Gender-affirming hormone therapy in cystic fibrosis - A case of new Pseudomonas infection.

BACKGROUND: Little is known about the impact of hormone therapy on transgender youth with Cystic Fibrosis (CF). This case report describes an 18-year-old affirmed female with CF who was treated with hormone therapy associated in timing with new growth of Pseudomonas aeruginosa in her sputum culture. DISCUSSION: We highlight important considerations, including the impact of gender-affirming hormone therapy on overall CF disease course. Evidence supports that females with CF have worse outcomes than males, which are partly attributed to estrogen effects. Pseudomonas aeruginosa is one of the most prevalent pathogens in people with CF. Here, we highlight a transfemale who grows Pseudomonas aeruginosa for the first time since her youth, nearly 1 year after starting estrogen therapy. This is consistent with previous literature of an association between high estrogen levels and Pseudomonas aeruginosa prevalence, but has never been evaluated in a transgender population. CONCLUSION: Through this case, we demonstrate the need for additional research to understand the relationship between gender-affirmative hormone transition and CF care and management.

Sex-related differences of fatty acid-binding protein 4 and leptin levels in atrial fibrillation.

AIMS: Adiposity plays a key role in the pathogenesis of atrial fibrillation (AF). Our aim was to study the sex differences in adipokines levels according to AF burden. METHODS AND RESULTS: Two independent cohorts of patients were studied: (i) consecutive patients with AF undergoing catheter ablation (n = 217) and (ii) a control group (n = 105). (i) Adipokines, oxidative stress, indirect autonomic markers, and leucocytes mRNA levels were analysed; (ii) correlation between biomarkers was explored with heatmaps and Kendall correlation coefficients; and (iii) logistic regression and random forest model were used to determine predictors of AF recurrence after ablation. Our results showed that: (i) fatty acid-binding protein 4 (FABP4) and leptin levels were higher in women than in men in both cohorts (P < 0.01). In women, FABP4 levels were higher on AF cohort (20 ± 14 control, 29 ± 18 paroxysmal AF and 31 ± 17 ng/mL persistent AF; P < 0.01). In men, leptin levels were lower on AF cohort (22 ± 15 control, 13 ± 16 paroxysmal AF and 13 ± 11 ng/mL persistent AF; P < 0.01). (ii) In female with paroxysmal AF, there was a lower acetylcholinesterase and higher carbonic anhydrase levels with respect to men (P < 0.05). (iii) Adipokines have an important role on discriminate AF recurrence after ablation. In persistent AF, FABP4 was the best predictor of recurrence after ablation (1.067, 95% confidence interval 1-1.14; P = 0.046). CONCLUSION: The major finding of the present study is the sex-based differences of FABP4 and leptin levels according to AF burden. These adipokines are associated with oxidative stress, inflammatory and autonomic indirect markers, indicating that they may play a role in AF perpetuation.

Impact of cadaveric practices on arthroscopic knee training for Orthopaedic Surgery and Traumatology residents. / Impacto de las prácticas cadavéricas en la formación artroscópica de rodilla de los residentes de Cirugía Ortopédica y Traumatología.

BACKGROUND AND OBJECTIVES: There currently is a considerable variability in the content of training programs and courses for orthopaedic surgeons in training. Besides this, there is still no consensus regarding which is the most effective methodology for improving learning of the technique or for its qualitative evaluation. A study was carried out to assess the influence of carrying out a cadaveric practical course on the acquisition of arthroscopic technical skills in fifth-year residents. MATERIAL AND METHODS: A knee arthroscopy cadaveric course was performed in which 48 students participated. Different technical aspects during a knee arthroscopy, as well as the residents skill and the execution time were evaluated before and after the course using a specific questionnaire. RESULTS: There was a significant statistic improvement between the initial and final evaluation, increasing from 11,7 till 17,1 (maximum 20) points. Also, a significant improvement in all the parameters analysed was observed; the identification of anatomic structures (p = 0.001), the palpation of specific structures (p = 0.032), and the time necessary for the arthroscopic knee check (p = 0.015). CONCLUSIONS: A knee arthroscopy cadaveric course improves significantly the technical skills of surgeons in training.

