitable for preclinical chemoprevention drug testing. Pioglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist shown to prevent lung tumors in preclinical models. We investigated pioglitazone's effect on lesion development and markers of potential preventive mechanisms in the NTCU model. Female FVB/N mice were exposed to vehicle, NTCU or NTCU + oral pioglitazone for 32 weeks. NTCU induces the appearance of basal cells in murine airways while decreasing/changing their epithelial cell makeup, resulting in development of bronchial dysplasia. H&E and keratin 5 (KRT5) staining were used to detect and grade squamous lesions in formalin fixed lungs. mRNA expression of epithelial to mesenchymal transition (EMT) markers and basal cell markers were measured by qPCR. Dysplasia persistence markers desmoglein 3 and polo like kinase 1 were measured by immunohistochemistry. Basal cell markers KRT14 and p63, club cell specific protein and ciliated cell marker acetylated tubulin were measured by immunofluorescence. Pioglitazone treatment significantly reduced squamous lesions and the presence of airway basal cells, along with increasing normal epithelial cells in the airways of NTCU-exposed mice. Pioglitazone also significantly influenced EMT gene expression to promote a more epithelial, and less mesenchymal, phenotype. Pioglitazone reduced the presence of squamous dysplasia and maintained normal airway cell composition. This work increases the knowledge of mechanistic pathways in PPARγ agonism for lung cancer interception and provides a basis for further investigation to advance this chemoprevention strategy.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Ratones , Femenino , Humanos , Animales , PPAR gamma , Queratina-5 , Transición Epitelial-Mesenquimal , Pioglitazona/efectos adversos , Tubulina (Proteína) , Desmogleína 3 , Carcinoma de Células Escamosas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/inducido químicamente , Pulmón/patología , Formaldehído/efectos adversos , ARN MensajeroRESUMEN
Squamous cell carcinoma (SCC) and premalignant endobronchial lesions have been difficult to study in murine models. In this study, we evaluate the topical N-nitroso-tris-chloroethylurea (NTCU) murine SCC model, determine the extent to which resulting premalignant airway dysplasia develops, discuss clinicopathologic grading criteria in lesion progression, and confirm that immunohistochemical (IHC) staining patterns are consistent with those observed in human endobronchial dysplasia and SCC. Male and female FVB mice were treated biweekly with topical NTCU (4, 8, or 40 mmol/L) or vehicle for 32 weeks. Following sacrifice, squamous cell lesions were enumerated and categorized into the following groups: flat atypia, low-grade dysplasia, high-grade dysplasia, and invasive SCC. The 40 mmol/L NTCU concentration produced the entire spectrum of premalignant dysplasias and squamous cell carcinomas, but was associated with poor survival. Concentrations of 4 and 8 mmol/L NTCU were better tolerated and produced only significant levels of flat atypia. Squamous origin of the range of observed lesions was confirmed with IHC staining for cytokeratin 5/6, p63, thyroid transcription factor-1 (TTF-1), and Napsin-A. This study shows that topical application of high-dose NTCU produces endobronchial premalignant lesions with classic squamous characteristics and should allow for improved preclinical evaluation of potential chemopreventive agents.
