Importance of immunometabolic markers for the classification of patients with major depressive disorder using machine learning.

BACKGROUND: Although there is scientific evidence of the presence of immunometabolic alterations in major depression, not all patients present them. Recent studies point to the association between an inflammatory phenotype and certain clinical symptoms in patients with depression. The objective of our study was to classify major depression disorder patients using supervised learning algorithms or machine learning, based on immunometabolic and oxidative stress biomarkers and lifestyle habits. METHODS: Taking into account a series of inflammatory and oxidative stress biomarkers (C-reactive protein (CRP), tumor necrosis factor (TNF), 4-hydroxynonenal (HNE) and glutathione), metabolic risk markers (blood pressure, waist circumference and glucose, triglyceride and cholesterol levels) and lifestyle habits of the participants (physical activity, smoking and alcohol consumption), a study was carried out using machine learning in a sample of 171 participants, 91 patients with depression (71.42% women, mean age = 50.64) and 80 healthy subjects (67.50% women, mean age = 49.12). The algorithm used was the support vector machine, performing cross validation, by which the subdivision of the sample in training (70%) and test (30%) was carried out in order to estimate the precision of the model. The prediction of belonging to the patient group (MDD patients versus control subjects), melancholic type (melancholic versus non-melancholic patients) or resistant depression group (treatment-resistant versus non-treatment-resistant) was based on the importance of each of the immunometabolic and lifestyle variables. RESULTS: With the application of the algorithm, controls versus patients, such as patients with melancholic symptoms versus non-melancholic symptoms, and resistant versus non-resistant symptoms in the test phase were optimally classified. The variables that showed greater importance, according to the results of the area under the ROC curve, for the discrimination between healthy subjects and patients with depression were current alcohol consumption (AUC = 0.62), TNF-α levels (AUC = 0.61), glutathione redox status (AUC = 0.60) and the performance of both moderate (AUC = 0.59) and vigorous physical exercise (AUC = 0.58). On the other hand, the most important variables for classifying melancholic patients in relation to lifestyle habits were past (AUC = 0.65) and current (AUC = 0.60) tobacco habit, as well as walking routinely (AUC = 0.59) and in relation to immunometabolic markers were the levels of CRP (AUC = 0.62) and glucose (AUC = 0.58). In the analysis of the importance of the variables for the classification of treatment-resistant patients versus non-resistant patients, the systolic blood pressure (SBP) variable was shown to be the most relevant (AUC = 0.67). Other immunometabolic variables were also among the most important such as TNF-α (AUC = 0.65) and waist circumference (AUC = 0.64). In this case, sex (AUC = 0.59) was also relevant along with alcohol (AUC = 0.58) and tobacco (AUC = 0.56) consumption. CONCLUSIONS: The results obtained in our study show that it is possible to predict the diagnosis of depression and its clinical typology from immunometabolic markers and lifestyle habits, using machine learning techniques. The use of this type of methodology could facilitate the identification of patients at risk of presenting depression and could be very useful for managing clinical heterogeneity.

Extensive pharmacokinetic variability of Levetiracetam. ¿Are doctors aware?

INTRODUCTION: Levetiracetam was presented as a drug with linear pharmacokinetics. There is currently evidence on its extensive pharmacokinetic variability in real clinical practice. OBJECTIVE: To describe levetiracetam pharmacokinetic variability in patients with epilepsy in real clinical practice. To evaluate the effect on levetiracetam levels of gender, age, renal function, and polytherapy. To describe how clinicians prescribe based on age and co-medication. METHODS: Retrospective analysis of epilepsy patients treated with levetiracetam for whom plasma levels were available. RESULTS: 151 patients. Median levetiracetam level of 17.75 mg/L, median dose of 2000 mg/day. There was a significant correlation between daily dose and serum levels (p < 0.01). There was a 18.1% increase in levetiracetam concentration/dose ratio in patients over 65 years of age (p < 0.05) that also correlated with decreased glomerular filtration (p < 0.01). Clinicians corrected doses so patients over 65 years had similar levels than younger patients. There was a 30.1% decrease of concentration/dose ratio in patients on polytherapy with potent enzyme inducer antiseizure medication (p < 0.05), and a 46.3% decrease for carbamazepine (p < 0.01). Clinicians did not correct doses, so patients treated with levetiracetam and carbamazepine had 27.5% lower levels than patients taking other polytherapy. CONCLUSION: The pharmacokinetic variability of levetiracetam is wider than originally thought. Age and co-medication with strong enzyme-inducing drugs, especially carbamazepine, significantly influence levetiracetam levels. Clinicians at our center did not consider this interaction and prescribed similar doses of levetiracetam when it was used in combination with these drugs or with others, so they probably were not aware of this interaction.

