Academia Nacional de Medicina

C3 glomerulopathy is an ultra-rare kidney disease driven by dysregulation of the alternative complement pathway fluid phase C3 convertase. We report the case of a previously healthy 13-year-old girl who presented with concurrent nephrotic and nephritic syndrome and low complement C3. Her initial kidney biopsy surprisingly showed mesangioproliferative glomerulonephritis with dominating IgA deposits resulting in a diagnosis of IgA nephropathy. Despite standard immunosuppressive treatment with prednisone and mycophenolic acid plus angiotensin-converting enzyme inhibitors, she achieved only partial remission and subsequently relapsed, exhibiting severe, persistent C3 consumption (6-8mg/dl) and sustained C5b9 activation (1059ng/ml). A repeat biopsy 1.2years later established the definitive diagnosis of C3 glomerulonephritis (C3GN) with a membranoproliferative pattern. C3NEF antibodies were negative, and no pathological variant was detected in the genetic study. After 1year and 9months without response to immunosuppressive treatment, the C3 inhibitor pegcetacoplan was initiated. The patient achieved rapid and complete remission within 3months, marked by normalization of proteinuria, from 2747mg/day (urine protein-to-creatinine ratio [UPCR] 2.66mg/mg) pre-treatment to 19mg/d (UPCR 0.02mg/mg) and complement activation markers (from 1162ng/ml pre-treatment to C5b9 92ng/ml; reference value 30-150ng/ml). This case highlights the inherent diagnostic complexity of C3GN, suggesting the critical role of repeat biopsies in treatment-refractory, complement-dysregulated glomerulonephritis. It strongly supports the potential efficacy of C3 inhibition as a targeted therapeutic approach for patients with C3GN.

Me es difícil abstraerme de la figura total del doctor José Gregorio Hernández Cisneros (26.10.1864 - 29.06.1919), y tengo mis razones… ¿No existe un notable parecido entre la disposición de los condenados en las galeras y la disposición de camas entre las salas del Hospital Vargas (en el centro, la estatua de Vargas, a derecha e izquierda servicios de cirugía y medicina y dentro de cada sala, enfrentadas las hileras de camas sin divisiones ni privacidad)? ¨ Cuando apenas comenzaba como ¨médico interno¨ -ínfimo grado en el escalafón profesional hospitalario-, ser llamado en la negritud de una fría noche decembrina durante una guardia en el Hospital Vargas de Caracas, -recuérdese que mi época era todavía temporada de carretones, espantos y aparecidos, ánimas benditas y entierros de dinero en las paredes-, en ciertas salas de escasa atención, bien de Medicina o Cirugía. En la tenebrosidad, aquellas salas más parecían galeotes, la chusma de esos que remaban forzados en las galeras; las camas o crujía enfrentadas las unas a las otras, tal vez ocho, tal vez diez, la luz de un bombillo menguado y triste, una enfermera casi siempre regordeta muy privada de luces personales y buenas maneras que fungía de cómitre -esa persona que en las galeras vigilaba y dirigía la boga y otras maniobras y a cuyo cargo estaba el castigo de remeros y forzados…

2010), que corresponde al texto 148 de Hrandner.

In a society whose needs are constantly changing, family planning plays a central role for women, men, and sustainable development. This comprehensive review and position statement summarises the proceedings of a meeting on contraception held in Rome in March 2024, supported by major scientific societies in the field. The aim is to inform the medical community about current medical and ethical issues of contraception use. First, the review addresses the complex ethical, religious, and social dimensions of contraceptive use and access; second, it provides a comprehensive analysis of traditional and modern contraceptive methods, discussing their safety and effectiveness; third, it examines current knowledge about male hormonal contraception. When prescribing a contraceptive method, medical indications or contraindications must be integrated to women’s religious beliefs, the geopolitical context in which they live, the risk of violence, their need for self-determination and their right to make decisions for themselves. If a partner is involved, the couple’s dynamics and shared needs must be considered. Healthcare providers are responsible for providing them with all the information they need to make informed choices, while ensuring individual autonomy. This position statement provides recommendations on how to guide contraceptive choice and identifies knowledge gaps about contraception today.

