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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which has led to an enormous burden on patient morbidity and mortality. The renin-angiotensin-aldosterone system (RAAS) plays a significant role in various pulmonary diseases. Since SARS-CoV-2 utilizes the angiotensin-converting enzyme (ACE)2 receptor to exert its virulence and pathogenicity, the RAAS is of particular importance in COVID 19. METHODS: Our preliminary study investigates retrospectively the influence of selected ACE-polymorphisms (I/D location at intron 16 in the B-coding sequence (rs4646994) and A-240T (rs 4291) at the A-promoter) as well as ACE1 and ACE2 serum levels on disease severity and the inflammatory response in inpatients and outpatients with COVID-19. RESULTS: Our study included 96 outpatients and 88 inpatients (65.9% male, mean age 60 years) with COVID-19 from April to December 2020 in four locations in Germany. Of the hospitalized patients, 88.6% participants were moderately ill (n = 78, 64% male, median age 60 years), and 11.4% participants were severely ill or deceased (n = 10, 90% male, median age 71 years). We found no polymorphism-related difference in disease, in age distribution, time to hospitalization and time of hospitalization for the inpatient group. ACE1 serum levels were significantly increased in the DD compared to the II polymorphism and in the TT compared to the AA polymorphism. There was no significant difference in ACE 1 serum levels l between moderately ill and severely ill patients. However, participants requiring oxygen supplementation had significantly elevated ACE1 levels compared to participants not requiring oxygen, with no difference in ACE2 levels whereas females had significantly higher ACE2 levels. CONCLUSIONS: Although there were no differences in the distribution of ACE polymorphisms in disease severity, we found increased proinflammatory regulation of the RAAS in patients with oxygen demand and increased serum ACE2 levels in women, indicating a possible enhanced anti-inflammatory immune response. CLINICAL TRIAL REGISTRATION: PreBiSeCov: German Clinical Trials Register, DRKS-ID: DRKS00021591, Registered on 27th April 2020.

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Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

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BACKGROUND: The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC. METHODS: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis. RESULTS: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids. CONCLUSION: We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.

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Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.

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INTRODUCTION: The diagnostic algorithm of primary aldosteronism is burdened with uncertainties and, recently, it has been suggested that the sensitivity of the aldosterone/renin ratio used as a screening test - based on the suppression aldosterone - is low. AIM: The primary aim was to test the accuracy of aldosterone/renin ratio. METHOD: In a retrospective analysis of 309 hypertensive patients supine and ambulatory aldosterone levels were independently examined. RESULTS: Aldosterone/renin ratio was elevated in 99 patients of whom 31 exhibited elevated supine aldosterone, as well. In 34 cases supine aldosterone was increased without elevation of the aldosterone/renin ratio. However, only 3 of them had concomitant low renin levels indicating that primary aldosteronism could not be ruled out. Abnormally increased renin was found in 69 patients, but only 59% of them had increased aldosterone level. CONCLUSION: Sensitivity of aldosterone/renin ratio is high (91%) if used only in justified cases.

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Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease. Recent studies demonstrate that in a significant part of diabetic patients the renal insufficiency is frequently caused by non-diabetic kidney diseases, so that an effective clarification of untypical clinical courses is mandatory. Important cornerstones of DKD therapy are an optimized glycaemic management as well as a good blood pressure control. Although the prognosis of DKD has been improved in the last years, it is, even with novel therapy approaches, not possible to prevent the development of DKD. It remains to hope that with extended knowledge, intensified preclinical studies and well-defined clinical trials novel nephroprotective therapies become available in the next years.

La néphropathie diabétique (ND) est la principale cause de maladie rénale terminale. Des études récentes démontrent que chez un grand nombre de patients diabétiques, l'insuffisance rénale est souvent causée par des maladies rénales non diabétiques, raison pour laquelle une réelle clarification des évolutions atypiques est nécessaire. Les piliers thérapeutiques de la ND sont une gestion glycémique optimisée ainsi qu'un solide contrôle de la pression artérielle. Bien que le pronostic de ND se soit amélioré, il est impossible d'empêcher son développement, même avec de nouvelles approches thérapeutiques. Il reste l'espoir qu'avec la connaissance accrue, l'intensification des études précliniques et des essais cliniques ciblés, des thérapies néphroprotectrices deviennent prochainement disponibles.

