Shared Proteins and Pathways of Cardiovascular and Cognitive Diseases: Relation to Vascular Cognitive Impairment.

One of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.

Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G.

Rainforest hunter-gatherers from Southeast Asia are characterized by specific morphological features including a particularly dark skin color (D), short stature (S), woolly hair (W), and the presence of steatopygia (S)-fat accumulation localized in the hips (DSWS phenotype). Based on previous evidence in the Andamanese population, we first characterized signatures of adaptive natural selection around the calcium-sensing receptor gene in Southeast Asian rainforest groups presenting the DSWS phenotype and identified the R990G substitution (rs1042636) as a putative adaptive variant for experimental follow-up. Although the calcium-sensing receptor has a critical role in calcium homeostasis by directly regulating the parathyroid hormone secretion, it is expressed in different tissues and has been described to be involved in many biological functions. Previous works have also characterized the R990G substitution as an activating polymorphism of the calcium-sensing receptor associated with hypocalcemia. Therefore, we generated a knock-in mouse for this substitution and investigated organismal phenotypes that could have become adaptive in rainforest hunter-gatherers from Southeast Asia. Interestingly, we found that mouse homozygous for the derived allele show not only lower serum calcium concentration but also greater body weight and fat accumulation, probably because of enhanced preadipocyte differentiation and lipolysis impairment resulting from the calcium-sensing receptor activation mediated by R990G. We speculate that such differential features in humans could have facilitated the survival of hunter-gatherer groups during periods of nutritional stress in the challenging conditions of the Southeast Asian tropical rainforests.

Risk of cognitive decline progression is associated to increased blood-brain-barrier permeability: A longitudinal study in a memory unit clinical cohort.

INTRODUCTION: This study examined the relationship between blood-brain-barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort. METHODS: This prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored. RESULTS: Male sex, diabetes mellitus, and cerebrovascular burden were associated with increased log-QAlb. Vascular cognitive impairment patients had the highest log-QAlb levels. Among the 273 participants with valid follow-up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log-QAlb. DISCUSSION: These results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis.

Technology adoption review for ageing well: analysis of technical solutions.

While several technological solutions are available for older adults to improve their wellbeing and quality of life, little is known about the gaps between the needs, provided solutions, and their adoption from a more pragmatic perspective. This paper reports on reviewing existing technological solutions for older adults, which span the work life, life in the community, and wellbeing at home. We analyzed 50 different solutions to uncover both negative and positive features of these solutions from the perspective of the impact of technology adoption on the quality of life of older adults. Our approach harnesses holistic reasoning to determine the most suitable technologies available today and provides suggestions for improvement toward designing and implementing better solutions.

Ectopic expression of the AtCDF1 transcription factor in potato enhances tuber starch and amino acid contents and yield under open field conditions.

Introduction: Cycling Dof transcription factors (CDFs) have been involved in different aspects of plant growth and development. In Arabidopsis and tomato, one member of this family (CDF1) has recently been associated with the regulation of primary metabolism and abiotic stress responses, but their roles in crop production under open field conditions remain unknown. Methods: In this study, we compared the growth, and tuber yield and composition of plants ectopically expressing the CDF1 gene from Arabidopsis under the control of the 35S promoter with wild-type (WT) potato plants cultured in growth chamber and open field conditions. Results: In growth chambers, the 35S::AtCDF1 plants showed a greater tuber yield than the WT by increasing the biomass partition for tuber development. Under field conditions, the ectopic expression of CDF1 also promoted the sink strength of the tubers, since 35S::AtCDF1 plants exhibited significant increases in tuber size and weight resulting in higher tuber yield. A metabolomic analysis revealed that tubers of 35S::AtCDF1 plants cultured under open field conditions accumulated higher levels of glucose, starch and amino acids than WT tubers. A comparative proteomic analysis of tubers of 35S::AtCDF1 and WT plants cultured under open field conditions revealed that these changes can be accounted for changes in the expression of proteins involved in energy production and different aspects of C and N metabolism. Discussion: The results from this study advance our collective understanding of the role of CDFs and are of great interest for the purposes of improving the yield and breeding of crop plants.

A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity.

