Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation.

Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.

Numerical path integral calculation of the probability function and exit time: an application to non-gradient drift forces.

We provide numerical solutions based on the path integral representation of stochastic processes for non-gradient drift Langevin forces in the presence of noise, to follow the temporal evolution of the probability density function and to compute exit times even for arbitrary noise. We compare the results with theoretical calculations, obtaining excellent agreement in the weak noise limit.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'.

Biosimilars to recombinant human FSH medicines: comparable efficacy and safety to the original biologic.

Two recombinant follicle-stimulating hormone (rFSH)-bearing similar biological medicines (biosimilars) have been authorized by the European Commission. Biosimilar is a regulatory concept alluding to the evidence-based high-standard comparability studies needed to demonstrate its equivalence to a reference original biologic. Because biosimilar development represents a shift from the long-lasting existing paradigms, a thorough understanding of the science behind it will contribute to helping prescribers make informed treatment choices. Contrary to chemically-synthesized medicines, biologics are subject to an inherent molecular variability. From the experience with original biologics, regulatory authorities have accumulated a wealth of knowledge as to what minor batch-to-batch physicochemical variations may be therapeutically acceptable in a given product. Furthermore, in spite of analytically detectable differences, the two original rFSH-bearing medicines currently on the market share fundamentally the same therapeutic profile. Unlike those original medicines, a biosimilar of an rFSH product and the corresponding reference biologic share essentially the same active pharmaceutical ingredient. They are also administered via the same route, at the same dose, and for the same indications. This article revises the background evidence over which the biosimilarity principle has been built, and highlights the therapeutic potential for follitropin biosimilars in order to reassure physicians on their benefit.

Biosimilar: what it is not.

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a 'stand-alone'. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA's criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients.

Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections.

Calcitonin gene-related peptide (CGRP) and histamine plasma concentrations increase during migraine attacks. Both mediators are potent vasodilators, and they have been shown to reciprocally contribute to the release of each other in the trigeminovascular system, possibly driving migraine development. A high-histamine-content diet triggers migraine in patients who have histamine degradation deficiency owing to diaminooxidase (DAO) gene mutations. Therefore, studying functional links between exogenous histamine and CGRP seems promising for the understanding of diet-induced migraine generation. Notably, there is a lack of knowledge about the interplay of the enteric nervous system and the spinal/trigeminal somatosensory system with regard to CGRP and histamine. Based on background evidence, we propose that a functional interconnection between exogenous histamine and CGRP contributes to migraine development.

Insights from the Twittersphere: a cross-sectional study of public perceptions, usage patterns, and geographical differences of tweets discussing cocaine.

Introduction: Cocaine abuse represents a major public health concern. The social perception of cocaine has been changing over the decades, a phenomenon closely tied to its patterns of use and abuse. Twitter is a valuable tool to understand the status of drug use and abuse globally. However, no specific studies discussing cocaine have been conducted on this platform. Methods: 111,508 English and Spanish tweets containing "cocaine" from 2018 to 2022 were analyzed. 550 were manually studied, and the largest subset underwent automated classification. Then, tweets related to cocaine were analyzed to examine their content, types of Twitter users, usage patterns, health effects, and personal experiences. Geolocation data was also considered to understand regional differences. Results: A total of 71,844 classifiable tweets were obtained. Among these, 15.95% of users discussed the harm of cocaine consumption to health. Media outlets had the highest number of tweets (35.11%) and the most frequent theme was social/political denunciation (67.88%). Regarding the experience related to consumption, there are more tweets with a negative sentiment. The 9.03% of tweets explicitly mention frequent use of the drug. The continent with the highest number of tweets was America (55.44% of the total). Discussion: The findings underscore the significance of cocaine as a current social and political issue, with a predominant focus on political and social denunciation in the majority of tweets. Notably, the study reveals a concentration of tweets from the United States and South American countries, reflecting the high prevalence of cocaine-related disorders and overdose cases in these regions. Alarmingly, the study highlights the trivialization of cocaine consumption on Twitter, accompanied by a misleading promotion of its health benefits, emphasizing the urgent need for targeted interventions and antidrug content on social media platforms. Finally, the unexpected advocacy for cocaine by healthcare professionals raises concerns about potential drug abuse within this demographic, warranting further investigation.

Regional insights on tobacco-related tweets: unveiling user opinions and usage patterns.