Relationship between immunometabolic status and cognitive performance among major depression disorder patients.

BACKGROUND: Alterations in cognitive performance have been described in patients with major depressive disorder (MDD). However, the specific risk factors of these changes are not yet known. This study aimed to explore whether inmunometabolic parameters are related to cognitive performance in MDD in comparison to healthy controls (HC) METHODS: Sample consisted of 84 MDD patients and 78 HC. Both groups were compared on the results of cognitive performance measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB), the presence of metabolic syndrome (MetS) and an inflammatory/oxidative index calculated by a principal component analysis of peripheral biomarkers (tumor necrosis factor, C-reactive protein and 4-hydroxynonenal). A multiple linear regression was carried out, to study the relationship between inmunometabolic variables and the global cognitive performance, being the latter the dependent variable. RESULTS: Significant differences were obtained in the inflammatory/oxidative index between both groups (F(1157)= 12.93; p < .001), also in cognitive performance (F(1157)= 56.75; p < .001). The inmunometabolic covariate regression model (i.e., condition (HC/MDD), sex, age and medication loading, MetS, inflammatory/oxidative index and the interaction between MetS and inflammatory/oxidative index) was statistically significant (F(7157)= 11.24; p < .01) and explained 31% of variance. The condition, being either MDD or HD, (B=-0.97; p < .001), age (B=-0.28; p < .001) and the interaction between inflammatory/oxidative index and MetS (B=-0.38; p = .02) were factors associated to cognitive performance. LIMITATIONS: Sample size was relatively small. The cross-sectional design of the study limits the possibilities of analysis. CONCLUSIONS: Our results provide evidence on the conjoint influence of metabolic and inflammatory dysregulation on cognitive dysfunction in MDD patients. In this way, our study opens a line of research in immunometabolic agents to deal with cognitive decline associated with MDD.

Herramientas para la evaluación de las competencias profesionales / Toolkit for professional competencies assessment of Medicine Laboratory specialists

No disponible

Recertificación de los especialistas en Análisis Clínicos y Bioquímica Clínica / Re-accreditation of specialists in Clinical Analysis and Clinical Biochemistry

La recertificación consiste en certificar la renovación de las competencias específicas de los profesionales titulados referidos en la ley de ordenación de las profesiones sanitarias. El objetivo es certificar que el profesional esté cualificado para realizar un ejercicio profesional con el fin de garantizar una asistencia sanitaria de calidad. Las organizaciones colegiales profesionales y las sociedades científicas deben contribuir a facilitar el camino del desarrollo profesional y a la Administración sanitaria le corresponde ser valedora y garante en todo el proceso (AU)

Re-accreditation consists in certifying the renewal of specific competencies of qualified professionals as mentioned in the health profession management law. The objective is to certify that the professional is qualified to perform a professional exercise in order to guarantee quality healthcare. The professional bodies and scientific societies should contribute by facilitating the continuing professional development, and the Health Administration should be responsible for guaranteeing the whole process (AU)

[Accidental finding of a cri du chat syndrome in an adult patient by means of array-CGH]. / Hallazgo inesperado de sindrome cri du chat en una paciente adulta mediante array-CGH.

