http://hdl.handle.net/10366/128025 2026-04-24T12:23:43Z http://hdl.handle.net/10366/169906 [EN]Background: Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but their relationship with the IgH isotype distribution within memory Bcell (MBC) and plasma cell (PCs) compartments remains to be investigated. Objective: We studied the age-related distribution of MBCs and PCs expressing different IgH isotypes in addition to the immature/transitional and naive B-cell compartments. Methods: B-cell and PC subsets and plasma IgH isotype levels were studied in cord blood (n 5 19) and peripheral blood (n 5 215) from healthy donors aged 0 to 90 years by using flow cytometry and nephelometry, respectively. Results: IgH-switched MBCs expressing IgG1, IgG2, IgG3, IgA1, and IgA2 were already detected in cord blood and newborns at very low counts, whereas CD271IgM11IgD1 MBCs only became detectable at 1 to 5 months and remained stable until 2 to 4 years, and IgD MBCs peaked at 2 to 4 years, with both populations decreasing thereafter. MBCs expressing IgH isotypes of the second immunoglobulin heavy chain constant region (IGHC) gene block (IgG1, IgG3, and IgA1) peaked later during childhood (2-4 years), whereas MBCs expressing third IGHC gene block immunoglobulin isotypes (IgG2, IgG4, and IgA2) reached maximum values during adulthood. PCs were already detected in newborns, increasing in number until 6 to 11 months for IgM, IgG1, IgG2, IgG3, IgA1, and IgA2; until 2 to 4 years for IgD; and until 5 to 9 years for IgG4 and decreasing thereafter. For most IgH isotypes (except IgD and IgG4), maximum plasma levels were reached after PC and MBC counts peaked. Conclusions: PC counts reach maximum values early in life, followed by MBC counts and plasma IgH isotypes. Importantly, IgH isotypes from different IGHC gene blocks show different patterns, probably reflecting consecutive cycles of IgH isotype switch recombination through life. 2018-01-01T00:00:00Z http://hdl.handle.net/10366/169904 [EN]Introduction: Secretory phospholipase A2 regulates surfactant catabolism and inflammatory cascade. This enzyme is correlated with compliance, oxygenation and major outcomes in various forms of acute respiratory failure. Steroids inhibit secretory phospholipase A2 in cell culture and are widely used to boost surfactant production before preterm delivery. No data are available about the effect of antenatal steroids on secretory phospholipase A2 in the offspring: we aimed to study this effect in a rat model of preterm lung. Material and methods: Fifteen pregnant Wistar rats were randomized to receive betamethasone, dexamethasone or placebo at 20 and 21 days gestation. Newborn rats were supported for 8 h and then sacrificed: lung tissue was analysed for secretory phospholipase A2 expression and activity, inflammatory mediators and protein content. Lipidomics was analysed using liquid chromatography-mass spectrometry. Results: Secretory phospholipase A2 expression was significantly reduced by antenatal steroids (p < 0.001). Secretory phospholipase A2 activity, TNFa and lysophosphatidylethanolamine, a product of phospholipase reaction, were lowest in betamethasone-treated rats (p < 0.001). There was a strong correlation between secretory phospholipase A2 activity and lysophosphatidylethanolamine (r ¼ 0.75; p ¼ 0.001) and this remained significant after adjustment for total proteins or phospholipids. Conclusions: Antenatal steroids decrease secretory phospholipase A2 in rat model of preterm lung. 2016-01-01T00:00:00Z http://hdl.handle.net/10366/169883 [EN]Vascular endothelial growth factor (VEGF) is an endothelial cell growth factor expressed in normal lung tissue. The aim of the study was to investigate the expression of VEGF and its repercussions as regards alveolarization in the developing rat lung. We studied pulmonary VEGF expression at 0 and 14 days of life in Wistar rats. Rat pups were exposed to hypoxia for two hours during the first hours of life and recovered under conditions of hyperoxia or normoxia for a further two hours, or not recovered. The animals of the control group were only exposed to conditions of normoxia. Our results showed that VEGF was increased in the lungs of the animals that were exposed to hypoxia but we did not find any correlation with the septation. The VEGF was decreased in the lungs of animals exposed to hyperoxia after neonatal hypoxia. We observed this at 0 and 14 days of life, and it was correlated with a lower degree of alveolarization at 14 days of life. Our data suggest that hyperoxia after neonatal hypoxia at birth may give rise to a decrease in the expression of VEGF, possibly permanently, together with a reduction in alveolar development. 