Alzheimer's disease (AD) is known to be caused by amyloid ß-peptide (Aß) misfolded into ß-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aß toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aß1-42. We identified 81 mammalian orthologue genes that enhance Aß1-42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aß oligomers (oAß). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAß1-42, whereas SURF4 overexpression induced Aß1-42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aß toxicity and showed that SURF4 contributes to oAß1-42 neurotoxicity by decreasing SOCE activity.

Amyloid ß-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation.

Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aß) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aß oligomers (oAß) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAß on CaMKIIα. We found that oAß produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAß.

Addressing Psychosocial Factors in Cognitive Impairment Screening from a Holistic Perspective: The DeCo-Booklet Methodology Design and Pilot Study.

Cognitive impairment (CI), an intermediate phase between the decline in physiological cognition and dementia, is known to be mediated by a variety of risk and protective factors, with age being the most influential of these. The multifactorial nature of CI and the worldwide phenomenon of an aging population makes decoupling old age from disease through the concept of healthy aging (HA) a matter of major interest. Focusing on psychosocial variables and psychological constructs, here we designed and piloted a data collection booklet (DeCo-B) to assess CI and HA from a holistic perspective. The DeCo-B comprises six sections: sociodemographic factors, CI, meaning in life, psychosocial factors, health problems, and lifestyle. The estimated prevalence of CI and HA in our cohort were 24.4% and 6.6%, respectively. Spearman correlations mainly identified pairwise associations between the meaning in life domains and psychosocial variables. Moreover, age, marital status, purpose in life, resilience, chronic pain, cognitive reserve, and obstructive sleep apnea were significantly associated with an increased risk of CI. Our results showed that DeCo-B is a suitable tool for researching how modifiable risk and protective factors influence cognitive status. The complex interrelationships between variables should be further investigated and, for practical reasons, the questionnaire should be optimized in future work.

Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide.

Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid ß-peptide aggregation into ß-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid ß-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid ß-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid ß-peptide 1-40. Our results confirm that monomeric amyloid ß-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylations and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid ß-peptide 1-40 to insulin receptor. We found that oligomeric amyloid ß-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid ß-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid ß-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.

Big dynorphin is a neuroprotector scaffold against amyloid ß-peptide aggregation and cell toxicity.

Amyloid ß-peptide (Aß) misfolding into ß-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or to impair Aß aggregation are highly relevant as possible AD treatments since they should protect against Aß neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aß40 the most abundant species of Aß. Biophysical measurements indicate that Aß40 interacts with Big Dynorphin (BigDyn), lowering the amount of hydrophobic aggregates, and slowing down the aggregation kinetics. As expected, we found that BigDyn protects against Aß40 aggregates when studied in human neuroblastoma cells by cell survival assays. The cross-interaction between BigDyn and Aß40 provides insight into the mechanism of amyloid pathophysiology and may open up new therapy possibilities.

C-reactive protein cut-off for early tocilizumab and dexamethasone prescription in hospitalized patients with COVID-19.

Dexamethasone and tocilizumab have been associated with reduction in mortality, however, the beneficial effect is not for all patients and the impact on viral replication is not well defined. We hypostatized that C-reactive protein (CRP) could help in the identification of patients requiring anti-inflammatory therapy. Patients admitted for > 48 h in our hospital for a confirmed or suspected infection by SARS-CoV-2 from February 2020 to February 2021 were retrospectively evaluated. The primary outcome was mortality at 30 days. Demographics and the most relevant variables related with the outcome were included. CRP was stratified by percentiles. Univariate and multivariate analysis were performed. A total of 3218 patients were included with a median (IQR) age of 66 (74-78) years and 58.9% were males. The rate of intensive care unit admission was 24.4% and the 30-day mortality rate was 11.8%. Within the first 5 days from admission, 1018 (31.7%) patients received dexamethasone and 549 tocilizumab (17.1%). The crude analysis showed a mortality reduction in patients receiving dexamethasone when CRP was > 13.75 mg/dL and > 3.5 mg/dL for those receiving tocilizumab. Multivariate analysis identified the interaction of CRP > 13.75 mg/dL with dexamethasone (OR 0.57; CI 95% 0.37-0.89, P = 0014) and CRP > 3.5 mg/dL with tocilizumab (0.65; CI95%:0.44-0.95, P = 0.029) as independent predictors of mortality. Our results suggest that dexamethasone and tocilizumab are associated with a reduction in mortality when prescribed to patients with a certain inflammatory activity assessed by C-reactive protein.

