A Cross-Sectional Analysis of Self-Reported Needs and Health Service Utilization Among Transgender Women in Lima, Perú.

Purpose: Globally, transgender women (TGW) experience wide-ranging barriers to health and care, with disproportionately high risks of infectious and chronic diseases. Yet, research on transgender populations' access to care in low- and middle-income countries remains limited, focused on human immunodeficiency virus (HIV) infection, and assesses TGW as a homogenous group. We analyzed morbidity and health service uptake patterns among TGW in Lima, Perú, to understand health outreach and service needs to inform targeting and design of community-level interventions. Methods: This cross-sectional study surveyed a convenience sample of 301 TGW in metropolitan Lima during September-October 2020. We report descriptive statistics and bivariable and multivariable regression model results as adjusted prevalence ratios (aPRs). Results: Health coverage and access to care were suboptimal. Less education and older age were positively associated with illness and negatively associated with HIV and tuberculosis (TB) testing. In the first study to quantitatively examine health utilization by gender identity subgroup (i.e., woman, trans or transgender, transsexual, "transformista," "travesti," and other) in Perú, TGW who identified as women were more likely to ever test for HIV (aPR = 1.49, 95% confidence interval [CI]: 1.16-1.91) and use pre-exposure prophylaxis (PrEP) (aPR = 2.36, 95% CI: 1.15-4.80). Both awareness and interest regarding PrEP were low, as was usage among those who were interested in taking PrEP. Conclusion: Public health efforts should be tailored to meet TGW's diverse needs, expand TB testing, bridge the gap between PrEP interest and use, and increase insurance coverage and access to trans-friendly services for improved health.

Origin of the myotonic dystrophy type 1 mutation in Mexican population and influence of Amerindian ancestry on CTG repeat allelic distribution.

Myotonic dystrophy type 1 is caused by expansion of a CTG trinucleotide repeat situated in the DMPK gene. Worldwide genetic studies suggest a single or limited number of mutational events cause the disease. However, distribution of CTG alleles and disease incidence varies among ethnicities. Due to the great ethnic diversity of the Mexican population, the present study was aimed at analyzing the impact of different lineages in shaping the CTG-repeat allelic distribution in the contemporary Mexican-Mestizo population as well as to shed light on the DM1 ancestral origin. Distribution of CTG-repeat alleles was similar among Mestizo and Amerindian subpopulations with (CTG)11-13 being the most frequent alleles in both groups, which implies that Mexican-Mestizo allelic distribution has been modeled by Amerindian ancestry. We diagnosed a relatively high number of cases, consistent with the high frequency of large-normal alleles found in Mexican subpopulations. Haplotype analysis using various polymorphic-markers in proximity to DMPK gene indicates that a single founder mutation originates myotonic dystrophy type 1 in Mexico; however, Y-STR haplogroups data and the presence of pre-mutated and large normal alleles in Amerindians support the hypothesis that both European and Amerindian ancestral chromosomes might have introduced the disease to the Mexican population, which was further disseminated through mestizaje.

Interethnic variation of the MMP-9 microsatellite in Amerindian and Mexican Mestizo populations: considerations for genetic association studies.

We studied the interethnic variation of the MMP-9 microsatellite in the Mestizo and Amerindian populations using blood samples collected from 435 healthy unrelated individuals from the Central Valley of Mexico. DNA samples were genotyped using the -90 (CA)12-27 repeat near the MMP transcriptional start site using capillary electrophoresis. Our data were compared with those from African, Asian, and European populations (N = 729). Both Mestizo and Amerindian populations were in Hardy-Weinberg equilibrium (P ≥ 0.05). However, strong genetic heterogeneity was found within the Mestizo population (94%, P ≤ 0.0001), which exhibited the highest frequency of Amerindian, African, and European alleles. Likewise, Amerindians showed 6.7% variation among populations (P ≤ 0.0001), suggesting a genetic substructure potentially associated with linguistic affiliations. These findings were corroborated with principal component and population differentiation analyses, which showed relative proximity among the Mestizos and their historical parental populations: Asian (FST ≥ 0.05), European (FST ≥ 0.09), and African (FST ≥ 0.02). Nevertheless, important differences were found between Mestizo and Nahuas (P ≤ 0.0001), and between Mestizo and Me'Phaas (P ≤ 0.0001). These findings highlight the importance of determining local-specific patterns to establish the population variability of MMP-9 and other polymorphic markers. Validation of candidate markers is critical to identifying risk factors; however, this depends on knowledge of population genetic variation, which increases the possibility of finding true causative variants. We also show that dissimilar ethnic backgrounds might lead to spurious associations. Our study provides useful considerations for greater accuracy and robustness in future genetic association studies.