2009-01-01T00:00:00Z http://hdl.handle.net/10366/169881 [EN]The use of antenatal corticosteroids is widespread and it is important to know their effect(s) on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone under normoxia, hypoxia and oxidative stress, and to evaluate its impact on alveolarization. Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats. Newborn rats were randomized to room air, hypoxia followed by hyperoxia, or hypoxia followed by air. Pulmonary VEGF protein, VEGF mRNA, and alveolarization were evaluated at 4 days of life. Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization. Antenatal dexamethasone decreased VEGF expression, and dexamethasone and hyperoxia had an additive effect on the inhibition of VEGF with a reduction in alveolardevelopment. Betamethasone appeared to have an effect on the induction of the expression of VEGF, and it seemed to inhibit the negative action of hyperoxia on VEGF. Moreover, betamethasone did not produce a decrease in alveolarization. Our results support the notion that betamethasone could be better than dexamethasone for antenatal lung maturation. 2010-01-01T00:00:00Z http://hdl.handle.net/10366/169880 [EN]Fetal and postnatal lung development is regulated by glucocorticoids. The use of antenatal corticosteroids is reported to produce effects on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. Objectives: The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone and to evaluate its impact on the alveolarization period of rats (0–14 days of life). Methods: Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats on 20th and 21st days of gestation. Pulmonary VEGF mRNA, VEGF protein expression, and alveolarization changes were evaluated at birth and at 14 days of life. Results: Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization on both days of study. Antenatal dexamethasone decreased VEGF expression, betamethasone tended to produce the induction of the expression of VEGF, and moreover, betamethasone did not produce a decrease in alveolarization as seen in the animals 2011-01-01T00:00:00Z http://hdl.handle.net/10366/169773 [EN]Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread. 2021-07-19T00:00:00Z http://hdl.handle.net/10366/169485 [ES]Este trabajo analiza la trayectoria científica y las principales aportaciones embriológicas de José María Genis Gálvez (1924–2003) durante la dictadura franquista, situándolas en el contexto de la anatomía y la embriología españolas de mediados del siglo XX. A partir del estudio de archivos institucionales —especialmente los de la Fundación Juan March y la Del Amo Foundation— y del archivo personal del propio investigador, se reconstruye su formación, su inserción en la escuela de Francisco Orts Llorca y su progresiva especialización en la embriología ocular. El artículo presta especial atención al papel desempeñado por Genis en la introducción y consolidación de la embriología bioquímica en España, así como a sus estancias formativas en Estados Unidos y a la influencia de la ciencia norteamericana en la configuración de su enfoque morfobioquímico del desarrollo. Asimismo, se examinan sus contribuciones experimentales al estudio del desarrollo del cristalino y de la retina, su producción científica internacional y su labor institucional en la creación de laboratorios de embriología experimental en Salamanca, Granada y Sevilla. En conjunto, el estudio pone de relieve cómo, a pesar de las limitaciones políticas, económicas e institucionales del franquismo, la obra de Genis Gálvez contribuyó decisivamente a la modernización de la embriología española y a su conexión con las corrientes internacionales de la biología del desarrollo. 2014-01-01T00:00:00Z http://hdl.handle.net/10366/169421 [EN]Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. 2015-10-01T00:00:00Z http://hdl.handle.net/10366/169385 As in the case of other heavy metals, a considerable body of evidence suggests that overexposure to uranium may cause pathological alterations to the kidneys in both humans and animals. In the present work, our aim was to analyze the available data from a critical perspective that should provide a view of the real danger of the nephrotoxicity of this metal for human beings. A further aim was to elaborate a comparative compilation of the renal pathophysiological data obtained in humans and experimental animals with a view to gaining more insight into our knowledge of the mechanisms of action and renal damage. Finally, we address the existing perspectives for the improvement of diagnostic methods and the treatment of intoxications by uranium, performing an integrated analysis of all these aspects. 