Entropy-Variance Curves of Binary Sequences Generated by Random Substitutions of Constant Length.

We study some properties of binary sequences generated by random substitutions of constant length. Specifically, assuming the alphabet {0,1}, we consider the following asymmetric substitution rule of length k: 0→⟨0,0,…,0⟩ and 1→⟨Y1,Y2,…,Yk⟩, where Yi is a Bernoulli random variable with parameter p∈[0,1]. We obtain by recurrence the discrete probability distribution of the stochastic variable that counts the number of ones in the sequence formed after a number i of substitutions (iterations). We derive its first two statistical moments, mean and variance, and the entropy of the generated sequences as a function of the substitution length k for any successive iteration i, and characterize the values of p where the maxima of these measures occur. Finally, we obtain the parametric curves entropy-variance for each iteration and substitution length. We find two regimes of dependence between these two variables that, to our knowledge, have not been previously described. Besides, it allows to compare sequences with the same entropy but different variance and vice versa.

Endoscopic full-thickness resection of T1 colorectal cancers: a retrospective analysis from a multicenter Dutch eFTR registry.

BACKGROUND: Complete endoscopic resection and accurate histological evaluation for T1 colorectal cancer (CRC) are critical in determining subsequent treatment. Endoscopic full-thickness resection (eFTR) is a new treatment option for T1 CRC < 2 cm. We aimed to report clinical outcomes and short-term results. METHODS: Consecutive eFTR procedures for T1 CRC, prospectively recorded in our national registry between November 2015 and April 2020, were retrospectively analyzed. Primary outcomes were technical success and R0 resection. Secondary outcomes were histological risk assessment, curative resection, adverse events, and short-term outcomes. RESULTS: We included 330 procedures: 132 primary resections and 198 secondary scar resections after incomplete T1 CRC resection. Overall technical success, R0 resection, and curative resection rates were 87.0 % (95 % confidence interval [CI] 82.7 %-90.3 %), 85.6 % (95 %CI 81.2 %-89.2 %), and 60.3 % (95 %CI 54.7 %-65.7 %). Curative resection rate was 23.7 % (95 %CI 15.9 %-33.6 %) for primary resection of T1 CRC and 60.8 % (95 %CI 50.4 %-70.4 %) after excluding deep submucosal invasion as a risk factor. Risk stratification was possible in 99.3 %. The severe adverse event rate was 2.2 %. Additional oncological surgery was performed in 49/320 (15.3 %), with residual cancer in 11/49 (22.4 %). Endoscopic follow-up was available in 200/242 (82.6 %), with a median of 4 months and residual cancer in 1 (0.5 %) following an incomplete resection. CONCLUSIONS: eFTR is relatively safe and effective for resection of small T1 CRC, both as primary and secondary treatment. eFTR can expand endoscopic treatment options for T1 CRC and could help to reduce surgical overtreatment. Future studies should focus on long-term outcomes.

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration.

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.

Laparoscopía de etapificación y citología peritoneal en cáncer gástrico: descripción de la técnica quirúrgica / Staging laparoscopy and peritoneal cytology in gastric cancer: technique description and review of the literature

Resumen Introducción: El cáncer gástrico continúa representando la más alta mortalidad por cáncer en hombres en Chile. En una revisión sistemática, evidenciaron que en el 59% de los pacientes que se catalogaron como M0 mediante diferentes estudios como TC, resonancia magnética y PET, se detectaron metástasis a la laparoscopia de etapificación. El objetivo de este estudio es describir la técnica quirúrgica de esta laparoscopía incluida la citología peritoneal y una revisión de la literatura en cuanto a sus indicaciones y posibilidad de cambio de conducta. Materiales y Método: Se realizó la búsqueda de artículos vía MED - LINE/PubMed (U.S.A. National Library of Medicine), Cochrane Library, Elsevier, SciELO; no se aplicó análisis estadístico, se incluyeron 23 referencias relacionadas al tema y materias afines internacionales y nacionales. El procedimiento que describiremos será la laparoscopia diagnóstica y la citología de líquido peritoneal para estudio anatomopatológico. Discusión y Conclusiones: La laparoscopía de etapificación, logra un cambio de conducta en un 20% aproximadamente de los casos, pero hacen faltan más estudios de validación de esta en los centros que tratan dicha enfermedad en el país.

