Estudio de la citoqueratina- 18 como marcador no invasivo en pacientes con enfermedad de hígado graso no alcohólico

Introducción: La enfermedad por hígado graso no alcohólico es una de las principales causas de afección hepática. La citoqueratina 18 surge como marcador no invasivo para la valoración de fibrosis hepática. El objetivo del trabajo fue validar el uso de la citoqueratina 18 en sangre periférica en el diagnóstico y evolución de los pacientes con enfermedad por hígado graso no alcohólico. Metodología: Para validar la citoqueratina 18 en el diagnóstico se realizó un estudio de tipo caso-control. El grupo caso fueron los pacientes mayores de 18 años, de ambos sexos, con diagnóstico de enfermedad por hígado graso no alcohólico vinculado al síndrome metabólico, captados entre 2/2/2019 al 2/2/2020. El grupo control fueron personas donantes de sangre. Se parearon 1-1 por edad y sexo. Se cuantificó la citoqueratina 18 en sangre periférica de ambos grupos. Para validar la citoqueratina 18 en la evolución de los pacientes con enfermedad de hígado graso no alcohólico se realizó un trabajo prospectivo, longitudinal. El grupo de pacientes captados fueron seguidos durante un año bajo tratamiento estándar, finalizando el mismo se realizó la cuantificación de citoqueratina 18 en sangre periférica. Las variables continuas se expresan con la media y desvío estándar. Se analizó con test de t Student, error α < 5% Resultados: 13 pacientes integran el grupo caso (12 mujeres), de 53 ± 11 años, con IMC 35.01 ± 8.9 kg/m2. El valor de citoqueratina 18 pre-tratamiento fue de 1410 ± 120 UI, y el valor post-tratamiento fue de 117 ± 56, p < 0,005.El grupo control fueron 13 personas (12 mujeres), de 43,4 ± 8,1 años e IMC 28,10 ± 5,4 kg/m2 El valor de citoqueratina 18 fue de 193 ± 7.2 UI, p < 0.005 vs grupo caso pretratamiento. Conclusiones: La citoqueratina 18 es más elevada en los pacientes con enfermedad hígado graso no alcohólico, siendo estadísticamente significativa y disminuye con el tratamiento con significación estadística, pudiendo constituirse en un marcador útil en este grupo de pacientes.

Introduction: Nonalcoholic fatty liver disease is one of the main causes of liver disease. Cytokeratin 18 emerges as a non-invasive marker for the assessment of liver fibrosis. The objective of the work was to validate the use of cytokeratin 18 in peripheral blood in the diagnosis and evolution of patients with non-alcoholic fatty liver disease. Methodology: To validate cytokeratin 18 in the diagnosis, a case-control study was carried out. The case group was patients over 18 years of age, of both sexes, with a diagnosis of non-alcoholic fatty liver disease linked to metabolic syndrome, recruited between 2/2/2019 to 2/2/2020. The control group were blood donors. They were matched 1-1 for age and sex. Cytokeratin 18 was quantified in peripheral blood of both groups. To validate cytokeratin 18 in the evolution of patients with non-alcoholic fatty liver disease, a prospective, longitudinal study was carried out. The group of patients recruited were followed for one year under standard treatment, at the end of which cytokeratin 18 was quantified in peripheral blood. Continuous variables are expressed with the mean and standard deviation. It was analyzed with Student's t test, α error < 5%. Results: 13 patients make up the case group (12 women), 53 ± 11 years old, with BMI 35.01 ± 8.9 kg/m2. The pre-treatment cytokeratin 18 value was 1410 ± 120 IU, and the post-treatment value was 117 ± 56, p < 0.005. The control group was 13 people (12 women), 43.4 ± 8.1 years and BMI 28.10 ± 5.4 kg/m2 The cytokeratin 18 value was 193 ± 7.2 IU, p < 0.005 vs. pretreatment case group. Conclusions: Cytokeratin 18 is higher in patients with non-alcoholic fatty liver disease, being statistically significant, and decreases with treatment with statistical significance, and may become a useful marker in this group of patients.

