Implicaciones patogénicas, pronósticas y terapéuticas del complemento en las vasculitis asociadas a anticuerpo anticitoplasma de neutrófilo con afectación renal / Complement in vasculitis associated with anti-neutrophil cytoplasm antibodies with renal involvement: pathogenic, prognostic and therapeutic implications

Las vasculitis asociadas a anticuerpo anticitoplasma de neutrófilo son vasculitis primarias, que afectan a vasos pequeños de diversos órganos, entre ellos el riñón. La afectación renal, se caracteriza por presencia de glomerulonefritis con semilunas y necrosis en microscopia óptica y un patrón pauciinmune en la inmunofluorescencia. La participación del complemento en la patogenia de estas entidades se ha puesto en valor en los últimos años, inicialmente en modelos animales y posteriormente en estudios en humanos, al demostrarse la presencia de fragmentos de la vía alternativa complemento, en plasma y en orina, junto con depósitos de complemento en glomérulos y pequeños vasos de pacientes afectos por vasculitis anticuerpo anticitoplasma de neutrófilo. La presencia de complemento en estas entidades confiere peor pronóstico general y renal (AU)

ntineutrophil cytoplasmic antibody-associated vasculitides are primary vasculitides that affect small vessels in various organs, including the kidney. Renal involvement is characterized by the presence of glomerulonephritis with crescents and necrosis in light microscopy and a pauci-immune pattern in immunofluorescence. The participation of complement in the pathogenesis of these entities has been valued in recent years, initially in animal models and later in studies in humans, by demonstrating the presence of fragments of the alternative complement pathway, in plasma and urine, together with complement deposits in glomeruli and small vessels of patients affected by antineutrophil cytoplasmic antibody vasculitis. The presence of complement in these entities confers a worse general and renal prognosis (AU)

[Complement in vasculitis associated with anti-neutrophil cytoplasm antibodies with renal involvement: pathogenic, prognostic and therapeutic implications]. / Implicaciones patogénicas, pronósticas y terapéuticas del complemento en las vasculitis asociadas a anticuerpo anticitoplasma de neutrófilo con afectación renal.

Antineutrophil cytoplasmic antibody-associated vasculitides are primary vasculitides that affect small vessels in various organs, including the kidney. Renal involvement is characterized by the presence of glomerulonephritis with crescents and necrosis in light microscopy and a pauci-immune pattern in immunofluorescence. The participation of complement in the pathogenesis of these entities has been valued in recent years, initially in animal models and later in studies in humans, by demonstrating the presence of fragments of the alternative complement pathway, in plasma and urine, together with complement deposits in glomeruli and small vessels of patients affected by antineutrophil cytoplasmic antibody vasculitis. The presence of complement in these entities confers a worse general and renal prognosis.

Fear Detection in Multimodal Affective Computing: Physiological Signals versus Catecholamine Concentration.

Affective computing through physiological signals monitoring is currently a hot topic in the scientific literature, but also in the industry. Many wearable devices are being developed for health or wellness tracking during daily life or sports activity. Likewise, other applications are being proposed for the early detection of risk situations involving sexual or violent aggressions, with the identification of panic or fear emotions. The use of other sources of information, such as video or audio signals will make multimodal affective computing a more powerful tool for emotion classification, improving the detection capability. There are other biological elements that have not been explored yet and that could provide additional information to better disentangle negative emotions, such as fear or panic. Catecholamines are hormones produced by the adrenal glands, two small glands located above the kidneys. These hormones are released in the body in response to physical or emotional stress. The main catecholamines, namely adrenaline, noradrenaline and dopamine have been analysed, as well as four physiological variables: skin temperature, electrodermal activity, blood volume pulse (to calculate heart rate activity. i.e., beats per minute) and respiration rate. This work presents a comparison of the results provided by the analysis of physiological signals in reference to catecholamine, from an experimental task with 21 female volunteers receiving audiovisual stimuli through an immersive environment in virtual reality. Artificial intelligence algorithms for fear classification with physiological variables and plasma catecholamine concentration levels have been proposed and tested. The best results have been obtained with the features extracted from the physiological variables. Adding catecholamine's maximum variation during the five minutes after the video clip visualization, as well as adding the five measurements (1-min interval) of these levels, are not providing better performance in the classifiers.

Severe Hyponatremia Masking Central Diabetes Insipidus in a Patient with a Lung Adenocarcinoma.