INTRODUCTION: The cri du chat syndrome (CDCS) come from a partial or total deletion of the short arm of chromosome 5, being one of the most common deletion syndromes in human beings. The great majority of patients are diagnosed between the first month and first year of life, but herein we report a finding of a CDCS in a woman with a suspect of spinocerebellar ataxia, and a family medical record of ataxia and bipolar disorder. We pay special attention to the clinical features as well as the diagnostics tests, used to identify the CDCS. CASE REPORT: We report a case of a 46 years-old woman showing a borderline intelligence and bilateral cataract surgery at the age of 43. Beginning of symptoms in childhood included hypoacusia, ataxia, dysarthria, dysphagia, depression, cognitive impairment and bipolar disorder. Physical examination showed microcephaly, micrognathia, talipes equinovarus and ataxia. Karyotype and array-CGH were carried out on peripheral blood. The patient showed a rearrangement involving chromosomes 5 and 15, as well as an inversion of chromosome 9: 45,XX,inv9(p11q13);t(5,15)(p15.33;q11.2). Array comparative genomic hybridization was performed showing a 2.91 Mb deletion at 5p15.33, genomic formula arr 5p15.33 (151537-3057771)x1. The deletion involved 20 genes, including TERT gene. CONCLUSIONS: The multiple gene deletions confirmed the CDCS diagnosis, being responsible for the patient phenotype. It has been showed up the importance of using the correct diagnosis techniques (array-CGH, peripheral blood karyotype) as well as their appropriate choice.

TITLE: Hallazgo inesperado de sindrome cri du chat en una paciente adulta mediante array-CGH.Introduccion. El sindrome cri du chat (SCDC) tiene su origen en una delecion parcial o total del brazo corto del cromosoma 5, y es uno de los sindromes de delecion cromosomica mas frecuentes en humanos. La mayoria de los pacientes se diagnostica entre el primer mes y el primer año de vida, si bien aqui se describe el hallazgo de un SCDC en una mujer con sospecha de ataxia espinocerebelar y antecedentes familiares de trastorno bipolar y ataxia, con especial atencion a las caracteristicas clinicas y las tecnicas diagnosticas que permitieron su identificacion. Caso clinico. Mujer de 46 años que presentaba una inteligencia limite, intervenida a los 43 años de faquectomia bilateral. El inicio de la sintomatologia fue durante la infancia, e incluia hipoacusia, ataxia, disartria, disfagia, depresion, deterioro cognitivo y trastorno bipolar. La exploracion fisica revelo microcefalia, micrognatia, pies equinos y ataxia. Se realizo cariotipo y array-CGH en sangre periferica. La paciente presentaba una traslocacion que involucraba los cromosomas 5 y 15, y una inversion del cromosoma 9: 45,XX,inv9(p11q13);t(5,15)(p15.33;q11.2). El array-CGH mostro una delecion de 2,91 Mb en 5p15.33, formula genomica arr 5p15.33 (151537-3057771)x1, que involucraba 20 genes, incluyendo el gen TERT. Conclusiones. La delecion de multiples genes confirmo el diagnostico de SCDC y es la responsable del fenotipo de la paciente. Se pone de manifiesto la importancia de utilizar tecnicas adecuadas de diagnostico (array-CGH, cariotipo en sangre periferica) y la correcta eleccion de estas.