Introdução: A doença hepática gordurosa não alcoólica é uma das principais causas de doença hepática. A citoqueratina 18 surge como um marcador não invasivo para avaliação de fibrose hepática. O objetivo do trabalho foi validar o uso da citoqueratina 18 no sangue periférico no diagnóstico e evolução de pacientes com doença hepática gordurosa não alcoólica. Metodologia: Para validar a citoqueratina 18 no diagnóstico, foi realizado um estudo caso-controle. O grupo caso foi composto por pacientes maiores de 18 anos, de ambos os sexos, com diagnóstico de doença hepática gordurosa não alcoólica ligada à síndrome metabólica, recrutados entre 02/02/2019 a 02/02/2020. O grupo controle eram doadores de sangue. Eles foram comparados em 1 a 1 por idade e sexo. A citoqueratina 18 foi quantificada no sangue periférico de ambos os grupos. Para validar a citoqueratina 18 na evolução de pacientes com doença hepática gordurosa não alcoólica, foi realizado um estudo prospectivo e longitudinal. O grupo de pacientes recrutados foi acompanhado durante um ano sob tratamento padrão, ao final do qual a citoqueratina 18 foi quantificada no sangue periférico. As variáveis ​​contínuas são expressas com média e desvio padrão. Foi analisado com teste t de Student, erro α < 5%. Resultados: Compõem o grupo caso 13 pacientes (12 mulheres), 53 ± 11 anos, com IMC 35,01 ± 8,9 kg/m2. O valor de citoqueratina 18 pré-tratamento foi de 1410 ± 120 UI e o valor pós-tratamento foi de 117 ± 56, p < 0,005. O grupo controle foi de 13 pessoas (12 mulheres), 43,4 ± 8,1 anos e IMC 28,10 ± 5,4 kg/m2 O valor da citoqueratina 18 foi de 193 ± 7,2 UI, p < 0,005 vs. grupo de casos pré-tratamento. Conclusões: A citoqueratina 18 é maior em pacientes com doença hepática gordurosa não alcoólica, sendo estatisticamente significativa, e diminui com o tratamento com significância estatística, podendo se tornar um marcador útil neste grupo de pacientes.

TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.

Earth Rights for the Advancement of a Planetary Health Agenda.

This article discusses Earth's Rights as an environmental justice mechanism of reparation, protection, and justice for indigenous communities, environmental defenders, and other populations in Latin America. We argue that Earth's rights encompass and include the right to health and can be integrated into international human rights frameworks to protect all forms of life, responding to colonial legacies of discrimination and violence. We respond to the scarcity of literature discussing Earth's rights in relation to situations where human rights and Earth's rights are violated. We ground our argument in the theoretical conceptualization of Latin American proposals of Earth's rights and its potential for actionable policy approaches that include human health as inevitably interconnected to our planet's well-being. We address the environmental injustices that affect the right to health and argue that an Earth's rights framework can support reparations for historically marginalized communities.

Sparkling Synergy: Enhancing Hydrogen Evolution with a Mesoporous CoP/FeP Interface.

The reaction kinetics is predominantly determined by the surface and interface engineering of electrocatalysts. Herein, we demonstrate the growth of cobalt monophosphide and iron monophosphide (CoP/FeP) with an effective solid interface. The surface of CoP/FeP is mesoporous, which is obtained by phosphidizing mesoporous CoFe2O4. The CoP/FeP electrode exhibits substantially superior hydrogen evolution reaction (HER) performance compared to CoP and FeP. The overpotentials (η) required to generate 10 mA cm-2 are determined to be around 98 mVRHE (CoP/FeP), 220 mVRHE (FeP), and 265 mVRHE (CoP) in an acidic electrolyte. The exchange current density and Tafel slopes suggest that CoP/FeP has better redox properties and kinetic abilities compared to FeP and CoP. Furthermore, the CoP/FeP electrode exhibits reduced electrochemical impedance and superior surface charge transport characteristics in comparison to both the CoP and FeP electrodes. In addition to having a greater number of catalytically active sites, the turnover frequency of CoP/FeP is approximately 2 and 5 times higher than that of FeP and CoP, respectively. The CoP/FeP electrode maintains a consistent current density of around 25 mA cm-2 for a continuous period of 24 h during the HER, attesting to the excellent durability of the CoP/FeP electrode. In addition, a relationship between differential hydrogen adsorption energy (ΔEH), the corresponding Gibbs free energy change (ΔGH), and the hydrogen coverage on distinct surfaces, namely, CoP, FeP, and CoP/FeP, is established. The calculation findings show that the CoP/FeP surface, which is predominantly exposed with CoP, exhibits the highest catalytic potential for the HER. The estimation of the specific HER activity of the electrodes, normalized to the electrochemically active surface area, corroborates the calculation findings.