Introduction: Tobacco consumption and its impact on health remain high worldwide. Additionally, it is a contentious issue generating significant controversy. Twitter has proven to be a useful platform for evaluating public health topics related to population health behaviors, and tobacco consumption. Objective: The objective of this study is to analyze the content of tweets related to tobacco. Moreover, geolocation data will be considered to understand regional differences. Methods: Tweets published between 2018 and 2022, in both English and Spanish, containing the keyword "tobacco," were analyzed. A total of 56,926 tweets were obtained. The tweets were classified into different categories. 550 tweets were manually analyzed, and an automated and computerized classification was performed for the remaining and largest subset of tweets. Results: The analysis yielded 30,812 classifiable tweets. Healthcare professionals were the most frequent contributors to the topic (50.2%), with the most common theme being general information about the toxic effects of tobacco. 57.9% of the tweets discussed the harmful effects of tobacco on health, with fear being the predominant emotion. The largest number of tweets were located in America. Conclusions: Our study revealed a substantial number of tweets highlighting the health risks and negative perceptions of tobacco consumption. Africa showed the lowest percentage of tweets discussing the health risks associated with tobacco, coinciding with the continent having the least developed anti-tobacco policies. Healthcare professionals emerged as the most prominent users discussing the topic, which is encouraging as they play a crucial role in disseminating accurate and scientific health information.

Locally administered prostaglandin E2 prevents aeroallergen-induced airway sensitization in mice through immunomodulatory mechanisms.

Prostaglandin E2 attenuates airway pathology in asthmatic patients and exerts a protective effect in antigen-sensitized mice when administered systemically. We aimed to establish the consequences of intranasal PGE2 administration on airway reactivity to aeroallergens in mice and reveal the underlying immunoinflammatory mechanisms. PGE2 was administered either daily during a 10-day exposure to house dust mite (HDM) extracts or for limited intervals. Airway hyperreactivity was measured by whole-body and invasive plethysmography. The phenotypes of lung immune cells and cytokine production were analysed by flow cytometry and ELISA, respectively. Airway hyperreactivity was sustainably reduced only when PGE2 administration was restricted to the initial 5 days of exposure to HDM. Lung inflammation, IL-4 production, and airway mast cell activity were also prevented under this early short-term treatment with PGE2. Interestingly, a Th2 response was already committed on day 5 of exposure to HDM. This was paralleled by GM-CSF and osteopontin upregulation and a decreased number of plasmacytoid dendritic and T regulatory cells, as well as a trend towards reduced IL-10 expression. Local PGE2 administration prevented the increase of airway IL-13 and osteopontin and kept lung plasmacytoid dendritic cell counts close to baseline. GM-CSF and Tregs were unaffected by the treatment. These findings suggest that the protection provided by PGE2 is a result of the modulation of early lung immunomodulatory mechanisms, and possibly a shift in the balance of dendritic cells towards a tolerogenic profile.

Combined analytical assays for the characterization of drugs binding to human IgE: Applicability to omalizumab-bearing biosimilar candidates assessment.

Analytical and functional comparison is key for substantiating the level of convergence (essential sameness) or divergence between versions or variants of a given biological medicine. Accordingly, an overlapping biological activity between products meant to be equal probably reflects a highly similar structure and anticipates a comparable pharmacodynamic behavior. We developed an orthogonal approach to compare the human IgE binding features of different lots and versions of Xolair® (omalizumab), an anti-human IgE monoclonal antibody. The IgE binding affinity and kinetics were measured by surface plasmon resonance. Ability to prevent mast cell activity was assessed in vitro and in vivo in mast cell-based models. The variability of monoclonal antibodies with identical amino acid sequences produced either in Chinese hamster ovarian cells or in human HEK293 cells, was compared. Monoclonal antibodies from the two sources exhibited slightly different human IgE binding and neutralizing features. A known variant exhibiting a three amino acid replacement in the Fab region had lower IgE binding affinity than the original omalizumab. The lower binding affinity translated into reduced IgE neutralizing capacity and, in turn, a difference in the ability to prevent mast cell activation in vitro and in vivo. The proposed set of analytical and functional assays was sensitive enough to detect Fab-linked differences between anti-IgE antibody versions exhibiting an identical aminoacid sequence. In addition to add value to the comparative assessment of biosimilar candidates bearing omalizumab, these methods can aid pre-assessments of new anti-IgE agents that aim to improve therapeutic performance.

Patient satisfaction and outcomes of crisis resolution home treatment for the management of acute psychiatric crises: a study during the COVID-19 pandemic in Madrid.