Plasma FABP4 levels are associated with left atrial fat volume in persistent atrial fibrillation and predict recurrence after catheter ablation.

BACKGROUND: Imaging techniques have shown the association between left atrial adipose tissue (LAAT) volume and atrial fibrillation (AF) risk. PURPOSE: To analyze 1) adipokines in peripheral and atrial plasma from patients undergoing AF ablation; 2) its association with LAAT volume measured by multislice CT and 3) its predictive value for AF recurrence. METHODS: Seventy consecutive patients undergoing AF catheter ablation were screened. Blood samples were extracted from the left atrium and peripheral vein before catheter ablation. Multiplex fluorimetric immunoassay, enzyme-linked immunoassay and Western blot techniques were used for analyzing some adipokines, fatty acid binding protein 4 (FABP4), and leptin and perilipin analysis, respectively. Patients were followed up with clinical visits until one year after ablation. Generalized additive regression (GAM) was used for determining the best indicator of LAAT volume. Logistic regression analysis determined the best predictor of AF recurrence after persistent AF catheter ablation. RESULTS: Our results showed 1) differences in the levels of FABP4 between peripheral and left atrial blood samples. 2) persistent AF patients had higher LAAT volume than those with paroxysmal AF (5.12 ±â€¯2.76 vs. 3.82 ±â€¯1.81 mL; p < 0.036). FABP4 was the best adipokine associated with LAAT in persistent AF (p < 0.01) 3) and predictive value for AF recurrence after catheter ablation (AUC-ROC 0.883 with 95% CI 0.739-1.028). CONCLUSIONS: Plasma FABP4 levels, which were associated with LAAT volume in persistent AF, can be predictors of recurrence after catheter ablation. Whether persistent AF patients require more intensive management and monitoring according to FABP4 deserves further investigation.

In silico design of mimosine containing peptides as new efficient chelators of aluminum.

The design of new and efficient chelators that can remove aluminium(iii), a metal with increasing recognition as a potential toxic agent, from biological systems is an area of high therapeutic relevance. In the present paper, we present an extensive computational study of a new promising type of these chelators based on mimosine containing peptides. The reason to choose mimosine is that the sidechain of this residue is similar to deferiprone, a ligand known to tightly interact with highly-valent metals, and in particular with Al(iii). In this article we analyze systematically, using a combination of methods that include QM/MM MD simulations, how the size and sequence of the polypeptides can alter the fundamental binding patterns to aluminum, in comparison with the binding to deferiprone. Particular attention is given towards the identification of the smallest peptide that interacts efficiently with aluminum, since polypeptide size is a fundamental factor to allow a given polypeptide to efficiently cross the cell membrane. The results indicate that the longest peptides, with 8 or 9 amino acids, show no difficulties interacting with Al(iii) in an optimum arrangement. By contrast, when the peptide contains five or six amino acids Al(iii) is pentacoordinated, reducing the stability of the resultant complex. In summary, our study demonstrates that the mimosine containing peptides can efficiently coordinate highly valent metals such as Al(iii), with a subtle dependence of the binding on the specific chain-lengths of the polypeptide. We believe that the present study sheds light on the adequacy of this new type of chelator towards aluminum binding.

Mortality and factors associated with phosphide poisoning: prospective cohort study / Mortalidad y factores asociados con intoxicación por fosfuros: estudio de cohorte prospectiva

Background: Aluminum and zinc phosphides are solid fumigants for pest control. Metal phosphide poisoning (PP) is common in suicide and suicide attempts. In Mexico, zinc phosphide is easily available, and is a common agent in poisonings. Objective: To identify mortality in PP, and associated factors in a poison control center. Material and methods: Prospective cohort study. The starting point was the exposure (PP) and it was made a follow-up on the outcome (mortality and non-mortality). Main factors associated to PP outcome were assessed (e.g.: personal and clinical factors, duration of poisoning, detoxification, and radiographic evidence of poisoning). It was used relative risk (RR) as a risk estimator with 95% CI, as well as chi-squared with Fisher's exact test, Kaplan-Meier survival curves, and Log- Rank test as a comparative mean. Results: 44 exposed patients, and 88 non-exposed were followed up. Mortality rate in PP was of 16% in acute phase patients; there were no deaths in either subacute or chronic phases. Mortality risk was 14 (95% CI, 2 110). Main factors associated with increased mortality were: time of first medical assistance > 6 hours, RR = 15 (95% CI, 1.7-128); dose of poison ≥ 1 bottle or 1 tablet, RR = 14 (95% CI, 1.8-108); radiographic evidence of poisoning, RR = 10 (95% CI, 1.3 77). Conclusion: Metal PP has a high mortality rate and is associated to long periods of exposure to the toxic chemical due to ineffective detoxification.