Altered natremia is a common electrolyte disorder in clinical practice and a paraneoplastic manifestation. The syndrome of inappropriate antidiuretic hormone secretion is the first diagnostic suspicion in a patient with cancer and hyponatremia, although entities such as adrenal insufficiency primary or secondary to metastatic involvement must be taken into account. Likewise, immunorelated endrocrinopathies such as hypophysitis have been reported after the introduction of checkpoint inhibitors. A 46-year-old man diagnosed with metastatic adenocarcinoma of the lung with severe hyponatremia (111 mmol/L) consulted due to altered level of consciousness. The initial cranial CT scan did not reveal pituitary brain metastatic involvement; however, an MRI could not be performed due to the patient's clinical situation and subsequent exitus. The water restriction test confirmed the diagnostic suspicion of central diabetes insipidus. Medical treatment with desmopressin was started to avoid fluid depletion with improvement of natremia figures. It represents an exceptional case of central diabetes insipidus masked by severe hyponatremia in a patient with metastatic lung adenocarcinoma without initial evidence of pituitary metastatic involvement by CT imaging in treatment with nivolumab (anti-PD-1 agent). Secondary adrenal insufficiency due to pituitary metastatic involvement and endocrinologic toxicity immunorelated to the new checkpoint inhibitors should be considered as possible etiologic agents of central diabetes insipidus, even with hyponatremia.

Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux.

Hutchinson-Gilford Progeria Syndrome is an ultrarare disease which is characterized by an accelerated senescence phenotype with deleterious consequences to people suffering this pathology. The production of an abnormal protein derived from lamin A, called progerin, presents a farnesylated domain, which is not eliminated by the causal mutation of the disease, and accumulates in the interior of the nucleus, provoking a disruption of nuclear membrane, chromatin organization and an altered gene expression. The mutation in these patients occurs in a single nucleotide change, which creates a de novo splicing site, producing a shorter version of the protein. Apart from this mutation, an alteration in the metalloproteinase Zmpste24, involved in the maturation of lamin A, causing a similar alteration than in progeria. However, in this case, patients accumulate a protein, called prelamin A, which generates similar alterations in the nucleus than progerin. The reduction of prelamin A protein levels facilitates the recovery of the phenotype in different mice models of the disease, reducing the aging process. Different strategies have been studied for eliminating this toxic protein. Here, we report that immortalization of primary cells derived from the Zmpste24 KO mice, facilitates prelamin A degradation by different mechanisms, being essential, the enhancing proliferative capacity that the immortalized cells present. Then, these data suggest that using different treatments for increasing proliferative capacity of these cells, potentially could have a beneficial effect, facilitating prelamin A toxicity.

Biological Actions and Molecular Mechanisms of Sambucus nigra L. in Neurodegeneration: A Cell Culture Approach.

Sambucus nigra flowers (elderflower) have been widely used in traditional medicine for the relief of early symptoms of common cold. Its chemical composition mainly consists of polyphenolic compounds such as flavonoids, hydroxycinnamic acids, and triterpenes. Although the antioxidant properties of polyphenols are well known, the aim of this study is to assess the antioxidant and protective potentials of Sambucus nigra flowers in the human neuroblastoma (SH-SY5Y) cell line using different in vitro approaches. The antioxidant capacity is first evaluated by the oxygen radical absorbance capacity (ORAC) and the free radical scavenging activity (DPPH) methods. Cell viability is assessed by the crystal violet method; furthermore, the intracellular ROS formation (DCFH-DA method) is determined, together with the effect on the cell antioxidant defenses: reduced glutathione (GSH) and antioxidant enzyme activities (GPx, GR). On the other hand, mTORC1 hyperactivation and autophagy blockage have been associated with an increase in the formation of protein aggregates, this promoting the transference and expansion of neurodegenerative diseases. Then, the ability of Sambucus nigra flowers in the regulation of mTORC1 signaling activity and the reduction in oxidative stress through the activation of autophagy/mitophagy flux is also examined. In this regard, search for different molecules with a potential inhibitory effect on mTORC1 activation could have multiple positive effects either in the molecular pathogenic events and/or in the progression of several diseases including neurodegenerative ones.

Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model.

BACKGROUND: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. METHODS: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. RESULTS: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels' imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. CONCLUSION: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.

Osteoporosis Remission and New Bone Formation with Mesoporous Silica Nanoparticles.