Introduction: Gastric cancer continues to represent the highest mortality from cancer in men in Chile. In a systematic review, they showed that 59% of the patients who were classified as M0 by different studies such as CT, magnetic resonance imaging and PET, metastases were detected at staging laparoscopy. The objective of this study is to describe the surgical technique of staging laparoscopy including peritoneal cytology and a review of the literature regarding its indications and the possibility of behavior change. Materials and Method: Articles were searched via MEDLINE/PubMed (U.S.A. National Library of Medicine), Cochrane Library, Elsevier, SciELO, no statistical analysis was applied, 23 references related to the topic and related international and national subjects were included. The procedure to be described will be diagnostic laparoscopy and peritoneal fluid cytology for pathological study. Discussion and Conclusions: Staging laparoscopy achieve a change in behavior in approximately 20% of the cases, but more validation studies are needed in the centers that treat this disease in the country.

Nigella and Milk Thistle Seed Oils: Potential Cytoprotective Effects against 7ß-Hydroxycholesterol-Induced Toxicity on SH-SY5Y Cells.

Oxysterols are assumed to be the driving force behind numerous neurodegenerative diseases. In this work, we aimed to study the ability of 7ß-hydroxycholesterol (7ß-OHC) to trigger oxidative stress and cell death in human neuroblastoma cells (SH-SY5Y) then the capacity of Nigella sativa and Milk thistle seed oils (NSO and MTSO, respectively) to oppose 7ß-OHC-induced side effects. The impact of 7ß-OHC, associated or not with NSO or MTSO, was studied on different criteria: cell viability; redox status, and apoptosis. Oxidative stress was assessed through the intracellular reactive oxygen species (ROS) production, levels of enzymatic and non-enzymatic antioxidants, lipid, and protein oxidation products. Our results indicate that 7ß-OHC (40 µg/mL) exhibit pr-oxidative and pro-apoptotic activities shown by a decrease of the antioxidant enzymatic activities and an increase of ROS production, lipid, and protein oxidation end products as well as nitrotyrosine formation and caspase 3 activation. However, under the pre-treatment with NSO, and especially with MTSO (100 µg/mL), a marked attenuation of oxidative damages was observed. Our study suggests harmful effects of 7ß-OHC consisting of pro-oxidative, anti-proliferative, and pro-apoptotic activities that may contribute to neurodegeneration. NSO and especially MTSO showed potential cytoprotection against the cytotoxicity of 7ß-OHC.

Estudio morfométrico del radio proximal en una población chilena / Morphometric study of the proximal radius in a Chilean population

RESUMEN: El objetivo de esta investigación fue determinar la morfometría del extremo proximal del radio, mediante mediciones efectuadas en la cabeza, cuello y tuberosidad del radio, en una población chilena y compararlas según sexo. Se efectuó un estudio transversal analizando exámenes de Tomografía Computarizada (TC) de codo, realizados entre enero de 2014 y diciembre de 2018. Se incluyó 32 TC, correspondientes a 16 hombres y 16 mujeres. Se transfirió las imágenes formateadas al software RadiAnt, para efectuar las mediciones en el radio proximal. El análisis estadístico de los resultados se realizó mediante el software SPSS 22. El diámetro de la cabeza del radio en hombres osciló entre 22,8±1,3 y 25,0±1,7 mm; en mujeres osciló entre 19,4±1,4 y 20,7±1,4 mm. El diámetro del cuello del radio proximal en hombres osciló entre 14,0±0,8 y 15,6±0,7 mm; en mujeres osciló entre 11,7±0,8 y 13,3±1,3 mm. El diámetro del cuello del radio distal en hombres osciló entre 14,4±1,0 y 16,0±1,2 mm; en mujeres osciló entre 12,5±1,0 y 13,8±1,5 mm. El diámetro de la tuberosidad radial en hombres osciló entre 15,1±1,5 y 17,7±1,8 mm; en mujeres osciló entre 13,2±1,1 y 15,5±1,8 mm. El promedio de altura de la cabeza del radio fue de 11,2±1,2 mm en hombres y de 9,5+0,8 mm en mujeres. El análisis comparativo entre sexos mostró diferencias estadísticamente significativas en todas las mediciones precedentes. El promedio de altura del cuello del radio fue de 11,2±1,2 mm en hombres y 10,1±1,6 mm en mujeres, sin diferencia significativa (p= 0,15). Los valores promedios de la morfometría del radio proximal de la población chilena difieren de los descritos para la población europea y presentan algunas similitudes con la población china. Nuestros resultados pueden ser de utilidad para el diseño de implantes y prótesis para el extremo proximal del radio y para una correcta planificación quirúrgica en ortopedia y traumatología.