Hallazgo inesperado de síndrome cri du chat en una paciente adulta mediante array-CGH / Accidental finding of a cri du chat syndrome in an adult patient by means of array-CGH

Introducción. El síndrome cri du chat (SCDC) tiene su origen en una deleción parcial o total del brazo corto del cromosoma 5, y es uno de los síndromes de deleción cromosómica más frecuentes en humanos. La mayoría de los pacientes se diagnostica entre el primer mes y el primer año de vida, si bien aquí se describe el hallazgo de un SCDC en una mujer con sospecha de ataxia espinocerebelar y antecedentes familiares de trastorno bipolar y ataxia, con especial atención a las características clínicas y las técnicas diagnósticas que permitieron su identificación. Caso clínico. Mujer de 46 años que presentaba una inteligencia límite, intervenida a los 43 años de faquectomía bilateral. El inicio de la sintomatología fue durante la infancia, e incluía hipoacusia, ataxia, disartria, disfagia, depresión, deterioro cognitivo y trastorno bipolar. La exploración física reveló microcefalia, micrognatia, pies equinos y ataxia. Se realizó cariotipo y array-CGH en sangre periférica. La paciente presentaba una traslocación que involucraba los cromosomas 5 y 15, y una inversión del cromosoma 9: 45,XX,inv9(p11q13);t(5,15)(p15.33;q11.2). El array-CGH mostró una deleción de 2,91 Mb en 5p15.33, fórmula genómica arr 5p15.33 (151537-3057771)x1, que involucraba 20 genes, incluyendo el gen TERT. Conclusiones. La deleción de múltiples genes confirmó el diagnóstico de SCDC y es la responsable del fenotipo de la paciente. Se pone de manifiesto la importancia de utilizar técnicas adecuadas de diagnóstico (array-CGH, cariotipo en sangre periférica) y la correcta elección de éstas (AU)

Introduction. The cri du chat syndrome (CDCS) come from a partial or total deletion of the short arm of chromosome 5, being one of the most common deletion syndromes in human beings. The great majority of patients are diagnosed between the first month and first year of life, but herein we report a finding of a CDCS in a woman with a suspect of spinocerebellar ataxia, and a family medical record of ataxia and bipolar disorder. We pay special attention to the clinical features as well as the diagnostics tests, used to identify the CDCS. Case report. We report a case of a 46 years-old woman showing a borderline intelligence and bilateral cataract surgery at the age of 43. Beginning of symptoms in childhood included hypoacusia, ataxia, dysarthria, dysphagia, depression, cognitive impairment and bipolar disorder. Physical examination showed microcephaly, micrognathia, talipes equinovarus and ataxia Karyotype and array-CGH were carried out on peripheral blood. The patient showed a rearrangement involving chromosomes 5 and 15, as well as an inversion of chromosome 9: 45,XX,inv9(p11q13);t(5,15)(p15.33;q11.2). Array comparative genomic hybridization was performed showing a 2.91 Mb deletion at 5p15.33, genomic formula arr 5p15.33 (151537-3057771)x1. The deletion involved 20 genes, including TERT gene. Conclusions. The multiple gene deletions confirmed the CDCS diagnosis, being responsible for the patient phenotype. It has been showed up the importance of using the correct diagnosis techniques (array-CGH, peripheral blood karyotype) as well as their appropriate choice (AU)

Macrocyclic receptor showing extremely high Sr(II)/Ca(II) and Pb(II)/Ca(II) selectivities with potential application in chelation treatment of metal intoxication.