GABA inhibition of immortalized gonadotropin-releasing hormone neuronal excitability involves GABA(A) receptors negatively coupled to cyclic adenosine monophosphate formation.

Gamma-aminobutyric acid (GABA) has been implicated in the regulation of reproduction, particularly in the developmental modulation of gonadotropin-releasing hormone (GnRH) secretion. GnRH neurons are innervated by GABA-containing processes, and the administration of GABA stimulates and inhibits GnRH secretion in vivo and in vitro. We have previously shown that GABA can exert both of these actions in sequence, by acting directly on immortalized GnRH neurons. While the stimulation is the result of a GABA(A) receptor-mediated depolarization of the plasma membrane, the mechanism involved in the delayed inhibition is the subject of the present investigation. GABA (1 nM-10 microM) decreased the intracellular concentration of cyclic adenosine monophosphate (cAMP) in a dose- and time-dependent fashion. This effect was blocked by bicuculline and mimicked by muscimol but not by baclofen. To analyze the effect of GABA on cellular excitability, we used fura-2 loaded GT1-7 cells. Activation of voltage-sensitive calcium channels by high K+-induced depolarization (35 mM) increased [Ca2+]i. GABA (10 microM) and muscimol (10 microM) reduced the amplitude of K+-induced [Ca2+]i transients. This inhibition was blocked by forskolin (20 microM) or 8-Br-cAMP (1 mM). Altogether, these results show that GABA(A) receptors mediate a sustained inhibitory effect of GABA on GnRH neurons, and suggest the involvement of the cAMP pathway decreasing cellular excitability.

Human umbilical vein endothelial cells express multiple prolactin isoforms.

Members of the prolactin (PRL) hormonal family have direct effects on endothelial cell proliferation, migration and tube formation. Moreover, isoforms of PRL may function as autocrine regulators of endothelial cells. Bovine brain capillary endothelial cells (BBCEC) express the PRL gene, while anti-PRL antibodies inhibit BBCEC proliferation. Here, we show the expression of the PRL gene into various PRL isoforms in endothelial cells from the human umbilical vein. Reverse transcription-polymerase chain reaction of total RNA from human umbilical vein endothelial cells (HUVEC) detected the full-length PRL mRNA as well as a 100 bp smaller PRL transcript similar to the one previously reported in BBCEC. HUVEC were positive to PRL immunocytochemistry. In addition, various PRL immunoreactive proteins were detected in HUVEC extracts and HUVEC conditioned media by metabolic labelling immunoprecipitation analysis. These PRL immunorelated proteins had apparent molecular masses of 60, 23, 21, 16 and 14 kDa. In contrast to previous findings in BBCEC, HUVEC conditioned media contained very little PRL bioactivity as determined by the selective bioassay of Nb2 cell proliferation. Moreover, some polyclonal or monoclonal antibodies directed against PRL stimulated HUVEC proliferation, in contrast to the inhibitory effect seen in BBCEC. The present findings extend the previous observations about the expression of PRL gene in endothelial cells from bovine brain capillaries to human cells of the umbilical vein, implicating that endothelium from different types of vessels and species share the expression of PRL gene but may differ in the putative autocrine role of the PRL isoforms expressed.

Proteolytic cleavage confers nitric oxide synthase inducing activity upon prolactin.

Prolactin (PRL), originally associated with milk secretion, is now known to possess a wide variety of biological actions and diverse sites of production beyond the pituitary. Proteolytic cleavage is a common post-translational modification that can either activate precursor proteins or confer upon the peptide fragment unique biological actions not exerted by the parent molecule. Recent studies have demonstrated that the 16-kDa N-terminal proteolytic cleavage product of PRL (16K-PRL) acts as a potent inhibitor of angiogenesis. Despite previous demonstrations of 16K-PRL production in vivo, biological functions beyond its antiangiogenic actions remain unknown. Here we show that 16K-PRL, but not full-length PRL, acts to promote the expression of the inducible isoform of nitric oxide synthase (iNOS) and nitric oxide (*NO) production by pulmonary fibroblasts and alveolar type II cells with potency comparable with the proinflammatory cytokines interleukin-1beta, interferon gamma, and tumor necrosis factor alpha. The differential effect of 16K-PRL versus PRL occurs through a receptor distinct from known PRL receptors. Additionally, pulmonary fibroblasts express the PRL gene and endogenously produce 16K-PRL, suggesting that this pathway may serve both autocrine and paracrine roles in the regulation of *NO production. These results reveal that proteolytic cleavage of PRL confers upon this classical hormone potent iNOS inducing activity, suggesting its role in inflammatory/immune processes.