Serologic Evidence for Early SARS-CoV-2 Circulation in Lima, Peru, 2020.

During early 2021, Peru had the highest COVID-19-associated per-capita mortality rate. Socioeconomic inequality, insufficiently prepared healthcare, and surveillance systems are factors explaining the mortality rate, which can be severely worsened by early undetected SARS-CoV-2 circulation. We tested 1,441 individuals with fever sampled during August 2019-May 2021, several months before the first SARS-CoV-2 seroprevalence study available so far in Lima, Peru, for SARS-CoV-2-specific antibodies. The testing algorithm included a chemiluminescence immunoassay and surrogate virus neutralization test. Early positive samples (N = 24) from January-March 2020 were further tested using a plaque-reduction neutralization test (PRNT) and avidity test against the SARS-CoV-2 spike and nucleoprotein. None of the early samples were PRNT-confirmed, in contrast to 81.8% (18/22) of a subsample from April 2020 onward (Fisher exact test; P <0.0001). Therefore, we excluded non-PRNT-confirmed samples from subsequent analyses. The SARS-CoV-2 antibody detection rate was 0.9% in mid-April 2020 (1/104; 95% CI: 0.1-5.8%), suggesting viral circulation in early-middle March 2020, consistent with the first molecular detection of SARS-CoV-2 in Peru on March 2020. Mean avidity increase of 62-77% to 81-94% from all PRNT-confirmed SARS-CoV-2-positive samples during early 2020 were consistent with onset of SARS-CoV-2 circulation during late February/March 2020. Early circulation was also confirmed in a susceptible, exposed, infected, and recovered mathematical model that calculated an effective reproduction number >1 during February-March 2020. Early introduction of SARS-CoV-2 thus contributed to the high COVID-19 mortality rate in Peru. Emphasizing the role of diagnostic confirmation in understanding the pandemic's trajectory, this study highlights the importance of early detection and accurate testing in managing infectious disease outbreaks.

Salvage reirradiation for recurrent glioblastoma: a retrospective case series analysis.

PURPOSE: To assess the clinical outcome of patients with recurrent glioblastoma treated with salvage reirradiation. METHODS: Between 2005 and 2022, data from adult patients with glioblastoma treated with surgery and radio-chemotherapy Stupp regimen who developed a local in-field relapse and received stereotactic radiotherapy (SRT) were retrospectively reviewed. RESULTS: The study population included 44 patients with recurrent glioblastoma (median of 9.5 months after the first radiotherapy). Reirradiation alone was given to 47.7% of patients. The median maximum diameter of the recurrence was 13.5 mm. The most common SRT regimen (52.3%) was 35 Gy in 10 fractions. Acute toxicity was mild, with transient worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 months, 40% presented radiological response, but a remarkable number of early distant progressions were recorded (32.5%). The median time to progression was 4.8 months, being the dose, the scheme, the size of the recurrence or the strategy (exclusive RT vs. combined) unrelated factors. The median overall survival (OS) was 14.9 months. Karnofsky index < 70 and the size of the recurrence (maximum diameter < 25 mm) were significant factors associated with OS. Radiological changes after reirradiation were commonly seen (> 50% of patients) hindering the response assessment. CONCLUSIONS: Reirradiation is a feasible and safe therapeutic option to treat localized glioblastoma recurrences, able to control the disease for a few months in selected patients, especially those with good functional status and small lesions. Hypofractionated schemes provided a suitable toxicity profile. Radiological changes were common.