Introducción: los fosfuros de aluminio y zinc son fumigantes sólidos para controlar plagas. La intoxicación por fosfuros (IpF) es un método común en suicidios o intentos de suicidio. En México los fosfuros son de fácil distribución y son un agente común en las intoxicaciones. Objetivo: identificar la mortalidad en la IpF y los factores asociados en un centro de toxicología. Material y métodos: estudio de cohorte prospectiva. Se partió de la exposición (IpF) y se siguió el desenlace (mortalidad y no mortalidad). Se evaluaron los principales factores asociados al desenlace de IpF (por ejemplo: clínicos, personales, tiempo de la intoxicación, descontaminación y evidencia radiográfica). Para estimar el riesgo se empleó el riesgo relativo (RR), con IC al 95%, chi cuadrada con prueba exacta de Fisher, curvas de supervivencia de Kaplan-Meier y su comparación por medio de Log-Rank. Resultados: se siguieron 44 pacientes expuestos y 88 no expuestos. La mortalidad por fosfuros fue del 16% de los pacientes intoxicados en la fase aguda; no hubo mortalidad en la fase subaguda y crónica. El riesgo de mortalidad fue de 14 (IC 95%: 2-110). Los factores de mayor magnitud asociados a la mortalidad en la IpF fueron: tiempo de primera atención > 6 horas, RR = 15 (IC 95% 1.7 128); dosis del tóxico ≥ 1 frasco o 1 pastilla, RR = 14 (IC 95%: 1.8 108); evidencia radiográfica del tóxico RR = 10, (IC 95%: 1.3 77). Conclusiones: la intoxicación por fosfuros metálicos tiene alta mortalidad y está asociada a estados prolongados de exposición al tóxico por descontaminación inadecuada.

Electron-Pair Distribution in Chemical Bond Formation.

The chemical formation process has been studied from relaxation holes, Δh(u), resulting from the difference between the radial intracule density and the nonrelaxed counterpart, which is obtained from atomic radial intracule densities and the pair density constructed from the overlap of the atomic densities. Δh(u) plots show that the internal reorganization of electron pairs prior to bond formation and the covalent bond formation from electrons in separate atoms are completely recognizable processes from the shape of the relaxation hole, Δh(u). The magnitude of Δh(u), the shape of Δh(u) ∀ u < Req, and the distance between the minimum and the maximum in Δh(u) provide further information about the nature of the chemical bond formed. A computational affordable approach to calculate the radial intracule density from approximate pair densities has been also suggested, paving the way to study electron-pair distributions in larger systems.

Backbone flexibility of extended metal atom chains. Ab initio molecular dynamics for Cr3(dpa)4X2 (X = NCS, CN, NO3) in gas and crystalline phases.

Recently published static DFT and CASSCF/CASPT2 calculations depicted extremely flat Potential Energy Surfaces (PESs) for the Cr-Cr flexibility of Cr3(dpa)4X2 (X = NCS-, CN-, NO3-) extended metal atom chains (EMACs) (M. Spivak, et al., Dalton Trans., 2017, 46, 6202). We herein explore the thermal and crystal packing effects on the structure of EMACs using ab initio molecular dynamics (MD). Car-Parrinello DFT-based simulations of the isolated molecules show that thermal energy favors asymmetric arrangements of the Cr3 chain due, in part, to the bending of the axial ligands (X) and the increased X-Cr distance, both of which weaken X → Cr σ-donation. This effect is even more prominent in the crystalline phase due to the interaction between the axial ligands of neighboring molecules in the unit cell. This could explain the typical discrepancies between the experimental and theoretical characterization of Cr3 EMACs observed in the literature.