Expression of prolactin mRNA and of prolactin-like proteins in endothelial cells: evidence for autocrine effects.

Formation of new capillary blood vessels, termed angiogenesis, is essential for the growth and development of tissues and underlies a variety of diseases including tumor growth. Members of the prolactin hormonal family bind to endothelial cell receptors and have direct effects on cell proliferation, migration and tube formation. Because many angiogenic and antiangiogenic factors are produced by endothelial cells, we investigated whether endothelial cells expressed the prolactin gene. Here we show that bovine brain capillary endothelial cells (BBCEC) in culture express the full-length prolactin messenger RNA, in addition to a novel prolactin transcript, lacking the third exon of the gene. In addition cultures of BBCEC synthesize and secrete prolactin-like immunoreactive proteins with apparent molecular masses of 23, 21 and 14 kDa. The prolactin-like nature of these proteins in supported by the observation that Nb2-cells, a prolactin-responsive cell line, were stimulated to proliferate when co-cultured with endothelial cells and this stimulation was neutralized with prolactin-directed antibodies. Finally, consistent with a possible autocrine effect of endothelial-derived prolactins, polyclonal and monoclonal prolactin antibodies specifically inhibited basal and basis fibroblast growth-factor-stimulated growth of endothelial cells. Taken together, the present findings support the hypothesis of the prolactin gene being expressed in endothelial cells as proteins that could act in an autocrine fashion to regulate cell proliferation.

Protein tyrosine phosphorylation in leukocyte activation through receptors for IgG.

Membrane receptors for the Fc portion of immunoglobulin G (IgG) antibodies (Fc(gamma)Rs) are expressed on almost every type of hematopoietic cells, where they mediate a wide variety of effector functions. A high degree of structural heterogeneity exists among Fc(gamma)Rs. The biological significance of such heterogeneity is unknown, since the structural diversity does not appear to be reflected in the binding specificity nor in the effector functions that each distinct receptor is able to mediate. Recent work has emphasized the essential role of protein tyrosine phosphorylation in the initiation of transmembrane signaling by these receptors. In this article we review the role of protein tyrosine phosphorylation in signal transduction by the different types of Fc(gamma)Rs in order to assess to what extent the structural heterogeneity of this receptor family is related to different activation pathways utilized by each of its members.

Histamine directly stimulates gonadotropin-releasing hormone secretion from GT1-1 cells via H1 receptors coupled to phosphoinositide hydrolysis.

It is unclear whether the central stimulating effect of histamine on GnRH secretion is exerted directly on GnRH neurosecretory neurons or indirectly via multisynaptic pathways, and controversy exists about the nature of the receptors involved. The current studies were undertaken to examine whether GnRH secretion from immortalized GnRH cell lines is directly regulated by histamine and, if so, to determine the identity of the receptors and the signaling pathways coupling this action. Histamine stimulated GnRH release from GT1-1 cells in a sustained and reversible manner and in a dose-dependent fashion. This effect was blocked by the selective H1 histamine receptor antagonist, mepyramine, but not by the H2 or H3 antagonists, ranitidine or thioperamide, respectively. Saturable and specific binding sites for [3H]mepyramine were demonstrated in GT1-1 cells, showing high affinity (apparent Kd, 37.8 nM) and density (apparent binding capacity, 279 fmol/mg protein) comparable to respective values in brain tissue. Competition of [3H]mepyramine binding was achieved with mepyramine at concentrations 3 orders of magnitude lower than those of ranitidine. Histamine also increased the production of inositol phosphates in GT1-1 cells in a dose- and time-dependent manner. This response was mimicked by the selective H1 receptor agonist 2-thiazolylethylamine and blocked by the H1 antagonists mepyramine, chlorpheniramine, and triprolidine. In contrast, histamine did not alter the formation of cAMP in GT1-1 cells. The present results show a direct action of histamine on immortalized GnRH neurons, suggesting that histamine may stimulate the reproductive axis by activation of H1 receptors on the surface of GnRH neurons coupled to the formation of inositol phosphates.