Heatwave events and concurrent ozone concentrations between 2006 and 2022 at two sites in southern and northern Spain.

Hotter-than-usual days are becoming more common, such that heat waves are expected to increase in intensity, frequency, duration, and spatial extent in Spain. Within this framework, this paper looks at the combined effects of extreme temperatures and air pollution in two cities in Spain, Córdoba and Valladolid, over the period 2006-2022. Synoptic patterns and air mass movement were analysed during the eleven coincident heat waves at both locations in order to study what impact orography and local meteorology have on ozone concentrations. Weak flow conditions were the most frequent synoptic pattern in the Iberian Peninsula during heat waves. Moreover, west and local circulations characterised the main air trajectories at low levels (500 m agl), while southwest maritime advections and African air mass transport were more frequent at higher levels (1500 and 3000 m agl) in Córdoba and Valladolid, respectively. On average, maximum ozone values were higher in Córdoba (105.1 µg m-3) than in Valladolid (80 µg m-3) and were strongly correlated with extreme temperatures at both locations (r up to 0.8, p-value < 0.05). Mean temperature in Córdoba was 31.9 °C, with the maximum value reaching 43.7 °C, while temperatures in Valladolid were lower (28.3 °C and 37.3 °C, respectively). Calculation and assessment of some indices helped to understand the impact of extreme events. Caution actions based on the Heat Index characterised heat wave periods. Moderate risk was the general Air Quality Health Index feature recorded and reached a very high risk of unhealthy air quality in the June 2022 event in Córdoba.

Statistical Model of Ocular Wavefronts With Accommodation.

Purpose: The purpose of this study was to determine the minimum number of orthonormal basis functions, applying Principal Component Analysis (PCA), to represent the most wavefront aberrations at different accommodation stages. The study also aims to generate synthetic wavefront data using these functions. Methods: Monocular wavefront data from 191 subjects (26.15 ± 5.56 years old) were measured with a Hartmann-Shack aberrometer, simulating accommodation from 0 diopters (D) to 5 D in 1 D steps. The wavefronts for each accommodative demand were rescaled for different pupil sizes: 4.66, 4.76, 4.40, 4.09, 4.07, and 3.68 mm. PCA was applied to 150 wavefront parameters (25 Zernike coefficients × 6 accommodation levels) to obtain eigenvectors for dimensional reduction. A total of 49 eigenvectors were modeled as a sum of 2 multivariate Gaussians, from which 1000 synthetic data sets were generated. Results: The first 49 eigenvectors preserved 99.97% of the original data variability. No significant differences were observed between the mean values and standard deviation of the generated and original 49 eigenvectors (two one-sided test [TOST], P > 0.05/49) and (F-test, P > 0.05/49), both with Bonferroni correction. The mean values of the generated parameters (1000) were statistically equal to those of the original data (TOST, P > 0.05/150). The variability of the generated data was similar to the original data for the most important Zernike coefficients (F-test, P > 0.05/150). Conclusions: PCA significantly reduces the dimensionality of wavefront aberration data across 6 accommodative demands, reducing the variable space by over 66%. The synthetic data generated by the proposed wavefront model for accommodation closely resemble the original clinical data.

Enhancing apple postharvest protection: Efficacy of pectin coatings containing Cryptococcus laurentii against Penicillium expansum.

The aim of this work is the application of pectin coatings containing Cryptococcus laurentii as a method of biocontrol of Penicillium expansum for postharvest protection of apples. For this purpose, the yeast was incorporated into a pectin matrix, and its viability and biocontrol activity in vitro and in vivo against P. expansum was evaluated over time. In addition, the influence of the sterilization process on coating thickness was studied. Results showed that pectin coating with C. laurentii enhanced mycelial growth inhibition in vitro studies, while no significant differences were observed in disease incidence and severity reduction in vivo studies. The sterilization process reduced the viscosity of the pectin solution, resulting in coating thicknesses ranging from 0.5 to 1 µm. As a general evaluation, in vitro and in vivo, biocontrol assays were useful in demonstrating better postharvest protection of the yeast at 7 °C concerning 25 °C.

