Cytochrome b5 reductase 3 overexpression and dietary nicotinamide riboside supplementation promote distinctive mitochondrial alterations in distal convoluted tubules of mouse kidneys during aging.

The kidney undergoes structural and physiological changes with age, predominantly studied in glomeruli and proximal tubules. However, limited knowledge is available about the impact of aging and anti-aging interventions on distal tubules. In this study, we investigated the effects of cytochrome b5 reductase 3 (CYB5R3) overexpression and/or dietary nicotinamide riboside (NR) supplementation on distal tubule mitochondria. Initially, transcriptomic data were analyzed to evaluate key genes related with distal tubules, CYB5R3, and NAD+ metabolism, showing significant differences between males and females in adult and old mice. Subsequently, our emphasis focused on assessing how these interventions, that have demonstrated the anti-aging potential, influenced structural parameters of distal tubule mitochondria, such as morphology and mass, as well as abundance, distance, and length of mitochondria-endoplasmic reticulum contact sites, employing an electron microscopy approach. Our findings indicate that both interventions have differential effects depending on the age and sex of the mice. Aging resulted in an increase in mitochondrial size and a decrease in mitochondrial abundance in males, while a reduction in abundance, size, and mitochondrial mass was observed in old females when compared with their adult counterparts. Combining both the interventions, CYB5R3 overexpression and dietary NR supplementation mitigated age-related changes; however, these effects were mainly accounted by NR in males and by transgenesis in females. In conclusion, the influence of CYB5R3 overexpression and dietary NR supplementation on distal tubule mitochondria depends on sex, genotype, and diet. This underscores the importance of incorporating these variables in subsequent studies to comprehensively address the multifaceted aspects of aging.

Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

Clinical features and immune mechanisms directly linked to the altered liver function in patients with rheumatoid arthritis.

BACKGROUND: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro. METHODS: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months. Clinical and laboratory parameters and markers of liver disease were collected. Mechanistic studies were carried out in both the CIA mouse model and hepatocytes treated with anti-citrullinated protein antibodies (ACPAs). RESULTS: RA patients have an increased risk of suffering from liver disease independent of obesity or T2DM. This risk was associated with factors such as insulin resistance, autoantibodies, inflammation, and component C3. Methotrexate treatment for six months was associated with liver abnormalities in those newly-diagnosed patients having CV risk factors. ACPAs induced a defective hepatocyte function, promoting IR and inflammation. The induction of arthritis in mice caused the infiltration of immune cells in the liver and increased inflammatory, apoptotic, and fibrotic processes. CONCLUSION: RA patients may experience mild to moderate liver inflammation due to the infiltration of T, B cells, and macrophages, and the action of ACPAs. This is independent of obesity or diabetes and linked to systemic inflammation, and disease activity levels. The negative effects of methotrexate on liver function could be restricted to the concomitant presence of cardiovascular risk factors.

Splicing machinery is profoundly altered in systemic lupus erythematosus and antiphospholipid syndrome and directly linked to key clinical features.

OBJECTIVES: To characterize the splicing machinery (SM) of leukocytes from primary antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome with lupus (APS + SLE) patients, and to assess its clinical involvement. METHODS: Monocytes, lymphocytes and neutrophils from 80 patients (22 APS, 35 SLE and 23 APS + SLE) and 50 HD were purified, and 45 selected SM components were evaluated by qPCR-microfluidic array. Relationship with clinical features and underlying regulatory mechanisms were assessed. RESULTS: APS, SLE and APS + SLE leukocytes displayed significant and specific alterations in SM-components (SMC), associated with clinical features [autoimmune profiles, disease activity, lupus nephritis (LN), and CV-risk markers]. A remarkable relationship among dysregulated SMC in monocytes and the presence of LN in SLE was highlighted, revealing a novel pathological mechanism, which was further explored. Immunohistology analysis of renal biopsies highlighted the pathological role of the myeloid compartment in LN. Transcriptomic analysis of monocytes from SLE-LN(+) vs SLE-LN(-) identified 271 genes differentially expressed, mainly involved in inflammation and IFN-signaling. Levels of IFN-related genes correlated with those of SMC in SLE-LN(+). These results were validated in two external SLE-LN(+) datasets of whole-blood and kidney biopsies. In vitro, SLE-LN(+)-serum promoted a concomitant dysregulation of both, the IFN signature and several SMC, further reversed by JAKinibs treatment. Interestingly, IFNs, key inflammatory cytokines in SLE pathology, also altered SMC. Lastly, the over/down-expression of selected SMC in SLE-monocytes reduced the release of inflammatory cytokines and their adhesion capacity. CONCLUSION: Overall, we have identified, for the first time, a specific alteration of SMC in leukocytes from APS, SLE and APS + SLE patients that would be responsible for the development of distinctive clinical profiles.