Background: Crisis Resolution Home Treatment (CRHT) seem to offer comparable results to the traditional hospitalization model, at a lower cost and offering greater flexibility and scope. However, in Madrid, its implementation in Mental Health did not occur until the midst of the COVID-19 pandemic. In this work we analysed the effectiveness of a mental health CRHT unit promoted during the COVID-19 pandemic, as well as the degree of satisfaction of patients and their families. Methods: 90 patients were treated by the CRHT unit in the period between October 2020 and June 2022. All patients met the inclusion criteria: (1) Acute psychopathological decompensation in patients suffering from psychotic disorders, major affective disorder, obsessive compulsive disorder, personality disorder and other severe mental disorders causing functional disability, according to ICD-10 diagnostic criteria; (2) Ages between 18-90 years old; (3) Living in the urban area of Vallecas, Madrid; and (4) Counting with sufficient social and family support. The effectiveness of the intervention was evaluated with the SF-36 health questionnaire, the caregiver burden with the Zarit questionnaire, and patient satisfaction with a survey specifically designed for this work. Results: 55 (61.1%) patients completed the SF-36 at baseline and at the end of hospitalization. Statistically significant improvements were observed in the 8 dimensions of the SF-36 (p < 0.05). However, CRHT did not achieve a statistically significant decrease in caregiver burden. Regarding the satisfaction of the patients with the attention and care received, an average score of 47.72/50 was obtained. Conclusion: The Crisis Resolution Home Treatment intervention resulted in significant improvement in patients' quality of life with high satisfaction scores. However, it did not effectively reduce caregiver burden. Future research should focus on randomized controlled trials with long-term follow-up to assess the effectiveness of CRHT compared to traditional hospitalization and utilize specific assessment scales for different mental disorders.

Current Opinions about the Use of Duloxetine: Results from a Survey Aimed at Psychiatrists.

Major depressive disorder (MDD) is a complex psychiatric disorder that, presented alone or with other comorbidities, requires different adjustments of antidepressant treatments. Some investigations have demonstrated that psychoactive drugs, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), can exert more effective and faster antidepressant effects than other common medications used, such as serotonin selective reuptake inhibitors (SSRIs), although these differences are still controversial. During the last five years, the SNRI duloxetine has shown favorable results in clinical practice for the treatment of MDD, anxiety, and fibromyalgia. Through an online self-completed survey, in the present article, we collected information from 163 psychiatrists regarding the use of duloxetine and its comparison with other psychiatric drugs, concerning psychiatrists' knowledge and experience, as well as patients' preferences, symptoms, and well-being. We discussed and contrasted physicians' reports and the scientific literature, finding satisfactory concordances, and finally concluded that there is agreement regarding the use of duloxetine, not only due to its tolerability and effectiveness but also due to the wide variety of situations in which it can be used (e.g., somatic symptoms in fibromyalgia, diabetes) as it relieves neuropathic pain as well.

The Placentas of Women Who Suffer an Episode of Psychosis during Pregnancy Have Increased Lipid Peroxidation with Evidence of Ferroptosis.

Psychosis is a complex entity characterized by psychological, behavioral, and motor alterations resulting in a loss of contact with reality. Although it is not common, pregnancy can be a period in which a first episode of psychosis can manifest, entailing detrimental consequences for both the fetus and the mother. The pathophysiological basis and study of maternofetal wellbeing need to be further elucidated. Lipid peroxidation and ferroptosis are two phenomena that are tightly linked to the placental dysfunction commonly observed in different complications of pregnancy. In the present study, we aim to explore the histopathological and gene expression of different markers of lipid peroxidation and ferroptosis in the placentas of women who underwent a first episode of psychosis during their pregnancy (n = 22). The aim is to then compare them with healthy pregnant women (n = 20). In order to achieve this goal, iron deposits were studied using Prussian Blue staining. In addition, the protein/gene expression of a transferrin receptor (TFRC), as well as an acyl-CoA synthetase long-chain family member 4 (ACSL-4), arachidonate lipoxygenase-5 (ALOX-5), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4) were all analyzed through gene expression (RT-qPCR) and immunohistochemical procedures. Our results demonstrate an increased presence of iron deposits that are accompanied by a further expression of TFRC, ACSL-4, ALOX-5, MDA, and GPX4-all of which are observed in the placenta tissue of women who have suffered from a first episode of psychosis. Therefore, in our study, a histopathological increase in lipid peroxidation and ferroptosis markers in the affected women is suggested. However, further studies are needed in order to validate our results and to establish possible consequences for the reported alterations.

Evidence of Increased Oxidative Stress in the Placental Tissue of Women Who Suffered an Episode of Psychosis during Pregnancy.

Psychosis is a complex clinical syndrome resulting in a loss of contact with reality and alterations in behavior and sensorial and motor functions. Although the onset of psychosis can be related to any medical condition, most cases of psychosis are not fully understood. Psychosis may manifest for the first time during pregnancy, which is detrimental to maternofetal well-being. The impact of having a first episode of psychosis during pregnancy on the placenta has not yet been explored. Oxidative stress is thought to take part in the etiopathogenesis of this complex disorder, and this condition can also affect the placenta as it is highly sensitive to changes in the maternal environment. In this sense, the aim of the present work was to study the gene and protein expression through RT-qPCR and immunohistochemistry, respectively, of oxidative stress markers (NOX-1, NOX-2, iNOS, eNOS and PARP) in the placental tissue of women who underwent a first episode of psychosis during pregnancy (FE-PW) in comparison to healthy pregnant women. Our results showed augmented gene and protein expression of NOX-1, NOX-2, iNOS and PARP in the placental tissue of FE-PW. For the first time, we demonstrated that oxidative stress may have an important pathophysiological role in this tissue, aiding in explaining the impact of psychosis on pregnancy and the need for future studies in this field to guide better clinical management of these patients.