Novel hippocampus-centered methodology for informative instance selection in Alzheimer's disease data.

The quantity and quality of a dataset play a crucial role in the performance of prediction models. Increasing the amount of data increases the computational requirements and can introduce negligible variations, outliers, and noise. These significantly impact the model performance. Thus, instance selection techniques are crucial for building prediction models with informative data, reducing the dataset size, improving performance, and minimizing computational costs. This study proposed a novel methodology for identifying the most informative two-dimensional slices derived from magnetic resonance imaging (MRI) to study Alzheimer's disease. The efficacy of our methodology was attributable to a hippocampus-centered analysis using data from multiple atlases. The methodology was evaluated by constructing convolutional neural networks to identify Alzheimer's disease, using a consolidated dataset constructed from three standard datasets: Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and Open Access Series of Imaging Studies. The proposed methodology demonstrated a commendable subject-level classification accuracy of approximately ( 95.00 % ) when distinguishing between normal cognition and Alzheimer's.

Thyroid Hormone Upregulates Cav1.2 Channels in Cardiac Cells via the Downregulation of the Channels' ß4 Subunit.

Thyroid hormone binds to specific nuclear receptors, regulating the expression of target genes, with major effects on cardiac function. Triiodothyronine (T3) increases the expression of key proteins related to calcium homeostasis, such as the sarcoplasmic reticulum calcium ATPase pump, but the detailed mechanism of gene regulation by T3 in cardiac voltage-gated calcium (Cav1.2) channels remains incompletely explored. Furthermore, the effects of T3 on Cav1.2 auxiliary subunits have not been investigated. We conducted quantitative reverse transcriptase polymerase chain reaction, Western blot, and immunofluorescence experiments in H9c2 cells derived from rat ventricular tissue, examining the effects of T3 on the expression of α1c, the principal subunit of Cav1.2 channels, and Cavß4, an auxiliary Cav1.2 subunit that regulates gene expression. The translocation of phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB) by T3 was also examined. We found that T3 has opposite effects on these channel proteins, upregulating α1c and downregulating Cavß4, and that it increases the nuclear translocation of pCREB while decreasing the translocation of Cavß4. Finally, we found that overexpression of Cavß4 represses the mRNA expression of α1c, suggesting that T3 upregulates the expression of the α1c subunit in response to a decrease in Cavß4 subunit expression.

Clinical and molecular characterization of steatotic liver disease in the setting of immune-mediated inflammatory diseases.

Background & Aims: Growing evidence suggests an increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). We aimed to clinically and mechanistically characterize steatotic liver disease (SLD) in a prospective cohort of patients with IMID compared to controls. Methods: Cross-sectional, case-control study including a subset of patients with IMID. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched at a 1:2 ratio. SLD was established using controlled attenuation parameter. Liver biopsies were obtained when significant liver fibrosis was suspected. Total RNA was extracted from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with 'limma-voom'. Gene set-enrichment analysis was performed using the fgsea R package with a preranked "limma t-statistic" gene list. Results: A total of 1,456 patients with IMID and 2,945 controls were included. Advanced SLD (liver stiffness measurement ≥9.7 kPa) (13.46% vs. 3.79%; p <0.001) and advanced MASLD (12.8% vs. 2.8%; p <0.001) prevalence were significantly higher among patients with IMID than controls. In multivariate analysis, concomitant IMID was an independent, and the strongest, predictor of advanced SLD (adjusted odds ratio 3.318; 95% CI 2.225-4.947; p <0.001). Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID-MASLD and control-MASLD. IMID-MASLD cases displayed an enriched expression of genes implicated in pro-tumoral activities or the control of the cell cycle concomitant with a negative expression of genes related to metabolism. Conclusions: The prevalence of advanced SLD and MASLD is disproportionately elevated in IMID cohorts. Our findings suggest that IMIDs may catalyze a distinct MASLD pathway, divergent from classical metabolic routes, highlighting the need for tailored clinical management strategies. Impact and implications: The prevalence of steatotic liver disease with advanced fibrosis is increased in patients with immune-mediated inflammatory diseases, independent of classic metabolic risk factors or high-risk alcohol consumption. Transcriptomic analysis revealed a unique gene expression signature associated with cellular activities that are compatible with a liver condition leading to an accelerated and aggressive form of steatotic liver disease. Our findings underscore the importance of heightened screening for advanced liver disease risk across various medical disciplines overseeing patients with immune-mediated inflammatory diseases.