Estudio clínico radiológico de las fracturas esternales en edad pediátrica / Clinical and radiological study of sternal fractures in pediatrics

Las fracturas esternales se consideran infrecuentes en la edad pediátrica. Clásicamente se han descrito como fracturas secundarias a traumatismos de alta energía y con riesgo de lesiones asociadas. Objetivo: Describir los aspectos clínicos y de imagen de las fracturas esternales en niños menores de 18 años. Material y métodos: Se realiza una revisión retrospectiva de 79 pacientes pediátricos con diagnóstico de fractura esternal tras traumatismo. Resultado: Demostramos que en el 92,4% de los casos, las fracturas son causadas por mecanismos de baja energía y que únicamente en 3 (4%) pacientes se presentan lesiones asociadas. Conclusión: Nuestros resultados sugieren que las fracturas esternales en niños son frecuentemente causadas por traumatismo menor, con escasa incidencia de lesiones asociadas

Sternal fractures are considered uncommon in pediatric patients. Classically, they have been described as fractures secondary to high-energy trauma that have a risk of associated lesions. Objective: To describe the clinical and imaging features of sternal fractures in patients less than 18 years of age. Material and methods: We retrospectively reviewed 79 pediatric patients diagnosed with sternal fractures after trauma. Results: We found that 92.4% of the fractures were caused by low-energy trauma and that associated lesions were present in only 3 (4%) patients. Conclusion: Our results suggest that sternal fractures in children are often due to lesser trauma and that associated lesions are rare

Clinical and radiological study of sternal fractures in pediatrics. / Estudio clínico radiológico de las fracturas esternales en edad pediátrica.

Sternal fractures are considered uncommon in pediatric patients. Classically, they have been described as fractures secondary to high-energy trauma that have a risk of associated lesions. OBJECTIVE: To describe the clinical and imaging features of sternal fractures in patients less than 18 years of age. MATERIAL AND METHODS: We retrospectively reviewed 79 pediatric patients diagnosed with sternal fractures after trauma. RESULTS: We found that 92.4% of the fractures were caused by low-energy trauma and that associated lesions were present in only 3 (4%) patients. CONCLUSION: Our results suggest that sternal fractures in children are often due to lesser trauma and that associated lesions are rare.

Altered Eating Attitudes in Nursing Home Residents and Its Relationship with their Cognitive and Nutritional Status.

BACKGROUND: although eating disorders are usually linked to young adolescents, these mental disorders can also appear in the elderly, especially in those living in nursing homes, which might be associated or not with the cognitive decline; however, there are few data regarding elderly subjects. OBJECTIVES: the objective of the present work was to evaluate the presence of abnormal eating attitudes in nursing home residents and its relation with several cognitive, nutritional and psychological factors that could be influencing their nutritional state. DESIGN AND SETTING: a observational experimental study was carried out at several nursing homes of Murcia, Spain. SUBJECTS: 139 nursing home residents. METHODS: EAT-26 test was used to screen classic eating disorders (anorexia and bulimia). Blandford's scale was employed to determine aversive eating attitudes. Moreover, subjective appetite sensations, body image perception, nutritional (MNA and diet composition) and biochemical data were also evaluated. RESULTS: 33% of the subjects had malnutrition. No subject showed symptoms of anorexia or bulimia; however, subjects with cognitive decline frequently showed aversive feeding behaviours (21.6%). Albumin values were significantly lower in subjects with cognitive impairment. CONCLUSIONS: our data showed a clear relation between cognitive impairment and altered eating attitudes, which was reflected by both biochemical (albumin) and nutritional parameters, while no classic eating disorder was observed in residents with normal cognitive-status. These data confirm the need to strengthen our efforts towards maintaining the nutritional status of the subjects with cognitive impairment.

Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues.

BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of insulin resistance (IR); however, the specific mechanisms mediating this association are currently unknown. OBJECTIVE: To investigate whether the inflammatory activity associated with RA accounts for the observed defective glucose metabolism and lipid metabolism in these patients. METHODS: We followed two main strategies: (i) extensive metabolic profiling of a RA cohort of 100 patients and 50 healthy control subjects and (ii) mechanistic studies carried out in both a collagen-induced arthritis mouse model and 3T3-L1 adipocytes treated with conditioned serum from RA patients. RESULTS: Following the exclusion of obese and diabetic subjects, data from RA patients demonstrated a strong link between the degree of systemic inflammation and the development of IR. These results were strengthened by the observation that induction of arthritis in mice resulted in a global inflammatory state characterized by defective carbohydrate and lipid metabolism in different tissues. Adipose tissue was most susceptible to the RA-induced metabolic alterations. These metabolic effects were confirmed in adipocytes treated with serum from RA patients. CONCLUSIONS: Our results show that the metabolic disturbances associated with RA depend on the degree of inflammation and identify inflammation of adipose tissue as the initial target leading to IR and the associated molecular disorders of carbohydrate and lipid homeostasis. Thus, we anticipate that therapeutic strategies based on tighter control of inflammation and flares could provide promising approaches to normalize and/or prevent metabolic alterations associated with RA.

Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in Rheumatoid Arthritis patients.

OBJECTIVES: 1) To assess the association of NETosis and NETosis-derived products with the activity of the disease and the development of cardiovascular disease in RA; 2) To evaluate the involvement of NETosis on the effects of biologic therapies such as anti-TNF alpha (Infliximab) and anti-IL6R drugs (Tocilizumab). METHODS: One hundred and six RA patients and 40 healthy donors were evaluated for the occurrence of NETosis. Carotid-intimae media thickness was analyzed as early atherosclerosis marker. Inflammatory and oxidative stress mediators were quantified in plasma and neutrophils. Two additional cohorts of 75 RA patients, treated either with Infliximab (n = 55) or Tocilizumab (n = 20) for six months, were evaluated. RESULTS: NETosis was found increased in RA patients, beside myeloperoxidase and neutrophil elastase protein levels. Cell-free nucleosomes plasma levels were elevated, and strongly correlated with the activity of the disease and the positivity for autoantibodies, alongside inflammatory and oxidative profiles in plasma and neutrophils. Moreover, ROC analyses showed that cell-free nucleosomes levels could identify RA patients showing early atherosclerosis with high specificity. RA patients treated either with IFX or TCZ for six months exhibited decreased generation of NETs. Concomitantly, clinical parameters and serum markers of inflammation were found reduced. Mechanistic in vitro analyses showed that inhibition of NETs extrusion by either DNase, IFX or TCZ, further abridged the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system. CONCLUSIONS: NETosis-derived products may have diagnostic potential for disease activity and atherosclerosis, as well as for the assessment of therapeutic effectiveness in RA.

'Atherothrombosis-associated microRNAs in Antiphospholipid syndrome and Systemic Lupus Erythematosus patients'.

MicroRNAs markedly affect the immune system, and have a relevant role in CVD and autoimmune diseases. Yet, no study has analyzed their involvement in atherothrombosis related to APS and SLE patients. This study intended to: 1) identify and characterize microRNAs linked to CVD in APS and SLE; 2) assess the effects of specific autoantibodies. Six microRNAs, involved in atherothrombosis development, were quantified in purified leukocytes from 23 APS and 64 SLE patients, and 56 healthy donors. Levels of microRNAs in neutrophils were lower in APS and SLE than in healthy donors. Gene and protein expression of miRNA biogenesis-related molecules were also reduced. Accordingly, more than 75% of identified miRNAs by miRNA profiling were underexpressed. In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated. Altered microRNAs' expression was linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in both pathologies. In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG or anti-dsDNA-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins. Monocyte transfections with pre-miR-124a and/or -125a caused reduction in atherothrombosis-related target molecules. In conclusion, microRNA biogenesis, significantly altered in neutrophils of APS and SLE patients, is associated to their atherothrombotic status, further modulated by specific autoantibodies.