2010-12-01T00:00:00Z http://hdl.handle.net/10366/169383 [EN]Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death. 2011-02-01T00:00:00Z http://hdl.handle.net/10366/169306 [ES]A través de un rico expediente conservado en el Archivo Diocesano de Segovia, este estudio aborda la impotencia masculina, no solo como causa jurídica de nulidad matrimonial, sino como constructo médico-social y como etiqueta diagnóstica con profundas implicaciones en los entornos nobiliarios. La investigación combina enfoques de la historia social de la medicina, los estudios de género y la historia de las familias y la vida privada para explorar cómo, en el contexto particular de la nobleza castellana del siglo XVIII, esta enfermedad desafió los modelos hegemónicos de masculinidad, generó itinerarios terapéuticos transnacionales y favoreció la producción de conocimiento médico-legal en los tribunales eclesiásticos. El caso Piscatori-Casado es un ejemplo revelador de las prácticas generadas alrededor de las enfermedades marginadas y los enfermos estigmatizados en el mundo moderno y sobre cómo la impotencia en particular se filtraba en la convivencia doméstica, en la estructura familiar y en la construcción de masculinidades alternativas y subordinadas. ABSTRACT: Drawing on a detailed matrimonial case file preserved in the Diocesan Archive of Segovia (Spain), this study examines male impo-tence not only as a legal ground for annulment, but also as a medico-social construct and diagnostic label with far-reaching implications within noble environments. The research brings together approaches from the social history of medicine, gender studies, and the history of family and private life to explore how, in the specific context of 18th-century Castilian nobil-ity, this condition challenged hegemonic models of masculinity, generated transnational therapeutic itineraries, and contributed to the production of medico-legal knowledge in ecclesiastical courts. The Piscatori-Casado case offers a revealing example of the practices surrounding marginalised illnesses and stigmatised patients in the early modern world, and high-lights how impotence permeated domestic life, familial structures, and the construction of alternative and subordinate masculinities. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/169201 [EN]Background Chronic cough (cough lasting for ⩾8 weeks) can lead to significant impairment in quality of life (QoL). Using patient-reported outcomes, this cohort study assessed the perceived impact of chronic cough on QoL and everyday life in patients from outpatient hospital clinics with refractory chronic cough (RCC) or unexplained chronic cough (UCC). Methods This was a multicentre, non-interventional survey study. Cough severity was assessed on a 0−100 mm Visual Analogue Scale (VAS). Frequency, intensity and disruptiveness of cough were assessed using an adaptation of the Cough Severity Diary. The impact of cough on QoL was assessed using the Leicester Cough Questionnaire (LCQ). The physical impact of cough and associated impact on everyday life activities were explored using purpose-designed questions. Results 191 patients responded to the survey; 121 (63.4%) had RCC and 149 were women (78.0%). Mean score on the cough severity VAS was 62.9 mm. Mean LCQ total score of 11.9 indicated reduced QoL. Cough impaired patients’ everyday life, including the inability to speak fluently (58.0% of patients) and feeling tired/drained (46.6%). Women perceived poorer chronic cough-related QoL than men, as reflected by lower LCQ scores, and greater impairment of physical health, including cough-related stress urinary incontinence, and psychological health. Conclusions Patients with RCC/UCC experience a significant burden in their everyday life, including impaired QoL, and perceive a negative impact on physical and psychological health and everyday activities, affecting work, relationships and leisure activities. The impact appears to be greater in women than men for several of the aspects studied. 