Impact and Effectiveness of COVID-19 Vaccines Based on Machine Learning Analysis of a Time Series: A Population-Based Study.

Background: Although confirmed cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been declining since late 2020 due to general vaccination, little research has been performed regarding the impact of vaccines against SARS-CoV-2 in Spain in terms of hospitalizations and deaths. Objective: Our aim was to identify the reduction in severity and mortality of coronavirus disease 2019 (COVID-19) at a nationwide level due to vaccination. Methods: We designed a retrospective, population-based study to define waves of infection and to describe the characteristics of the hospitalized population. We also studied the rollout of vaccination and its relationship with the decline in hospitalizations and deaths. Finally, we developed two mathematical models to estimate non-vaccination scenarios using machine learning modeling (with the ElasticNet and RandomForest algorithms). The vaccination and non-vaccination scenarios were eventually compared to estimate the number of averted hospitalizations and deaths. Results: In total, 498,789 patients were included, with a global mortality of 14.3%. We identified six waves or epidemic outbreaks during the observed period. We established a strong relationship between the beginning of vaccination and the decline in both hospitalizations and deaths due to COVID-19 in all age groups. We also estimated that vaccination prevented 170,959 hospitalizations (CI 95% 77,844-264,075) and 24,546 deaths (CI 95% 2548-46,543) in Spain between March 2021 and December 2021. We estimated a global reduction of 9.19% in total deaths during the first year of COVID-19 vaccination. Conclusions: Demographic and clinical profiles changed over the first months of the pandemic. In Spain, patients over 80 years old and other age groups obtained clinical benefit from early vaccination. The severity of COVID-19, in terms of hospitalizations and deaths, decreased due to vaccination. Our use of machine learning models provided a detailed estimation of the averted burden of the pandemic, demonstrating the effectiveness of vaccination at a population-wide level.

3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds.

Indazoles have previously been identified as molecules with antiprotozoal activity. In this study, we evaluate the in vitro activity of thirteen 3-alkoxy-1-benzyl-5-nitroindazole derivatives (series D) against L. amazonensis, L. infantum, and L. mexicana. In vitro, cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for all compounds, and those showing adequate activity and selectivity were tested against intracellular amastigotes. Transmission and scanning electron microscopy were employed to study the effects of 3-alkoxy-1-benzyl-5-nitroindazole and 2-benzyl-5-nitroindazolin-3-one derivatives on promastigotes of L. amazonensis. Compounds NV6 and NV8 were active in the two life stages of the three species, with the latter showing the best indicators of activity and selectivity. 3-alkoxy-1-benzyl-5-nitroindazole derivatives (series D) showed in vitro activity comparable to that of amphotericin B against the promastigote stage of Leishmania spp. Two compounds were also found to be active the amastigote stage. Electron microscopy studies confirmed the antileishmanial activity of the indazole derivatives studied and support future research on this family of compounds as antileishmanial agents.

The Neuroconnective Endophenotype, A New Approach Toward Typing Functional Neurological Disorder: A Case-Control Study.