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Neoplasias de los Bronquios/inducido químicamente , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Carmustina/análogos & derivados , Modelos Animales de Enfermedad , Lesiones Precancerosas/inducido químicamente , Administración Tópica , Animales , Neoplasias de los Bronquios/mortalidad , Neoplasias de los Bronquios/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carmustina/toxicidad , Femenino , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos BALB C , Invasividad Neoplásica , Lesiones Precancerosas/mortalidad , Lesiones Precancerosas/patología , Tasa de SupervivenciaRESUMEN
INTRODUCTION: We hypothesized that the combination of the EGFR tyrosine kinase inhibitor (TKI) gefitinib with the powerful chemopreventive manipulation of lung-specific transgenic prostacyclin synthase (PGIS) overexpression on tumorigenesis in FVB/N mice would result in augmented chemoprevention. MATERIALS AND METHODS: Wildtype and littermate PGIS overexpressors (OE) were given urethane, 1 mg/kg i.p. followed by thrice weekly i.p. injections of gefitinib, 50 mg/kg or 100 mg/kg, or vehicle. Pulmonary adenomas were enumerated and measured. RESULTS: Gefitinib at either 50 mg/kg or 100 mg/kg administered i.p. three times weekly was effective in inhibiting EGF induced EGFR tyrosine phosphorylation and downstream signaling. The PGIS overexpressors showed significant decreases in tumor multiplicity consistent with prior studies. Gefitinib had no effect on tumor multiplicity or volume in wildtype mice. Among the PGIS overexpressors, a significant reduction in tumor multiplicity was shown in the 50 mg/kg, but not the 100 mg/kg, gefitinib treatment group vs. vehicle control animals (1.13+/-0.29 vs. 2.29+/-0.32 tumors/mouse, p=0.015). We examined the phosphorylation status in selected downstream effectors of EGFR (Erk, Akt, Src, PTEN). The major difference in the 50 mg/kg vs. 100 mg/kg group was an increase in p-Src in the PGIS OE mice receiving the higher dose. CONCLUSION: We conclude that gefitinib alone has no chemopreventive efficacy in this model; it augmented the effect of PGIS overexpression at 50 mg/kg but not 100 mg/kg. Increased p-Src is correlated with loss of efficacy at the higher dose, suggesting the potential for combined EGFR and Src inhibition strategies in chemoprevention.
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Sistema Enzimático del Citocromo P-450/biosíntesis , Oxidorreductasas Intramoleculares/biosíntesis , Neoplasias Pulmonares/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Adenoma/enzimología , Adenoma/genética , Adenoma/metabolismo , Adenoma/prevención & control , Animales , Antineoplásicos/farmacología , Cadherinas/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Dinoprostona/metabolismo , Epoprostenol/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Gefitinib , Oxidorreductasas Intramoleculares/genética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Transgénicos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical- and cigarette-smoke-induced murine lung cancer models. Prostacyclin signals through a single G-protein-coupled receptor (IP), which signals through cyclic AMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGIS-overexpressing mice were crossed to mice that lack the IP receptor [IP(-/-)]. Carcinogen-induced lung tumor incidence was similar in IP(+/+), IP(+/-), and IP(-/-) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Because prostacyclin can activate members of the peroxisomal proliferator-activated receptor (PPAR) family of nuclear receptors, we examined the role of PPARgamma in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARgamma in nontransformed bronchial epithelial cells and in a subset of human non-small-cell lung cancer cell lines. Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung-specific PPARgamma overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARgamma is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.
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Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Epoprostenol/uso terapéutico , Neoplasias Pulmonares/prevención & control , PPAR gamma/agonistas , Receptores de Epoprostenol/fisiología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Sistema Enzimático del Citocromo P-450/genética , Evaluación Preclínica de Medicamentos , Epoprostenol/análogos & derivados , Epoprostenol/farmacología , Genotipo , Humanos , Iloprost/farmacología , Iloprost/uso terapéutico , Oxidorreductasas Intramoleculares/genética , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , PPAR gamma/genética , PPAR gamma/metabolismo , PPAR gamma/fisiología , Ratas , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Manipulating prostaglandin (PG) production modulates tumor development. Elevated PGI2 production prevents murine lung cancer, while decreasing PGE2 content protects against colon cancer. PGE2 receptor subtype 2 (EP2) -deficient mice were hypothesized to be resistant to lung tumorigenesis. MATERIALS AND METHODS: EP2 null BALB/c mice and their wild-type littermates were exposed to an initiation-promotion carcinogenesis protocol and lung tumorigenesis was examined. Chronic lung inflammation was induced to determine whether EP2 ablation influenced inflammatory cell infiltration. RESULTS: Tumor multiplicity in EP2 null mice was 34% lower than in their wild-type littermates (21.9+/-3.0 vs. 14.5+/-2.9 tumors/mouse, p<0.001). The lung tumor burden, an indicator of growth rate, also declined (57%, p<0.05). All the mice exhibited similar inflammatory cell infiltration. CONCLUSION: PGE2, acting through EP2, enhanced lung tumorigenesis through a mechanism that may be distinct from its proinflammatory activity. Thus, EP2 is a potential target for novel chemoprevention strategies.