Immunotherapy in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a disorder characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity with the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and/or anti-ß2-glycoprotein I antibodies). Thrombosis is the major manifestation in patients with aPLs, but the spectrum of symptoms and signs associated with aPLs has broadened considerably, and other manifestations, such as thrombocytopenia, non-thrombotic neurological syndromes, psychiatric manifestations, livedo reticularis, skin ulcers, hemolytic anemia, pulmonary hypertension, cardiac valve abnormality, and atherosclerosis, have also been related to the presence of those antibodies. Several studies have contributed to uncovering the basis of antiphospholipid antibody pathogenicity, including the targeted cellular components, affected systems, involved receptors, intracellular pathways used, and the effector molecules that are altered in the process. Therapy for thrombosis traditionally has been based on long-term oral anticoagulation; however, bleeding complications and recurrence despite high-intensity anticoagulation can occur. The currently accepted first-line treatment for obstetric APS (OAPS) is low-dose aspirin plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). However, in approximately 20% of OAPS cases, the final endpoint, i.e. a live birth, cannot be achieved. Based on all the data obtained in different research studies, new potential therapeutic approaches have been proposed, including the use of new oral anticoagulants, statins, hydroxychloroquine, coenzyme Q10, B-cell depletion, platelet and TF inhibitors, peptide therapy or complement inhibition among others. Current best practice in use of these treatments is discussed.

Identification of miRNAs as potential modulators of tissue factor expression in patients with systemic lupus erythematosus and antiphospholipid syndrome.

BACKGROUND: Tissue factor (TF) is the main initiator of the coagulation cascade and elements that may upregulate its expression might provoke thrombotic events. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune diseases characterized by a high TF expression in monocytes. OBJECTIVES: To examine the role of microRNAs (miRNAs) in TF expression and to evaluate their levels in SLE and APS patients. METHODS: An in silico search was performed to find potential putative binding sites of miRNAs in TF mRNA. In vitro validation was performed transfecting cells expressing TF (THP-1 and MDA-MB-231) with oligonucleotide miRNA precursors and inhibitors. Additionally, reporter assays were performed to test for the binding of miR-20a to TF mRNA. Levels of miRNAs and TF were measured by quantitative (qRT-PCR) in patients with APS and SLE. RESULTS: Overexpression of miRNA precursors, but not inhibitors, of two of the members of cluster miR-17∼92, for example miR-19b and miR-20a, in cells expressing TF decreased TF mRNA, protein levels, and procoagulant activity between 30% and 60%. Reporter assays showed that miR-20a binds to TF mRNA. Finally, we measured levels of miR-19b and miR-20a in monocytes from patients with APS and SLE and observed significantly lower miRNAs levels in comparison with healthy subjects inversely correlated with the levels of TF. CONCLUSIONS: Down-regulation of miR-19b and miR-20a observed in patients with SLE and APS could contribute to increased TF expression and thus provoke the hypercoagulable state characteristic of these patients.

Tumor mixto de la estroma endometrial y del músculo liso: recurrencia atípica. Presentación de un caso y revisión de la bibliografía / Mixed endometrial stromal and smooth muscle tumor: atypical recurrence. Case report and review of the literature

Los tumores mixtos de la estroma endometrial y del músculo liso son tumores raros. Para clasificar un tumor dentro de este grupo debe presentar al menos un 30% de cada tipo celular, y diagnosticarse por la evaluación con microscopio óptico. Clásicamente se denominaban «stromomyomas». El comportamiento de los tumores mixtos de la estroma endometrial y del músculo liso suele ser benigno. En este caso la paciente presentó una recurrencia pélvica, con un tumor puro únicamente de músculo liso al año de la primera intervención (AU)

Mixed endometrial stromal and smooth muscle tumors of the uterus are unusual. For tumors to be classified within this group, at least 30% of each component must be present and diagnosis must be based on light microscopy. Traditionally these tumors were named stromomyomas. Mixed endometrial stromal and smooth muscle tumors are usually benign. In the present case, the tumor recurred in the pelvis 12 months after surgery as a pure smooth muscle tumor (AU)

La evaluación como actividad orientada a la transformación de los procesos formativos / The evaluation as an activity oriented to the transformation of formative processes