OBJECTIVE: Functional neurological disorder (FND) is a core neuropsychiatric condition that includes both physical and mental symptoms. Recently, a validated clinical phenotype termed neuroconnective endophenotype (NEP), which includes several physical and psychological characteristics together with joint hypermobility (hypermobility spectrum disorders), was found at a significantly higher frequency among patients with anxiety. The purpose of the present study was to examine the presence of the NEP among patients with FND. METHODS: The authors conducted a multicenter case-control study comprising 27 FND patients and 27 healthy control participants (matched by sex and age) ages 13 to 58 years. Eight questionnaires were administered. Proportional differences were examined with Student's t tests, one-way analyses of variance, and chi-square tests. RESULTS: Differences between FND patients and control participants were observed. FND patients had higher sensory sensitivity, increased prevalence of hypermobility features (including relevant physical signs and symptoms), greater frequency of polarized behaviors, a greater number of both psychiatric and physical comorbidities, and an increase in the characteristics and sensations typical of anxiety. Particularly striking was the presence of the hypermobility spectrum in more than 75% of FND patients compared with 15% among control participants. CONCLUSIONS: FND patients presented higher scores in all five dimensions included in the NEP. Thus, this phenotype, solidifying the original association between anxiety and the hypermobility spectrum, could help to identify an FND subtype when evaluating and managing FND patients, because it provides a new global view of patients' physical and mental symptoms.

Lipocalin-2 Serum Levels in Rheumatoid Arthritis Patients Treated with Adalimumab and Its Correlation with Proinflammatory Factors.

Background: Obesity is associated with an increased risk for different chronic diseases such as osteoarthritis (OA) or rheumatoid arthritis (RA). In fact, adipose tissue is now recognized as an endocrine organ able to secrete a wide variety of factors called adipokines, which have been demonstrated to participate in the pathophysiology of RA by regulating inflammation and immunity. LCN2 is one of these adipose tissue-derived factors. However, scarce information is available about the levels of this adipokine in different rheumatic diseases. Therefore, we aimed to analyze LCN2 serum levels in healthy, OA, and RA patients under different treatments. Methods: Serum levels of LCN2, among other proinflammatory and chemotactic factors, have been measured by ELISA or Multiplex in the following four groups of individuals: healthy, OA, and RA patients treated with conventional treatment or adalimumab. Results: We found increased serum levels of LCN2 in OA and RA patients. Interestingly, LCN2 serum levels show a similar pattern to that observed for different proinflammatory and chemotactic factors, being increased in RA conventional treated patients in comparison to RA patients treated with adalimumab. Also, RA patients under conventional treatment revealed a positive and significant correlation between LCN2 and CCL2, CCL3, IL-8, IL-1ß, IL-6, and CRP. In patients with RA treated with adalimumab, only IL-6 and CRP correlated significantly with LCN2. Conclusions: Our results clearly suggest that LCN2 is modulated and associated with inflammation in rheumatic diseases. Therefore, the serum levels of this adipokine might be used as an additional biomarker of the inflammatory/disease activity.