2023-01-01T00:00:00Z http://hdl.handle.net/10366/169137 [EN]The primary aim of this study was to describe all cases of fetal hemivertebrae diagnosed prenatally at the Hospital Clínico Universitario de Salamanca over the last 15 years. Additionally, the presence of associated malformations was assessed, pregnancy outcomes were evaluated, and child development results were analyzed in affected cases. We undertook a prospective observational analysis of all cases (N = 10) of prenatally diagnosed hemivertebrae at our hospital between 2007 and 2022. Postnatal follow-up was performed through telephone interviews and reviewing medical records. Most cases were diagnosed during the second-trimester ultrasound, with the lumbar region being the most frequently affected site (60%). Multiple hemivertebrae were detected in 4 of 10 cases. One case of Marfan syndrome and two cases of VACTERL association (vertebral defects, anal atresia, tracheoesophageal fistula, renal dysplasia, and limb abnormalities) were documented. Six cases presented with additional malformations. Cases involving multiple hemivertebrae (40%) were more likely to be associated with other anomalies and poorer prognoses, while isolated single hemivertebra showed favorable outcomes, with normal development during childhood. Vaginal delivery occurred in six cases, while cesarean sections were performed for standard obstetric indications unrelated to the hemivertebra diagnosis. Prenatal diagnosis of hemivertebra is achievable and holds critical neonatal and postnatal relevance. Hemivertebrae are often linked to additional disorders, including genetic syndromes, and carry significant prognostic implications depending on the associated anomalies and the extent of vertebral involvement. 2025-09-16T00:00:00Z http://hdl.handle.net/10366/169133 [EN]Although generally reversible, contrast media toxicity often induces contrast-induced nephropathy (CIN), which is associated with longer hospitalization time, the need for dialysis, and higher incidence of later cardiovascular events and higher mortality. Preventive cotreatments have been assayed at the preclinical and clinical levels, but recent meta-analysis has not demonstrated a beneficial effect, which supports the search for new nephroprotective strategies. We have assessed if the administration of cardiotrophin-1 (CT-1), an endogenous cytokine with protective properties on the heart and liver, might mitigate CIN in rats. We have developed a model of CIN induced by the administration of the contrast medium gastrographin iv (3.7mg/kg) in rats sensitized by previous administration of subnephrotoxic doses of gentamicin (50mg/kg/day, ip) for 6 days. The severity of CIN was assessed by the measurement of renal function; renal histological damage; urinary excretion of markers of tubular damage, including N-acetyl beta glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and plasminogen activator inhibitor 1; lipid peroxidation; and renal apoptosis. Treatment with CT-1 almost completely prevented the renal tissue damage, as evidenced by almost total prevention of tubular desepithelization and tubular obstruction, reduced caspase activation, and cell proliferation. Besides, CT-1 also prevented the increment in renal tissue levels of renal tissue injury markers NAG, KIM-1, and neutrophil gelatinase-associated lipocalin. Oxidative stress, a hallmark of CIN, was also prevented by CT-1. Administration of CT-1 also prevented the derangement in kidney function induced by CIN. Renal hemodynamics, also impaired by the contrast medium, was normal in rats cotreated with CT-1. CT-1 administration significantly prevents the alterations in renal function and structure observed in a rat model of CIN. 2013-04-01T00:00:00Z http://hdl.handle.net/10366/169129 [EN]Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion. 2014-08-22T00:00:00Z http://hdl.handle.net/10366/169122 [EN] Background: Providing the patient with the health care they need in a personalized and appropriate manner and without adverse effects (AEs) is a part of quality of care and patient safety. The aim of this applied research project was the assessment of AEs as a clinical risk in patients with high social vulnerability such as persons with intellectual and developmental disabilities (PwIDD). (2) Methods: A retrospective epidemiological cohort study was performed on exposed and unexposed groups (the control group) in order to estimate the incidence of AEs in PwIDDs and assess their importance for this category of patients. (3) Results: AEs were observed with a frequency of 30.4% (95% CI) in the PwIDD exposed group, with significant differences to the unexposed group (p = 0.009). No differences were observed with regards to gender. Age was as a marker of care risk, with the highest incidence of AEs in the group of 60–69 years. (4) Conclusions: PwIDDs have a high risk of suffering AEs while receiving health care assistance due to their high social and clinical vulnerability. Health care practitioners must therefore be aware of these results and keep these observations in mind in order to carry out personalized, preventive, competent, effective, and safe medical care. 2022-01-01T00:00:00Z