Unveiling the Catalytic Role of B-Block Histidine in the N-S Acyl Shift Step of Protein Splicing.

Protein splicing is a post-translational modification that involves the excision of a segment denoted as "intein" and the joining of its two flanking segments. The process is autocatalytic, making inteins appealing for many applications in biotechnology, bioengineering, or medicine. The canonical mechanism of protein splicing is composed of four sequential steps, and is initialized by an N-S or N-O acyl shift to form a linear ester. It is well-established that a histidine, the most conserved amino acid in all inteins, catalyzes this initial step, even though its role remains to be understood. In this study, we combine molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) hybrid calculations to investigate the alternative reaction pathways proposed for the N-S acyl shift in Mycobacterium tuberculosis RecA intein. The results rule out the histidine acting as a base and activating the side chain of Cys1; instead, an aspartate performs this action. In the reaction mechanism proposed herein, denoted as the "Asp422 activated" mechanism, two sequential roles are attributed to the histidine: (i) ground-state destabilization by straining the scissile peptide bond and (ii) protonation of the leaving amide group. In summary, the study provides relevant data to understand the catalytic role of this histidine, and proposes a reaction pathway for the N-S acyl shift reaction in protein splicing that fits with the available experimental data.

A multiconfigurational approach to the electronic structure of trichromium extended metal atom chains.

Density functional theory, Complete Active Space Self-Consistent Field (CASSCF) and perturbation theory (CASPT2) methodologies have been used to explore the electronic structure of a series of trichromium Extended Metal Atom Chains (EMACS) with different capping ligands. The study is motivated by the very different structural properties of these systems observed in X-ray experiments: the CN--capped example has a symmetric Cr3 unit while for the NO3--capped analogue the same unit has two very different Cr-Cr bond lengths. Density functional theory fails to locate an unsymmetric minimum for any of the systems studied, although the surface corresponding to the asymmetric stretch is very flat. CASPT2, in contrast, does locate an unsymmetric minimum only for the NO3--capped system, although again the surface is very flat. We use the Generalized active space (GASSCF) technique and effective Hamiltonian theory to interrogate the multi-configurational wavefunctions of these systems, and show that the increase in the σ-σ* separation as the chain becomes unsymmetric plays a defining role in the stability of the ground state and its expansion in terms of configuration state functions.

Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia

Purpose: Pentoxifylline (PTX) has been shown to increase chemotherapy-induced apoptosis. A clinical trial was developed to evaluate the effect of the addition of PTX to the induction steroid window phase in children with acute lymphoblastic leukemia (ALL). Methods: Thirty-two children were enrolled on this study. Children with a new diagnosis of ALL were randomly assigned to receive prednisone (PRD) 40 mg/m2/day only during the 7-day treatment pre-phase (PRD group, 11 patients) or to receive PRD with PTX (10 mg/kg/day) (PTX group, 11 patients); the control group included children with normal bone marrow (10 patients). Bone marrow aspiration (BMA) was performed at diagnosis (day -7) in all groups, and at day 0 (end of PRD window) for patients with ALL (PRD and PTX groups). Apoptosis was evaluated by flow cytometry (FC) using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) stains. Statistical analysis was performed using the Mann–Whitney U test. Results: Apoptotic index at day -7 was similar in all groups. However, at day 0 post-treatment, apoptosis was significantly higher in the PTX group than in the PRD group (p < 0.001). There were no serious adverse effects associated with PTX. Conclusions: PTX potentiates blast apoptosis induced by PRD in children with ALL during steroid window phase (AU)

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[Trend of antimicrobial susceptibility in a neonatal and pediatric intensive care unit]. / Tendencia de sensibilidad antimicrobiana en una terapia intensiva neonatal y pediátrica.