SUMMARY: The aim of this research was to determine the morphometry of the proximal radius in a Chilean population, by means of measurements made in head of radius, neck of radius and radial tuberosity, and to compare them according to sex. A cross-sectional study was conducted analyzing Computed Tomography scans (CT) of elbows, performed between January 2014 and December 2018. Thirty-two CT corresponding to 16 men and 16 women were included. The formatted images were transferred to the RadiAnt software in order to perform measurements in the proximal radius. The statistical analysis of the results was performed using the SPSS 22 software. The diameter of the head of radius in men ranged between 22.8±1.3 and 25.0±1.7 mm; in women it ranged between 19.4±1.4 and 20.7±1.4 mm. The diameter of the proximal neck of radius in men ranged between 14.0±0.8 and 15.6±0.7 mm; in women, it ranged between 11.7±0.8 and 13.3±1.3 mm. The diameter of the distal neck of radius in men ranged between 14.4±1.0 and 16.0±1.2 mm; in women, it ranged between 12.5±1.0 and 13.8±1.5 mm. The diameter of radial tuberosty in men ranged between 15.1±1.5 and 17.7±1.8 mm; in women, it ranged between 13.2±1.1 and 15.5±1.8 mm. The mean height of the head of radius was 11.2±1.2 mm in men and 9.5±0.8 mm in women. Statistically significant sex differences were revealed in all the preceding measurements. The mean height of the neck of radius was 11.2±1.2 mm in men and 10.1±1.6 mm in women, with no significant difference (p= 0.15). The average values of morphometry of the proximal radius of the Chilean population differ from those describing the European population, and show some similarities with the Chinese population. Our results may be useful to design of implants and prostheses for the proximal radius, and to correct surgical planning in orthopedics and traumatology.

A case-control emergency department-based analysis of acute pancreatitis in Covid-19: Results of the UMC-19-S6.

BACKGROUND/PURPOSE: We investigated the incidence, risk factors, clinical characteristics and outcomes of acute pancreatitis (AP) in patients with COVID-19 attending the emergency department (ED), before hospitalization. METHODS: We retrospectively reviewed all COVID patients diagnosed with AP in 62 Spanish EDs (20% of Spanish EDs, COVID-AP) during the COVID outbreak. We formed two control groups: COVID patients without AP (COVID-non-AP) and non-COVID patients with AP (non-COVID-AP). Unadjusted comparisons between cases and controls were performed regarding 59 baseline and clinical characteristics and four outcomes. RESULTS: We identified 54 AP in 74 814 patients with COVID-19 attending the ED (frequency = 0.72‰, 95% CI = 0.54-0.94‰). This frequency was lower than in non-COVID patients (2231/1 388 879, 1.61‰, 95% CI = 1.54-1.67; OR = 0.44, 95% CI = 0.34-0.58). Etiology of AP was similar in both groups, being biliary origin in about 50%. Twenty-six clinical characteristics of COVID patients were associated with a higher risk of developing AP: abdominal pain (OR = 59.4, 95% CI = 23.7-149), raised blood amylase (OR = 31.8; 95% CI = 1.60-632) and vomiting (OR = 15.8, 95% CI = 6.69-37.2) being the strongest, and some inflammatory markers (C-reactive protein, procalcitonin, platelets, D-dimer) were more increased. Compared to non-COVID-AP, COVID-AP patients differed in 23 variables; the strongest ones related to COVID symptoms, but less abdominal pain was reported, pancreatic enzymes raise was lower, and severity (estimated by BISAP and SOFA score at ED arrival) was higher. The in-hospital mortality (adjusted for age and sex) of COVID-AP did not differ from COVID-non-AP (OR = 1.12, 95% CI = 0.45-245) but was higher than non-COVID-AP (OR = 2.46, 95% CI = 1.35-4.48). CONCLUSIONS: Acute pancreatitis as presenting form of COVID-19 in the ED is unusual (<1‰ cases). Some clinically distinctive characteristics are present compared to the remaining COVID patients and can help to identify this unusual manifestation. In-hospital mortality of COVID-AP does not differ from COVID-non-AP but is higher than non-COVID-AP, and the higher severity of AP in COVID patients could partially contribute to this increment.