Herein we report a detailed investigation of the complexation properties of the macrocyclic decadentate receptor N,N'-Bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H(2)bp18c6) toward different divalent metal ions [Zn(II), Cd(II), Pb(II), Sr(II), and Ca(II)] in aqueous solution. We have found that this ligand is especially suited for the complexation of large metal ions such as Sr(II) and Pb(II), which results in very high Pb(II)/Ca(II) and Pb(II)/Zn(II) selectivities (in fact, higher than those found for ligands widely used for the treatment of lead poisoning such as ethylenediaminetetraacetic acid (edta)), as well as in the highest Sr(II)/Ca(II) selectivity reported so far. These results have been rationalized on the basis of the structure of the complexes. X-ray crystal diffraction, (1)H and (13)C NMR spectroscopy, as well as theoretical calculations at the density functional theory (B3LYP) level have been performed. Our results indicate that for large metal ions such as Pb(II) and Sr(II) the most stable conformation is Δ(δλδ)(δλδ), while for Ca(II) our calculations predict the Δ(λδλ)(λδλ) form being the most stable one. The selectivity that bp18c6(2-) shows for Sr(II) over Ca(II) can be attributed to a better fit between the large Sr(II) ions and the relatively large crown fragment of the ligand. The X-ray crystal structure of the Pb(II) complex shows that the Δ(δλδ)(δλδ) conformation observed in solution is also maintained in the solid state. The Pb(II) ion is endocyclically coordinated, being directly bound to the 10 donor atoms of the ligand. The bond distances to the donor atoms of the pendant arms (2.55-2.60 Å) are substantially shorter than those between the metal ion and the donor atoms of the crown moiety (2.92-3.04 Å). This is a typical situation observed for the so-called hemidirected compounds, in which the Pb(II) lone pair is stereochemically active. The X-ray structures of the Zn(II) and Cd(II) complexes show that these metal ions are exocyclically coordinated by the ligand, which explains the high Pb(II)/Cd(II) and Pb(II)/Zn(II) selectivities. Our receptor bp18c6(2-) shows promise for application in chelation treatment of metal intoxication by Pb(II) and (90)Sr(II).

Selective chelation of Cd(II) and Pb(II) versus Ca(II) and Zn(II) by using octadentate ligands containing pyridinecarboxylate and pyridyl pendants.

Herein we report the coordination properties toward Cd(II), Pb(II), Ca(II), and Zn(II) of a new octadentate ligand (py-H(2)bcpe) based on a ethane-1,2-diamine unit containing two picolinate and two pyridyl pendants, which is structurally derived from the previous reported ligand bcpe. Potentiometric studies have been carried out to determine the protonation constants of the ligand and the stability constants of the complexes with these cations. The introduction of the pyridyl pendants in bcpe provokes a very important increase of the logK(ML) values obtained for the Pb(II) and Cd(II) complexes, while this effect is less important in the case of the Zn(II) analogue. As a result, py-bcpe shows a certain selectivity for Cd(II) and Pb(II) over Zn(II) while keeping good Pb(II)/Ca(II) and Cd(II)/Ca(II) selectivities, and the new receptor py-bcpe can be considered as a new structural framework for the design of novel Cd(II) and Pb(II) extracting agents. Likewise, the stabilities of the Cd(II) and Pb(II) complexes are higher than those of the corresponding EDTA analogues. The X-ray crystal structure of [Zn(py-bcpe)] shows hexadentate binding of the ligand to the metal ion, the coordination polyhedron being best described as a severely distorted octahedron. However, the X-ray crystal structure of the Pb(II) analogue shows octadentate binding of the ligand to the metal ion. A detailed investigation of the structure in aqueous solution of the complexes by using nuclear magnetic resonance (NMR) techniques and density functional theory (DFT) calculations (B3LYP) shows that while in the Zn(II) complex the metal ion is six-coordinated, in the Pb(II) and Ca(II) analogues the metal ions are eight-coordinated. For the Cd(II) complex, our results suggest that in solution the complex exists as a mixture of seven- and eight-coordinated species. DFT calculations performed both in the gas phase and in aqueous solution have been also used to investigate the role of the Pb(II) lone pair in the structure of the [Pb(py-bcpe)] complex.

Eight-coordinate Zn(II), Cd(II), and Pb(II) complexes based on a 1,7-diaza-12-crown-4 platform endowed with a remarkable selectivity over Ca(II).