Herein, we demonstrate that extracellular vesicles (EVs) present in healthy human plasma regulate macrophage activation by triggering MERTK-dependent signaling in a growth arrest-specific 6 (GAS6)- and protein S (PROS1)-dependent manner. Moreover, EVs regulate oxidative burst and degranulation in neutrophils and the PAMP-stimulated secretion of the pro-inflammatory cytokine interleukin (IL)-1β while enhancing the secretion of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). Neutrophil regulation is mediated by the biochemical activity of the EV-exposed extracellular nucleotidases CD39 and CD73, which degrade inflammatory extracellular ATP into anti-inflammatory adenosine. In turn, adenosine modulates neutrophil oxidative burst by acting through the A2A receptor. Additionally, we demonstrate that the incubation of live neutrophils with EVs enhances their interaction with macrophages, resulting in the formation of neutrophil-macrophage conjugates and the modulation of the macrophage response to an inflammatory stimulus. In conclusion, we propose that EVs from plasma serve as homeostatic regulators of inflammation by acting on multiple immune cell populations through distinct regulatory mechanisms.

Abstract Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has evolved strategies to evade innate immunity and establish persistent infection. However, the mechanisms by which M. tuberculosis reprograms human macrophage metabolism remain incompletely defined. Tuberculous pleural effusion (TB-PE), a common extrapulmonary manifestation that frequently coexists with pulmonary TB, offers a unique, clinically relevant immunometabolic window into the TB microenvironment. Here, using patient-derived TB-PE samples, we demonstrate that this microenvironment induces a metabolic state in human macrophages that compromises their antimicrobial function. Lipidomic analysis identified an enrichment of the specialized pro-resolving mediator Resolvin D5 (RvD5), which signals through GPR32 to suppress macrophage microbicidal activity. The acellular fraction of TPE was sufficient to induce RvD5 secretion by monocytes, correlating with increased expression of RvD5 biosynthetic enzymes in pleural monocytes from TB patients. Mechanistically, RvD5-GPR32 signaling inhibited glycolysis without promoting oxidative phosphorylation, reducing HIF-1α activity and impairing intracellular M. tuberculosis control. HIF-1α stabilization restored antimicrobial function. These findings uncover the RvD5-GPR32-HIF-1α axis as a mechanism of metabolic immune suppression and a potential target for host-directed TB therapy. Significance statement Tuberculosis (TB) persists as a global threat because Mycobacterium tuberculosis hijacks host lipid metabolism to subvert immunity. This study investigates how TB-induced host lipids reprogram macrophage metabolism to weaken their antimicrobial activity. We show that tuberculous pleural effusion, a fluid accumulation in the pleural cavity, is enriched with the lipid mediator Resolvin D5 (RvD5). RvD5 impairs macrophage function by blocking glycolysis via the GPR32 receptor, leading to an energy-deficient state that compromises bacteria killing. Remarkably, restoring the metabolic regulator HIF-1α rescues this antimicrobial defect. By revealing a mechanism through which TB exploits host-derived lipids to evade immune control, this work deepens our understanding of infection-induced immune dysfunction and highlights potential therapeutic targets for TB and other infectious diseases.