BACKGROUND: Nosocomial infections in intensive care units are a health problem worldwide due to their incidence, prevalence and clinical impact. The objective of this article was to describe the trend of antimicrobial susceptibility during a 10-years period in both a pediatric and a neonatal intensive care unit. METHODS: This is a follow-up cohort study. In 10 years of follow-up, the antimicrobial used was considered the independent variable, and the antimicrobial susceptibility as the dependent variable. By using chi squared with Fisher exact test, the initial and final susceptibilities were compared, and also the most prevalent diagnoses and the antimicrobials. A two-tailed p value < 0.05 was considered statistically significant. SPSS 8 and Epi-Info 0.6 were used for statistical analysis. RESULTS: Antimicrobial susceptibility decreased from 66 to 45 % in 10 years, representing a global loss of 13 % (p = 0.002). The most affected antimicrobials were first-generation cephalosporin (p = 0.02), ciprofloxacin (p = 0.05), erythromycin (p = 0.001), imipenem (p = 0.001), and trimethoprim/sulfamethoxazole (p = 0.05). CONCLUSION: There is an alarming loss of effectiveness in antimicrobial agents.

Introducción: las infecciones en las unidades de cuidados intensivos son un problema de salud pública mundial por su incidencia, prevalencia e impacto clínico. El objetivo fue determinar la tendencia de sensibilidad a los antimicrobianos en un periodo de 10 años en una unidad de cuidados intensivos pediátricos. Métodos: estudio de seguimiento de cohorte. Se consideró variable independiente el antimicrobiano utilizado y variable dependiente la sensibilidad antimicrobiana con seguimiento a 10 años. Se comparó la sensibilidad inicial y final, y los diagnósticos más prevalentes y antimicrobianos con chi cuadrada con prueba exacta de Fisher. Se consideró significación estadística con p a dos colas de 0.05. Los datos se analizaron mediante los programas estadísticos SPSS 8 y Epi-Info 0.6 Resultados: la sensibilidad a los antimicrobianos pasó del 66 al 45 % en 10 años, lo cual representó una pérdida global del 13 % (p = 0.002). Los antimicrobianos que más perdieron sensibilidad fueron la cefalosporina de primera generación (p = 0.02), el ciprofloxacino (p = 0.05), la eritromicina (p = 0.001), el imipenem (p = 0.001) y el trimetroprim-sulfametoxasol (p = 0.05). Conclusión: existe una pérdida preocupante de efectividad de los antimicrobianos.

Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia.

PURPOSE: Pentoxifylline (PTX) has been shown to increase chemotherapy-induced apoptosis. A clinical trial was developed to evaluate the effect of the addition of PTX to the induction steroid window phase in children with acute lymphoblastic leukemia (ALL). METHODS: Thirty-two children were enrolled on this study. Children with a new diagnosis of ALL were randomly assigned to receive prednisone (PRD) 40 mg/m(2)/day only during the 7-day treatment pre-phase (PRD group, 11 patients) or to receive PRD with PTX (10 mg/kg/day) (PTX group, 11 patients); the control group included children with normal bone marrow (10 patients). Bone marrow aspiration (BMA) was performed at diagnosis (day -7) in all groups, and at day 0 (end of PRD window) for patients with ALL (PRD and PTX groups). Apoptosis was evaluated by flow cytometry (FC) using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) stains. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: Apoptotic index at day -7 was similar in all groups. However, at day 0 post-treatment, apoptosis was significantly higher in the PTX group than in the PRD group (p < 0.001). There were no serious adverse effects associated with PTX. CONCLUSIONS: PTX potentiates blast apoptosis induced by PRD in children with ALL during steroid window phase.

Microsatellite instable vs stable colon carcinomas: analysis of tumour heterogeneity, inflammation and angiogenesis.