Overlapping biosimilar and originator follitropin alfa preparations: How much closer can they get?

Unfounded skepticism relating to biosimilars, arising from the assertion that they are not molecularly identical to their original counterpart, fails to acknowledge that no biological medicine, including Gonal-f® (from Merck Serono) is identical to itself. Molecular differences between the biosimilar and the reference medicines are irrelevant and clinically undetectable as long as they are contained within the accepted variability for the original medicine. Accordingly, the minor differences in 'ongoing pregnancy rate' and 'live birth' rate reported in a recent meta-analysis of biosimilars of Gonal-f® from Chua et al. are probably driven by product-unrelated factors, notwithstanding the fact that of the four products under analysis, only Ovaleap® (from Theramex UK Ltd) and Bemfola® (from Gedeon Richter Plc) can unambiguously be considered to be biosimilars. The EU Biosimilars model has proven successful, but some healthcare professionals, building on highly arguable premises, voice a distrust in biosimilars. Only if such scientifically unfounded distrust is reverted, the full promise of rFSH alfa biosimilars for reproductive medicine patients is likely to be fulfilled.

Addressing the Treatment and Service Needs of Young Adults with Attention Deficit Hyperactivity Disorder.

The transition from adolescence to adulthood is a complex period in which multiple changes take place (education, work, independent living, and social relations). This stage is especially difficult for adolescents suffering from attention deficit hyperactivity disorder (ADHD), who have to move on from child and adolescent mental health services to adult mental health services. This review analyzes developmental and environmental risk and protective factors as well as critical variables such as executive functioning and self-monitoring that influence the course of ADHD in transitional age youth and guide the priorities for an optimal transition of care. The influence of the COVID-19 pandemic is also discussed. We reflect on the unmet needs for an optimal transition of care and propose practice and policy recommendations to achieve this goal.

Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review.

INTRODUCTION: Vortioxetine is a multimodal-acting antidepressant that provides improvements on cognitive function aside from antidepressants and anxiolytic effects. Vortioxetine has been found to be one of the most effective and best tolerated options for major depressive disorder (MDD) in head-to-head trials. AREAS COVERED: The present review intends to gather the most relevant and pragmatic data of vortioxetine in MDD, specially focusing on new studies that emerged between 2015 and 2020. EXPERT OPINION: Vortioxetine is the first antidepressant that has shown improvements both in depression and cognitive symptoms, due to the unique multimodal mechanism of action that combine the 5-HT reuptake inhibition with modulations of other key pre- and post-synaptic 5-HT receptors (agonism of 5-HT1A receptor, partial agonism of 5-HT1B receptor, and antagonism of 5-HT3, 5-HT1D and 5-HT7 receptors). This new mechanism of action can explain the dose-dependent effect and can be responsible for its effects on cognitive functioning and improved tolerability profile. Potential analgesic and anti-inflammatory properties observed in preclinical studies as well as interesting efficacy and tolerability results of clinical studies with specific target groups render it a promising therapeutic option for patients with MDD and concomitant conditions (as menopause symptoms, pain, inflammation, apathy, sleep and/or metabolic abnormalities).

Nutrition, Epigenetics, and Major Depressive Disorder: Understanding the Connection.

Major depressive disorder (MDD) is a complex, multifactorial disorder of rising prevalence and incidence worldwide. Nearly, 280 million of people suffer from this leading cause of disability in the world. Moreover, patients with this condition are frequently co-affected by essential nutrient deficiency. The typical scene with stress and hustle in developed countries tends to be accompanied by eating disorders implying overnutrition from high-carbohydrates and high-fat diets with low micronutrients intake. In fact, currently, coronavirus disease 2019 (COVID-19) pandemic has drawn more attention to this underdiagnosed condition, besides the importance of the nutritional status in shaping immunomodulation, in which minerals, vitamins, or omega 3 polyunsaturated fatty acids (ω-3 PUFA) play an important role. The awareness of nutritional assessment is greater and greater in the patients with depression since antidepressant treatments have such a significant probability of failing. As diet is considered a crucial environmental factor, underlying epigenetic mechanisms that experience an adaptation or consequence on their signaling and expression mechanisms are reviewed. In this study, we included metabolic changes derived from an impairment in cellular processes due to lacking some essential nutrients in diet and therefore in the organism. Finally, aspects related to nutritional interventions and recommendations are also addressed.