En el presente trabajo se reflejan las características fundamentales del proceso evaluativo con la finalidad de motivar la reflexión en todos aquellos, que de una forma u otra participan en este proceso. Se parte del valor que posee esta actividad en todos los sectores del país, para sus ejecutivos y procesos educativos y especialmente, para los del sector de la Salud, de ahí los fundamentos que se exponen sobre las bases teóricas que lo sustentan y su necesaria observancia en la práctica. Se presenta la evaluación como un proceso dialéctico, contradictorio, universal y particular, según las condiciones histórico-concretas de que se trate y se hace referencia al desbalance entre los tipos de evaluaciones sumativas y formativas, que actúan como contrarios dialécticos. Se plasman los elementos básicos que deben tenerse en cuenta al desarrollar un proceso evaluativo que permita comprobar conocimientos y objetivos y a la vez constituir el punto de partida de nuevas transformaciones como resultado de la evaluación realizada(AU)

La evaluación como actividad orientada a la transformación de los procesos formativos / The evaluation as an activity oriented to the transformation of formative processes

En el presente trabajo se reflejan las características fundamentales del proceso evaluativo con la finalidad de motivar la reflexión en todos aquellos, que de una forma u otra participan en este proceso. Se parte del valor que posee esta actividad en todos los sectores del país, para sus ejecutivos y procesos educativos y especialmente, para los del sector de la Salud, de ahí los fundamentos que se exponen sobre las bases teóricas que lo sustentan y su necesaria observancia en la práctica. Se presenta la evaluación como un proceso dialéctico, contradictorio, universal y particular, según las condiciones histórico-concretas de que se trate y se hace referencia al desbalance entre los tipos de evaluaciones sumativas y formativas, que actúan como contrarios dialécticos. Se plasman los elementos básicos que deben tenerse en cuenta al desarrollar un proceso evaluativo que permita comprobar conocimientos y objetivos y a la vez constituir el punto de partida de nuevas transformaciones como resultado de la evaluación realizada

[Laryngeal actinomycosis]. / Actinomicosis laríngea.

Actinomycosis is a rare infectious disease in our practice and clinically it is charactherized by the presence of granulomatous lesions of subacute or chronic evolution. Most of the cases of actinomycosis are localised in the cervico-facial area, being the laryngeal one uncommon. We present a clinical case of a 53 years-old male diagnosed of primary laryngeal actinomycosis and we realise a bibliographic revision on this subject emphazising the diagnosis techniques and the differential diagnosis of this kind of lesions.

Prenatal diagnosis of an interstitial 12q chromosome deletion.

Rearrangements involving long arm of chromosome 12 are rare events. To our knowledge, we present the first case of an interstitial deletion of the long arm of chromosome 12 in a prenatal diagnosis. A review of the literature is included in our report.

Actinomicosis laríngea / Laryngeal actinomycosìs

La actinomicosis es una enfermedad infecciosa poco común en nuestro medio que clínicamente se caracteriza por la presencia de lesiones granulomatosas de evolución subaguda o crónica. La mayoría de los casos de actinomicosis se producen en la región cervico-facial, siendo la localización laríngea rara. Presentamos el caso clínico de un varón de 53 años diagnosticado de actinomicosis laríngea primaria y realizamos una revisión bibliográfica del tema, haciendo especial hincapié en las técnicas diagnósticas y en el diagnóstico diferencial que este tipo de lesiones nos pueden plantear en la práctica clínica diaria (AU)

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Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter.

Although the promoters of both the Bax and p21 genes are activated by p53, they differ in the effect on this activation of the POU family transcription factor Brn-3a. Thus, Brn-3a inhibits activation of the Bax promoter by p53 but enhances the ability of p53 to activate the p21 promoter. We demonstrate that repression of p53-mediated activation of the Bax promoter involves a complex upstream sequence in which two Brn-3a response elements flank the p53 response element. In contrast, a minimal p21 promoter is activated by Brn-3a and such activation cannot be abolished without abolishing basal promoter activity. Moreover, synergistic activation by Brn-3a and p53 continues to be observed when the p53-binding sites in the p21 promoter are substituted by the Bax p53 site or by the region of the Bax promoter essential for Brn-3a-mediated repression, indicating that the p21 core promoter plays a central role in this response. The significance of these effects is discussed in terms of the different responses of the Bax and p21 promoters and the overlapping but distinct roles of Brn-3a and p53 in neuronal growth arrest and apoptosis.