BACKGROUND: Microsatellite instability (MSI) accounts for 15% of all colorectal tumours. Several specific clinicopathologicals (e.g., preference for the proximal colon over the distal colon, improved prognosis and altered response to chemotherapeutics) are described for this subset of tumours. This study aimed to analyse morphological, inflammatory and angiogenic features of MSI vs microsatellite stable (MSS) tumours. METHODS: Twenty-seven MSS and 29 MSI, TNM stage matched, colorectal tumours were selected from the archive of the Department of Pathology, UZ Leuven. Morphology was analysed on haematoxylin-eosin sections. Immunohistochemistry for CD3, CD4, CD8, CD20 and CD68 was used to map tumour infiltration in both a digital and traditional microscope-based manner for all distinct morphological components of the tumour. CD31 immunostains were performed to assess angiogenesis. RESULTS: Morphological tumour heterogeneity was a marked feature of MSI tumours, occurring in 53% of the cases as compared with 11% of the MSS tumours (P<0.001). Digital immune quantification showed an increased number of tumour-infiltrating cytotoxic T-lymphocytes (CD8+) in MSI compared with MSS tumours for both the tumour (P=0.02) and peritumoural area (P=0.03). Traditional microscope-based quantification confirmed these results (P<0.001 for both) and, in addition, revealed large numbers of CD68+ macrophages in the peritumoural area of MSI cancers (P=0.001). Moreover, traditional microscope-based analysis was able to distinguish between lymphocytes directly infiltrating the tumoural glands (intra-epithelial) and those infiltrating only the neoplastic stroma around the glands (intratumoural). Quantification showed high numbers of intra-epithelial CD3+, CD4+, CD8+, CD20+ and CD68+ cells in MSI compared with MSS cancers (P<0.001, P=0.01, P<0.001, P<0.001 and P=0.006, respectively). Higher microvessel density (MVD) was observed in MSI tumours compared with their MSS counterpart. CONCLUSIONS: Mixed morphology, reflecting tumour heterogeneity, is an important feature of MSI tumours and may have both diagnostic and therapeutic impact. The inflammatory reaction also presented with significant differences in MSI vs MSS colorectal tumours. MSI cancers showed mainly infiltration by cytotoxic T-cells in both the tumour and the close border around the tumour, as well as increased intra-epithelial infiltration in contrast to MSS tumours. The type of immune cell and the compartment it resides in (intratumoural or intra-epithelial) depend both on MSI status and morphology. Finally, MSI tumours showed a higher angiogenic capacity represented by an increased MVD, hinting for possible therapeutic consequences.

Symbolic dynamics marker of heart rate variability combined with clinical variables enhance obstructive sleep apnea screening.

Many sleep centres try to perform a reduced portable test in order to decrease the number of overnight polysomnographies that are expensive, time-consuming, and disturbing. With some limitations, heart rate variability (HRV) has been useful in this task. The aim of this investigation was to evaluate if inclusion of symbolic dynamics variables to a logistic regression model integrating clinical and physical variables, can improve the detection of subjects for further polysomnographies. To our knowledge, this is the first contribution that innovates in that strategy. A group of 133 patients has been referred to the sleep center for suspected sleep apnea. Clinical assessment of the patients consisted of a sleep related questionnaire and a physical examination. The clinical variables related to apnea and selected in the statistical model were age (p < 10(-3)), neck circumference (p < 10(-3)), score on a questionnaire scale intended to quantify daytime sleepiness (p < 10(-3)), and intensity of snoring (p < 10(-3)). The validation of this model demonstrated an increase in classification performance when a variable based on non-linear dynamics of HRV (p < 0.01) was used additionally to the other variables. For diagnostic rule based only on clinical and physical variables, the corresponding area under the receiver operating characteristic (ROC) curve was 0.907 (95% confidence interval (CI) = 0.848, 0.967), (sensitivity 87.10% and specificity 80%). For the model including the average of a symbolic dynamic variable, the area under the ROC curve was increased to 0.941 (95% = 0.897, 0.985), (sensitivity 88.71% and specificity 82.86%). In conclusion, symbolic dynamics, coupled with significant clinical and physical variables can help to prioritize polysomnographies in patients with a high probability of apnea. In addition, the processing of the HRV is a well established low cost and robust technique.

Aluminum interaction with glutamate and α-ketoglutarate: a computational study.