The rise of reemerging pathogens such as DENV and CHIKV presents a major public health threat. With half the global population at risk, Paraguay experiences particularly high infection rates. Despite this, data on the seroprevalence of these viruses in this country is lacking. This study aims to assess the seroprevalence of anti-DENV IgG and anti-CHIKV IgG among blood donors in Paraguay. Serum samples from 546 blood donors across seven regional districts and Asunción were collected from March to May 2023. Participants filled out a questionnaire and underwent eligibility screening. Serum samples were tested for anti-DENV IgG and anti-CHIKV IgG antibodies using immunoassays. Data were analyzed using IBM SPSS version 23.0. The median (IQR) age of donors was 34 (26-44), and 47.1% were female. Anti-DENV IgG prevalence was 87.7%, ranging from 73.7% to 100% by location, with an age-related association. Donors aged 18 to 25 had a 79.2% seroprevalence, while those over 46 had the highest at 91.5% (p = 0.010). Anti-CHIKV IgG prevalence was 37.2%, with men showing a seroprevalence nearly 10% higher than women, but no significant age-related differences were observed. Regional variation in CHIKV seroprevalence was not significant. In conclusion, this study suggests a high seroprevalence of both DENV and CHIKV in Paraguayan blood donors. The high DENV seroprevalence reflects the impact of past outbreaks, while the notable CHIKV prevalence underscores the effects of recent outbreaks. Continuous surveillance, improved diagnostics, and effective vector control measures are essential to mitigate these arboviruses' impact in Paraguay.

Depression is a highly prevalent psychiatric condition referred to as a major depressive episode (MDE). The underlying causes and mechanisms of depression remain poorly elucidated and, in consequence, the efficacy of the current therapies. Inflammation has been proposed to contribute to the pathophysiology of MDE with altered innate and adaptive immune responses. The present work aimed to shed light on the effector CD4+ T helper (Th) cell subsets response and the activation and exhaustion condition of CD8+ lymphocytes in the peripheral blood of patients with MDE. Patients with MDE (n = 57) and healthy controls (HCs) (n = 34) were recruited. The intracellular production of interferon (IFN) γ (Th1), interleukin (IL)-17 (Th17), and IL-10 (CD4+ IL-10+) as the activation and exhausted status of CD8+ lymphocytes were evaluated by flow cytometry. The frequencies of Th1 and Th17 cells did not show statistical differences, but a lower percentage of CD4+IL-10+ cells (P < 0.05) and CD4+IFNγ+IL-10+ cells (P < .01) were found in patients with MDE compared with HCs. The reduction in the CD4+IL-10+ and CD4+IFNγ+IL-10+ population negatively correlated with the number of depressive episodes (P < .05 and P < .01) and duration of illness (P < .01). A higher proportion of activated CD8+CD69+ (P < .0001) with potentially exhausted phenotype CD8+PD1+LAG3+ (P < .0001) were observed, which positively correlated with the severity, number of episodes, and duration of illness in MDE compared with HCs. Altogether, patients with MDE are characterized by unbalanced Th1/Th17/CD4+IL-10+ cells and increased activation and exhaustion of cytotoxic CD8+ T cells. Therapeutic strategies restoring this balance and effective control of inflammatory responses may be beneficial in MDE. SIGNIFICANCE STATEMENT: The pathophysiology of major depressive episode (MDE) remains poorly defined, hampering the development of more tailored therapeutic interventions. Inflammation has been proposed to initiate or maintain the MDE. This study demonstrates that effector CD4+ T helper cells are altered in MDE, showing a reduction in CD4+IL-10+ cells; meanwhile, CD8+ lymphocytes are more activated but with an exhausted phenotype. This study provides valuable insights into the lymphocyte response, which should lead to advances in the therapeutics of mood disorders.

In manuscripts devoted to emotions and will published in the second and third volumes of the Studies on the Structure of Consciousness (XLIII/2-3), Husserl raises a pivotal question concerning the existence of a distinct and inherent form of expectation within emotion and willing (Hua XLIII/3, 285). Specifically, he introduces the terms “willing expectations” (Willenserwartungen) and “emotional expectations” (Gemütserwartungen), to describe a form of future-directedness that diverges from empirical and intellectual expectations, and which belong to the emotional sphere (Gemüt), broadly constructed. By delving into a selection of these manuscripts, this paper clarifies the meaning of these forms of anticipation of the future which involve an affective tension and a conception of the future as a practical horizon of realization of a goal. It also clarifies how these are different from what Husserl calls “intellectual (or theoretical) expectations” and empirically motivated expectations.