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Albumin is a negatively charged, relatively small protein synthesized by liver cells. Is the most abundant protein in extracellular fluid and accounts for about 70% of the plasma colloid osmotic pressure. Therefore it plays a crucial role in regulating fluid distribution in the body. In addition, albumin possesses functional domains with important non-oncotic properties, such as potent anti-oxydant and scavenging activities, binding of highly toxic reactive metal species and a great amount of endogenous and exogenous substances. We have recently learned that albumin in cirrhosis undergoes a number of post-transcriptional changes that greatly impair its non-oncotic properties. The overall assessment of these changes clearly shows that the relative abundance of the native form of albumin is significantly reduced in hospitalized patients with cirrhosis and that these abnormalities worsen in parallel with the increasing severity of the disease. Thus, it is time to abandon the concept of serum albumin concentration and refer to the effective albumin concentration, that is the native intact albumin. Given the pathophysiological context in which we use human albumin in patients with cirrhosis, who are characterized by peripheral vasodilation and a low-grade but sustained inflammatory state, the use of albumin in patients with cirrhosis should aim at enhancing effective hypovolemia and exploiting its antioxidant and scavenging activities. The indications for the use of albumin in cirrhosis that clearly emerge from evidence-based medicine are represented by conditions characterized by an acute aggravation of effective hypovolemia and inflammation, such as such post-paracentesis circulatory dysfunction, spontaneous bacterial peritonitis, and hepatorenal syndrome. Other indications to the use of albumin that still require further studies are represented by bacterial infections other than spontaneous bacterial peritonitis, hepatic encephalopathy and long-term treatment of ascites, which has been debated for the last half-century.

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Heart failure is the second pathology of importance in long-lived dogs. It has been suggested that heart failure can be considered as a neurohormonal or neuroendocrine model, in which heart failure progresses as a result of over-expression of biologically active molecules that are able to exert a deleterious effect on the heart and circulation. Among these molecules is the rennin angiotensin aldosterone and its main effector peptide: the angiotensin II. In recent years, the pathophysiological consequences of the system have been the main focus of attention, being more relevant the alternative routes of angiotensin II synthesis and the participation of other enzymes such as the angiotensin converting enzyme. Therefore, this review aimed to describe the pathophysiological importance of the renin angiotensin aldosterone on Congestive Heart Failure.

La insuficiencia cardiaca es la segunda patología en perros longevos. Se ha sugerido que la insuficiencia cardiaca puede ser vista como un modelo neurohormonal o neuroendocrino, ya que la progresión de la enfermedad se da como resultado de la sobreexpresión de moléculas activadas biológicamente que son capaces de ejercer un efecto deletéreo sobre el corazón y la circulación. Dentro de estas moléculas está el Sistema Renina Angiotensina Aldosterona y su principal péptido efector, la angiotensina II. En los últimos años, las consecuencias fisiopatológicas del sistema han sido el foco principal de atención, siendo más relevantes las vías alternativas de síntesis de la angiotensina II y la participación de otras enzimas similares a la enzima convertidora de angiotensina. Por lo tanto, esta revisión pretende describir el valor fisiopatológico del sistema renina angiotensina aldosterona sobre la Insuficiencia Cardíaca Congestiva.

A insuficiência cardíaca é a segunda doença em cães longevos. Tem sido sugerido que a insuficiência cardíaca pode ser vista como um modelo neurohormonal ou neuroendócrino, já que a progressão da doença apresenta-se como um resultado da sobre-expressão de moléculas activadas biologicamente que são capazes de exercer um efeito deletério sobre o coração e a circulação. Dentre estas moléculas está o sistema renina-angiotensina-aldosterona e o seu peptídeo efetor principal, a angiotensina II. Nos últimos anos, as consequências fisiopatológicas deste sistema têm sido o foco principal de interesse, tendo maior relevância a síntese da angiotensina II e o envolvimento de outras enzimas como a enzima conversora da angiotensina. Portanto, esta revisão tem como objetivo descrever o valor fisiopatológico que tem o sistema renina-angiotensina-aldosterona sobre a insuficiência cardíaca congestiva.