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Neoplasias Pulmonares/prevención & control , Receptores de Prostaglandina E/deficiencia , Animales , Hidroxitolueno Butilado , Procesos de Crecimiento Celular/fisiología , Femenino , Leucocitos/inmunología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Metilcolantreno , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina ERESUMEN
Increased pulmonary production of prostaglandin I2 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lung-specific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher's exact test, P = 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg+ = 0.4 +/- 0.5 versus wild-type = 1.2 +/- 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin I2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E2 levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways.
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Sistema Enzimático del Citocromo P-450/biosíntesis , Oxidorreductasas Intramoleculares/biosíntesis , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/prevención & control , Pulmón/enzimología , Humo/efectos adversos , Animales , Bronquiolitis/etiología , Dinoprostona/biosíntesis , Epoprostenol/biosíntesis , Humanos , Neoplasias Pulmonares/etiología , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Alveolos Pulmonares/metabolismo , Ratas , Aumento de PesoRESUMEN
PURPOSE: The purpose of this study was to develop and characterize a quantitative assay of blood-retinal barrier (BRB) function in mice and to determine the effect of several purported vasopermeability factors on the BRB. METHODS: Adult C57BL/6J mice were treated with three regimens of increasingly extensive retinal cryopexy and subsequently were given an intraperitoneal injection of 1 microCi/g body weight of [(3)H]mannitol. At several time points, the amount of radioactivity per milligram tissue was compared in retina, lung, and kidney. Time points that maximize signal-to-background differential in the retina were identified, and the ratio of counts per minute (CPM) per milligram retina to CPM per milligram lung (retina-to-lung leakage ratio, RLLR) or kidney (retina-to-renal leakage ratio, RRLR) were calculated. This technique was then used to compare the amount of BRB breakdown that occurs after intravitreous injection of vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1, prostaglandin (PG) E(1), PGE(2), interleukin (IL)-1beta, or tumor necrosis factor (TNF)-alpha. RESULTS: Twenty-four hours after retinal cryopexy, there was a higher level of radioactivity in treated than in control retinas, and the signal-to-background difference was optimal when measurements were obtained 1 hour after injection of [(3)H]mannitol. In untreated mice, the RLLR was 0.30 +/- 0.02 and the RRLR was 0.22 +/- 0.01. Twenty-four hours after one 5-second application of retinal cryopexy, the RLLR was 0.73 +/- 0.20 and the RRLR was 0.71 +/- 0.23. With increasing amounts of cryopexy, there was an increase in the RLLR and RRLR, so that after two 10-second applications, the RLLR was 1.66 +/- 0.31 and the RRLR was 1.47 +/- 0.20. Intravitreous injection of VEGF, IGF-1, PGE(1), PGE(2), IL-1beta, or TNF-alpha each caused significant increases in the RLLR and RRLR, but there were some differences in potency and time course. VEGF caused prominent BRB breakdown at 6 hours that returned to near normal by 24 hours. IL-1beta also caused relatively rapid breakdown of the BRB, but its effect was more prolonged than that caused by VEGF. There was delayed, but substantial breakdown of the BRB after injection of TNF-alpha. IGF-1, PGE(2), and PGE(1) caused less severe, relatively delayed, and more prolonged BRB breakdown. CONCLUSIONS: Measurement of the RLLR or RRLR after intraperitoneal injection of [(3)H]mannitol in mice provides a quantitative assessment of BRB function that is normalized and can therefore be compared from assay to assay. Comparison of the extent and duration of BRB breakdown after intravitreous injection of vasoactive substances shows that agents can be grouped by resultant extent and time course of leakage. Additional studies are needed to determine whether this grouping has its basis in shared mechanisms of BRB disruption.