Nanotechnology changed the concept of treatment for a variety of diseases, producing a huge impact regarding drug and gene delivery. Among the different targeted diseases, osteoporosis has devastating clinical and economic consequences. Since current osteoporosis treatments present several side effects, new treatment approaches are needed. Recently, the application of small interfering RNA (siRNA) has become a promising alternative. Wnt/ß-catenin signaling pathway controls bone development and formation. This pathway is negatively regulated by sclerostin, which knock-down through siRNA application would potentially promote bone formation. However, the major bottleneck for siRNA-based treatments is the necessity of a delivery vector, bringing nanotechnology as a potential solution. Among the available nanocarriers, mesoporous silica nanoparticles (MSNs) have attracted great attention for intracellular delivery of siRNAs. The mesoporous structure of MSNs permits the delivery of siRNAs together with another biomolecule, achieving a combination therapy. Here, the effectiveness of a new potential osteoporosis treatment based on MSNs is evaluated. The proposed system is effective in delivering SOST siRNA and osteostatin through systemic injection to bone tissue. The nanoparticle administration produced an increase expression of osteogenic related genes improving the bone microarchitecture. The treated osteoporotic mice recovered values of a healthy situation approaching to osteoporosis remission.

Insulin Resistance and Diabetes Mellitus in Alzheimer's Disease.

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer's disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

Dietary Polyphenols in Metabolic and Neurodegenerative Diseases: Molecular Targets in Autophagy and Biological Effects.

Polyphenols represent a group of secondary metabolites of plants which have been analyzed as potent regulators of multiple biological processes, including cell proliferation, apoptosis, and autophagy, among others. These natural compounds exhibit beneficial effects and protection against inflammation, oxidative stress, and related injuries including metabolic diseases, such as cardiovascular damage, obesity and diabetes, and neurodegeneration. This review aims to summarize the mechanisms of action of polyphenols in relation to the activation of autophagy, stimulation of mitochondrial function and antioxidant defenses, attenuation of oxidative stress, and reduction in cell apoptosis, which may be responsible of the health promoting properties of these compounds.

Geographical clustering and socioeconomic factors associated with hypoglycemic events requiring emergency assistance in Andalusia (Spain).

INTRODUCTION: The geographical distribution of hypoglycemic events requiring emergency assistance was explored in Andalusia (Spain), and potentially associated societal factors were determined. RESEARCH DESIGN AND METHODS: This was a database analysis of hypoglycemia requiring prehospital emergency assistance from the Public Company for Health Emergencies (Empresa Pública de Emergencias Sanitarias (EPES)) in Andalusia during 2012, which served 8 393 159 people. Databases of the National Statistics Institute, Basic Spatial Data of Andalusia and System of Multiterritorial Information of Andalusia were used to retrieve spatial data and population characteristics. Geographic Information System software (QGIS and GeoDA) was used for analysis and linkage across databases. Spatial analyses of geographical location influence in hypoglycemic events were assessed using Moran's I statistics, and linear regressions were used to determine their association with population characteristics. RESULTS: The EPES attended 1 137 738 calls requesting medical assistance, with a mean hypoglycemia incidence of 95.0±61.6 cases per 100 000 inhabitants. There were significant differences in hypoglycemia incidence between basic healthcare zones attributable to their geographical location in the overall population (Moran's I index 0.122, z-score 7.870, p=0.001), women (Moran's I index 0.088, z-score 6.285, p=0.001), men (Moran's I index 0.076, z-score 4.914, p=0.001) and aged >64 years (Moran's I index 0.147, z-score 9.753, p=0.001). Hypoglycemia incidence was higher within unemployed individuals (ß=0.003, p=0.001) and unemployed women (ß=0.005, p=0.001), while lower within individuals aged <16 years (ß=-0.004, p=0.040), higher academic level (secondary studies) (ß=-0.003, p=0.004) and women with secondary studies (ß=-0.005, p<0.001). In subjects aged >64 years, lower rate of hypoglycemia was associated with more single-person homes (ß=-0.008, p=0.022) and sports facilities (ß=-0.342, p=0.012). CONCLUSIONS: This analysis supports the geographical distribution of hypoglycemia in the overall population, both genders and subjects aged >64 years, which was affected by societal factors such as unemployment, literacy/education, housing and sports facilities. These data can be useful to design specific prevention programs.