Aluminum, although a nonessential element in the human body, has been found to be involved in a variety of diseases. Thus, it has recently been reported that aluminum interferes with the metabolic tricarboxylic acid cycle, in which α-ketoglutarate (α-KG) is involved. α-KG is transformed to glutamate (or vice versa) by glutamate dehydrogenase (GDH). Al(III) inhibits the normal function of GDH, and it was speculated that the reason for this inhibition is triggered by the Al(III)-assisted tautomerization of α-KG from keto to enol. In the present study, we investigate the interaction of both tautomers of α-KG with Al(III) as well the complexation of glutamate to the metal. The results confirm that Al(III) indeed displaces the tautomerization reaction and favors the enol form of α-KG by 28 kcal/mol. However, when citrate is included in the system, the stabilization of the enol tautomer decreases, as this tautomer is only 1.5 kcal/mol more stable than the keto form of α-KG. Finally, possible routes for the complexation of these molecules to Al(III) in a biological environment are discussed; we propose that the ternary complexes formed by Al(III), citrate, and α-KG or glutamate can be the more likely species.

The intrapair electron correlation in natural orbital functional theory.

A previously proposed [M. Piris, X. Lopez, F. Ruipérez, J. M. Matxain, and J. M. Ugalde, J. Chem. Phys. 134, 164102 (2011)] formulation of the two-particle cumulant, based on an orbital-pairing scheme, is extended here for including more than two natural orbitals. This new approximation is used to reconstruct the two-particle reduced density matrix (2-RDM) constrained to the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. In this way, we have derived an extended version of the Piris natural orbital functional 5 (PNOF5e). An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is also used to generate the PNOF5e. The theory is applied to the homolytic dissociation of selected diatomic molecules: H2, LiH, and Li2. The Bader's theory of atoms in molecules is used to analyze the electron density and the presence of non-nuclear maxima in the case of a set of light atomic clusters: Li2, Li3(+), Li4(2+), and H3(+). The improvement of PNOF5e over PNOF5 was observed by visualizing the electron densities.

Formation of the OOH(·) radical at steps of the boehmite surface and its inhibition by gallic acid: A theoretical study including DFT-based dynamics.

The ability of boehmite surface to stabilize reactive oxygen species (ROS) was investigated with density functional theory (DFT) calculations. We provide evidence that the O2(·-)radical is stabilized at the AlOOH boehmite terrace defect-free surface, and that step favors the formation of the OOH(·) radical without activation energy required. These tendencies are confirmed when considering the explicit presence of water solvent. We propose that gallic acid (GA), a non-expensive, non-toxic, natural product and radical scavenger, may form a full layer on the (101) stepped boehmite surface. The quenching of O2- to OOH(·) reaction on the GA-functionalized boehmite surface is investigated. It is shown that gallic acid passivates the surface and that the formation of the OOH(·) radical is consequently inhibited. The interaction of the GA-functionalized boehmite surface with water mimicking the body fluid is also investigated by means of DFT-based molecular dynamics simulations at room temperature. Hydrogen bonds between the functionalized GA layer and the immediate interfacial water are characterized.

Epithelial expression of FHL2 is negatively associated with metastasis-free and overall survival in colorectal cancer.

BACKGROUND: Four-and-a-half LIM domains protein 2 (FHL2) is a component of the focal adhesion structures and has been suggested to have a role in cancer progression. It has been shown to be overexpressed in the colorectal cancer (CRC). METHODS: Here, we examined a possible prognostic value of FHL2 in CRC. Immunohistochemistry for FHL2 was performed on 296 CRCs without distant metastases at the time of surgery. Staining in the epithelial compartment was quantitatively evaluated using image analysis, and results were related to clinical variables. Antibody specificity was tested using small-interfering RNA transfection in hTERT-immortalised myofibroblasts. RESULTS: Varying degrees of cytoplasmic FHL2 expression by neoplastic epithelial cells were detectable in all cases. Higher FHL2 expression in the epithelial compartment was an independent adverse prognostic factor. Multivariate Cox analysis shows that expression in the tumour invasion front (P<0.001) as well as in the centre of the tumour (P<0.001) was associated with metachronous metastases independently of the clinicopathological variables; expression in the tumour invasion front was also associated with overall survival independently of the clinicopathological variables (P<0.01). CONCLUSION: Higher FHL2 expression is involved in CRC progression and correlates with the development of metachronous metastases and overall survival, suggesting that FHL2 is an independent adverse prognostic indicator for CRC.