Mexican calea (Calea zacatechichi Schltdl.) interferes with cholinergic and dopaminergic pathways and causes neuroglial toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of "Mexican calea" (Calea zacatechichi Schltdl.) in ritualistic ceremonies, due to its dream-inducing effects, was until recently limited to indigenous communities in Mexico. However, the plant has recently gained popularity in Western societies being commonly used in recreational settings. Despite the traditional and recreational uses, mechanisms underlying its reported oneirogenic effects remain unknown, with no data available on its neurotoxic profile. AIM OF THE STUDY: The scarcity of toxicological data and the unknown role of major neurotransmitter systems in the dream-inducing properties of the plant prompted us to investigate which neurotransmitters might be affected upon its consumption, as well as the potential cytotoxic effects on neurons and microglial cells. Furthermore, we aimed to explore a relationship between the recorded effects and specific constituents. MATERIALS AND METHODS: Effects on cholinergic and monoaminergic pathways were investigated using enzymatic assays, with the latter also being conducted in neuronal SH-SY5Y cells along with the impact on glutamate-induced excitotoxicity. Investigation of the neurotoxic profile was approached in neuronal SH-SY5Y and microglial BV-2 cells, evaluating effects on metabolic performance and membrane integrity using MTT and LDH leakage assays, respectively. Potential interference with oxidative stress was monitored by assessing free radical's levels, as well as 5-lipoxygenase mediated lipid peroxidation. Phenolic constituents were identified through HPLC-DAD-ESI(Ion Trap)MSn analysis. RESULTS: Based on the significant inhibition upon acetylcholinesterase (p < 0.05) and tyrosinase (IC50 = 60.87 ± 7.3 µg/mL; p < 0.05), the aqueous extract obtained from the aerial parts of C. zacatechichi interferes with the cholinergic and dopaminergic systems, but has no impact against monoamine oxidase A. Additionally, a notable cytotoxic effect was observed in SH-SY5Y and BV-2 cells at concentrations as low as 125 and 500 µg/mL (p < 0.05), respectively, LDH leakage suggesting apoptosis may occur at these concentrations, with necroptosis observed at higher ones. Despite the neurocytotoxic profile, these effects appear to be independent of radical stress, as the C. zacatechichi extract scavenged nitric oxide and superoxide radicals at concentrations as low as 62.5 µg/mL, significantly inhibiting also 5-lipoxygenase (IC50 = 72.60 ± 7.3 µg/mL; p < 0.05). Qualitative and quantitative analysis using HPLC-DAD-ESI(Ion Trap)MSn enabled the identification of 28 constituents, with 24 of them being previously unreported in this species. These include a series of dicaffeoylquinic, caffeoylpentoside, and feruloylquinic acids, along with 8 flavonols not previously known to occur in the species, mainly 3-O-monoglycosylated derivatives of quercetin, kaempferol, and isorhamnetin. CONCLUSIONS: Our findings regarding the neuroglial toxicity elicited by C. zacatechichi emphasize the necessity for a thorough elucidation of the plant's toxicity profile. Additionally, evidence is provided that the aerial parts of the plant inhibit both acetylcholinesterase and tyrosinase, potentially linking its psychopharmacological effects to the cholinergic and dopaminergic systems, with an apparent contribution from specific phenolic constituents previously unknown to occur in the species. Collectively, our results lay the groundwork for a regulatory framework on the consumption of C. zacatechichi in recreational settings and contribute to elucidating previous contradictory findings regarding the mechanisms underlying the dream-inducing effects of the plant.

Can we rely on magnetic resonance imaging for prostate cancer detection and surgical planning? Comprehensive analysis of a large cohort of patients undergoing transperineal mapped biopsies.

PURPOSE: To evaluate MRI and histological concordance in prostate cancer (PCa) identification via mapped transperineal biopsies. METHODOLOGY: Retrospective per-lesion analysis of patients undergoing MRI and transperineal biopsy at the Valencian Institute of Oncology (2016-2024) using CAPROSIVO PCa data. Patients underwent MRI, with or without regions of interest (ROI), followed by transperineal biopsies (3-5 cores/ROI, 20-30 systematic). Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and area under the curve (AUC) were calculated, considering PI-RADS 3 lesions as positive or negative. Gleason Grade Group (GG) > 1 defined clinically significant PCa (csPCa). RESULTS: 1817 lesions were analyzed from 1325 patients (median age 67, median PSA 6.3 ng/ml). 53% MRI were negative, GG > 1 prevalence was 38.4%. MRI-negative cases showed varying PCa rates: 57.4% negative, 30.2% GG 1, and 12.4% GG > 1. PI-RADS 3 lesions had mixed outcomes: 45.6% benign, 13.1% GG 1, and 41.3% GG > 1. 9.2% PI-RADS 4-5 lesions were negative, 9% GG 1, and 81.7% GG > 1. For PI-RADS 3 lesions considered positive, Se, Sp, NPV, PPV, and AUC were 82.9%, 75%, 87.6%, 67.4%, and 0.79 respectively. Considering PI-RADS 3 as negative yielded 64.8% Se, 91% Sp, 80.6% NPV, 81.7% PPV, and 0.78 AUC. CONCLUSION: MRI and mapped prostate biopsies exhibited moderate concordance. MRI could miss up to one in five csPCa foci and misinterpret one in three ROIs. Careful MRI interpretation is crucial for optimizing patient care.