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Objecfive To investigate the effects of endotoxin on nuclear factor-κB p65(NF-κB p65)mRNA expression and ahtosteron secretion in rat hepatic stellate cells(HSCs).Methods Cultured rat HSCs(HSC-T6)were divided into endotoxin-treated group and control group.Cells in endotoxin-treated group were exposure to 1 mg/ml.endotoxin.Aldosteron secretions of HSCs were determined by radioimmunoassay,and NF-κB p65 mRNA expressions of HSCs were detected by one-step RT-PCR.Results At 6,12,24 and 48 h,aldosteron secretions in endotoxin-treated group were significantly hisher than those in the control group(t=3.063,4.577,6.847 and 9.317,P<0.05),and the expressions of NF-κB p65 mRNA in endotoxin-treated group were also higher than those in control group(t=5.155,6.095,7.875 and 9.313,P<0.01).Aldosteron secretions and NF-κB p65 mRNA expressions in HSCs displayed a positive correlation(r=0.886,P<0.01).Conclusion Endotoxin can up-regulate the aldosteron secretion and NF-κB p65 mRNA expression in rat HSCs,which may be one of the mechanisms of liver fibrosis induced by endotoxin.

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La ascitis es el acúmulo anormal de líquido en la cavidad abdominal, que en el caso del paciente cirrótico obedece a una conjugación de factores determinantes. Diversas teorías se han elaborado al respecto a lo largo de las décadas anteriores, sin embargo el concepto actual es que el principal mecanismo patofisiológico de formación de ascitis es un estado de vasodilatación periférica permanente en el cirrótico, asociado a una relativa hipoperfusión renal que a su vez determina la activación de una serie de mecanismos retenedores de sodio y agua. Es un fenómeno progresivo cuya historia natural se puede ver como un espectro de enfermedad, teniendo como evento extremo al síndrome hepato-renal, con ascitis refractaria al tratamiento diurético y la mayor frecuencia de colonización bacteriana del líquido ascítico, fenómeno conocido como peritonitis bacteriana espontánea. El siguiente artículo revisa la patofisiología, diagnóstico, complicaciones y aspectos terapéuticos de la ascitis en el paciente cirrótico.

Ascites is the abnormal accumulation of fluid into the peritoneal cavity, which in the cirrhotic patient is due to a number of determinant factors. Many theories have been elaborated in that regard during the previous decades, however the current concept states that the chief pathophysiologic mechamism of ascites formation is a permanent state of peripheral vasodilation in the cirrhotic patient, associated with a relative renal hypoperfusion, which in turn activates a host of sodium and water retaining mechanisms. It is a progressive phenomenon and its natural history can be viewed as a spectrum of disease, having at one end of the spectrum the so called hepatorenal syndrome, with ascites refractory to diuretic treatment and a higher frequency of bacterial colonization of the ascitic fluid, so called spontaneous bacterial peritonitis. This article reviews the pathophysiology, diagnosis, complications and therapeutic aspects of ascites in the cirrhotic patient.

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Objective To report the clinical characteristics, biochemical profiles, diagnosis and treatment of one Chinese pedigree with glucocorticoid remediable aldosteronism. Methods Plasma and urine aldo~sterone and cortisol and plasma renin activity were dynamically tested and diagnostic therapy was undergone in 3 affected subjects. Results All of 4 affected members had hypertension, hypokalemia, 3 patients had low basic and provoked renin activity (0.017?0.015 vs 0.13?0.08)?g?L -1 ?h -1 . 3 patients were treated with 2 mg dexamethasone for 5～7 days, then the medication was reduced gradually and maintained at 0.5～0.75 mg per day after 1～1.5 month(s). 5 days after treatment, the plasma aldosterone concentrations (PACs) decreased significantly from (192?9)ng/L to (87?7)ng/L (P