Amyloid Beta-Peptide Increases BACE1 Translation through the Phosphorylation of the Eukaryotic Initiation Factor-2α.

Alzheimer's disease (AD) is tightly linked to oxidative stress since amyloid beta-peptide (Aß) aggregates generate free radicals. Moreover, the aggregation of Aß is increased by oxidative stress, and the neurotoxicity induced by the oligomers and fibrils is in part mediated by free radicals. Interestingly, it has been reported that oxidative stress can also induce BACE1 transcription and expression. BACE1 is the key enzyme in the cleavage of the amyloid precursor protein to produce Aß, and the expression of this enzyme has been previously shown to be enhanced in the brains of Alzheimer's patients. Here, we have found that BACE1 expression is increased in the hippocampi from AD patients at both the early (Braak stage II) and late (Braak stage VI) stages of the disease as studied by immunohistochemistry and western blot. To address the role of Aß and oxidative stress in the regulation of BACE1 expression, we have analyzed the effect of subtoxic concentrations of Aß oligomers (0.25 µM) and H2O2 (10 mM) on a human neuroblastoma cell line. Firstly, our results show that Aß oligomers and H2O2 induce an increase of BACE1 mRNA as we studied by qPCR. Regarding BACE1 translation, it is dependent on the phosphorylation of the eukaryotic initiation factor 2α (eIF2α), since BACE1 mRNA bears a 5'UTR that avoids its translation under basal conditions. BACE1 5'UTR contains four upstream initiating codons (uAUGs), and its translation is activated when eIF2α is phosphorylated. Consistently, we have obtained that Aß oligomers and H2O2 increase the levels of BACE1 and p-eIF2α assayed by western blot and confocal microscopy. Our results suggest that Aß oligomers increase BACE1 translation by phosphorylating eIF2α in a process that involves oxidative stress and conforms a pathophysiological loop, where the Aß once aggregated favors its own production continuously by the increase in BACE1 expression as observed in AD patients.

Guest Removal and External Pressure Variation Induce Spin Crossover in Halogen-Functionalized 2-D Hofmann Frameworks.

The effect of halogen functionalization on the spin crossover (SCO) properties of a family of 2-D Hofmann framework materials, [FeIIPd(CN)4(thioX)2]·2H2O (X = Cl and Br; thioCl = (E)-1-(5-chlorothiophen-2-yl)-N-(4H-1,2,4-triazol-4-yl)methanimine) and thioBr = (E)-1-(5-bromothiophen-2-yl)-N-(4H-1,2,4-triazol-4-yl)methanimine)), is reported. Inclusion of both the chloro- and bromo-functionalized ligands into the Hofmann-type frameworks (1Cl·2H2O and 2Br·2H2O) results in a blocking of spin-state transitions due to internal chemical pressure effects derived by the collective steric bulk of the halogen atoms and guest molecules. Cooperative one-step SCO transitions are revealed by either guest removal or the application of external physical pressure. Notably, removal of solvent water reveals a robust framework scaffold with only marginal variation between the solvated and desolvated structures (as investigated by powder and single crystal X-ray diffraction). Yet, one-step complete SCO transitions are revealed in 1Cl and 2Br with a transition temperature shift between the analogues due to various steric, structural, and electronic considerations. SCO can also be induced in the solvated species, 1Cl·2H2O and 2Br·2H2O, with the application of physical pressure, revealing a complete one-step SCO transition above 0.62 GPa (as investigated by magnetic susceptibility and single crystal X-ray diffraction measurements).