The thermodynamic stability of the Pb(II), Cd(II), Zn(II), and Ca(II) complexes with the dianionic macrocyclic ligand N,N'-bis[(6-carboxy-2-pyridyl)methyl]-1,7-diaza-12-crown-4 (H(2)bp12c4) has been investigated by pH-potentiometric titrations at 25 degrees C in 0.1 M KNO(3). The stability constants vary in the following order: Cd(II) > Zn(II) approximately Pb(II) > Ca(II). As a consequence, H(2)bp12c4 present an important Cd(II)/Ca(II) selectivity, as well as a certain selectivity for Cd(II) over Zn(II). To rationalize these results, a detailed investigation of the structure of these complexes has been carried out both in solid state and in aqueous solution. Furthermore, the [M(bp12c4)] complexes (M = Ca, Zn, Cd, or Pb) were characterized by means of density functional theory (DFT) calculations (B3LYP model) to obtain information on their solution structures and to investigate the possible stereochemical activity of the Pb(II) lone pair. Our results show that in all cases the metal ion is octacoordinated by the ligand, a situation that is particularly rare for Zn(II) complexes. The coordination polyhedra observed in the solid state for the [M(bp12c4)] complexes (M = Zn, Cd, or Ca) is closely related to the conformation adopted by the ligand in the corresponding complex: The Zn(II) complex adopts a Delta(lambdalambdalambdalambda) conformation in the solid state, which results in a square antiprismatic coordination, while the Delta(deltadeltadeltadelta) conformation observed for the Cd(II) and Ca(II) analogues yields inverted-square antiprismatic geometries. The X-ray crystal structure of the Pb(II) analogue shows that the metal ion is directly bound to the eight donor atoms of the ligand, but the bond distances of the metal coordination environment indicate an asymmetrical coordination of the cation by the ligand, which is attributed to the stereochemical activity of the Pb(II) lone pair. In aqueous solution the Ca(II), Zn(II), and Cd(II) complexes show rigid C(2) symmetries, while the Pb(II) analogue presents a more flexible structure.

Zn(ii), Cd(ii) and Pb(ii) complexation with pyridinecarboxylate containing ligands.

Herein, we report the coordination properties towards Zn(ii), Cd(ii) and Pb(ii) of two hexadentate ligands containing pyridinecarboxylate groups with ethane-1,2-diamine (bcpe) or cyclohexane-1,2-diamine (bcpc) backbones. The X-ray crystal structures of [Zn(bcpe)], [Cd(bcpe)] and [Cd(bcpc)] show hexadentate binding of the ligand to the metal ions, with the coordination polyhedron being best described as a severely distorted octahedron. The X-ray crystal structure of the Pb(ii) analogue shows the presence of tetrameric structural units [Pb(4)(bcpe)(4)] in which the four Pb(ii) ions are bridged by carboxylate oxygen atoms. While in the Zn(ii) and Cd(ii) complexes the bcpe ligand adopts a twist-wrap (tw) conformation in which the ligand wraps around the metal ion by twisting the pyridyl units relative to each other, for the Pb(ii) complex a twist-fold (tf) conformation, where a slight twisting of the pyridyl units is accompanied by an overall folding of the two pyridine units relative to each other is observed. Theoretical calculations performed at the DFT (B3LYP) level on the [Pb(bcpe)] and [Pb(bcpc)] systems indicate that the tf conformation is more stable than the tw form both in the solid state and in aqueous solution. The analysis of the natural bond orbitals (NBOs) indicate that the Pb(ii) lone-pair is polarized by a substantial 6p contribution, which results in a hemi-directed coordination geometry around the metal ion. Potentiometric studies have been carried out to determine the protonation constants of the ligands and the stability constants of the complexes with Zn(ii), Cd(ii), Pb(ii) and Ca(ii). The replacement of the ethylene backbone of bcpe by a cyclohexylene ring causes a very important increase in the stability constant of the Pb(ii) complex (ca. 2.3 logK units), while this effect is less important for Cd(ii) (ca. 1.4 logK units). However, the introduction of the cyclohexylene ring does not substantially affect the stability of the Zn(ii) and Ca(ii) complexes. The ligand bcpc shows Pb/Ca and Cd/Ca selectivities [10(8.9) and 10(9.8), respectively] superior to those of extracting agents, such as EDTA, already used in Pb(ii) and Cd(ii) removal from contaminated water and soils.