Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis

Biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Amongst these, polyarticular Juvenile-Idiopathic Arthritis (pJIA) and Rheumatoid Arthritis (RA) display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. Mechanisms and determinants of this heterogeneous response are diverse and complex, such that development of true “precision”-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in polyarticular JIA in comparison to what is known in RA. Although some biomarkers have been identified that stratify for the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centered and clinically-based approach, i.e. personalized instead of biomarker-based precision medicine in JIA

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects

Cama de frango como substrato para a produção de biogás após diferentes períodos de estocagem.

RESUMO: Na avicultura a cama de frango é produzida sazonalmente, em função do modo de produção. Para obter energia do biogás por meio da biodigestão da cama de frango, de forma contínua, o armazenamento do resíduo pode ser uma solução. Ensaios de Potencial Bioquímico de Metano (BMP) foram utilizados neste trabalho para estimar a capacidade de produção de biogás e metano da cama de frango removida após o sexto lote de reutilização e a diferentes tempos de armazenamento após a coleta, assim, verificar a viabilidade de utilização da cama de frango como um substrato em unidade produtora de biogás. A produção de biogás e metano, nas amostras em diferentes períodos de armazenamento, foi comparada: antes de armazenar 245 LN biogas.kgSV adic-1 e 159 LN CH4.kgSV adic-11, seis meses com 252 LN biogas.kgSV adic-1 e 160 LN CH4.kgSV adic-1 e um ano 209 LN biogas.kgSV adic-1 e 117 LNCH4.kgSV adic-1, demonstrando que o período de armazenamento é caracterizado por uma relativa perda do conteúdo de matéria orgânica após um ano, contudo, não há diferença significativa entre a produção de biogás e metano após seis meses armazenada e antes de armazenar. Verificou-se a viabilidade da estocagem de cama de frango do sexto lote de reutilização, no período de seis meses, sem perda significativa de matéria orgânica para a conversão em biogás e metano. ABSTRACT: In poultry litter is produced seasonally due to production mode. To get energy from biogas through the bio digestion of poultry litter, continuously, the storage of the residue can be a solution. Biochemical Methane Potential (BMP) assays were used in this study to estimate the production of biogas and methane poultry litter removed after the sixth lot of reuse and in different storage times after collect, so check the feasibility of use poultry litter as a feedstock in biogas producer unit. The production of biogas and methane in the samples in different periods of storage was compared: before storage 245 LN biogas.kgVS add-1 E 159 LN C H4 kg SV add-1, six months with 252 LN biogas.kgVS add-1 e 160 LN C H4 kg SV add-1 and a year 209 LN biogas.kgVS add-1 and one year 117 LN C H4 kg SV add-1, demonstrating that the storage period is characterized by a relative loss of content of organic matter after a year, however there's no significant difference between the production of biogas and methane in six months storaged and before storage . It was verified the viability of storage of poultry litter of the sixth lot of reuse, in the six-month period, without significant loss of organic matter for conversion to biogas and methane

Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation

\ua9 The Author(s) 2024.Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα

Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

During open heart surgery the influence of a series of factors such as cardiopulmonary bypass (CPB), hypothermia, operation and anaesthesia, as well as medication and transfusion can cause a diffuse trauma in the lungs. This injury leads mostly to a postoperative interstitial pulmonary oedema and abnormal gas exchange. Substantial improvements in all of the above mentioned factors may lead to a better lung function postoperatively. By avoiding CPB, reducing its time, or by minimizing the extracorporeal surface area with the use of miniaturized circuits of CPB, beneficial effects on lung function are reported. In addition, replacement of circuit surface with biocompatible surfaces like heparin-coated, and material-independent sources of blood activation, a better postoperative lung function is observed. Meticulous myocardial protection by using hypothermia and cardioplegia methods during ischemia and reperfusion remain one of the cornerstones of postoperative lung function. The partial restoration of pulmonary artery perfusion during CPB possibly contributes to prevent pulmonary ischemia and lung dysfunction. Using medication such as corticosteroids and aprotinin, which protect the lungs during CPB, and leukocyte depletion filters for operations expected to exceed 90 minutes in CPB-time appear to be protective against the toxic impact of CPB in the lungs. The newer methods of ultrafiltration used to scavenge pro-inflammatory factors seem to be protective for the lung function. In a similar way, reducing the use of cardiotomy suction device, as well as the contact-time between free blood and pericardium, it is expected that the postoperative lung function will be improved

Happiness around the world: A combined etic-emic approach across 63 countries

What does it mean to be happy? The vast majority of cross-cultural studies on happiness have employed a Western-origin, or "WEIRD" measure of happiness that conceptualizes it as a self-centered (or "independent"), high-arousal emotion. However, research from Eastern cultures, particularly Japan, conceptualizes happiness as including an interpersonal aspect emphasizing harmony and connectedness to others. Following a combined emicetic approach (Cheung, van de Vijver & Leong, 2011), we assessed the cross-cultural applicability of a measure of independent happiness developed in the US (Subjective Happiness Scale; Lyubomirsky & Lepper, 1999) and a measure of interdependent happiness developed in Japan (Interdependent Happiness Scale; Hitokoto & Uchida, 2015), with data from 63 countries representing 7 sociocultural regions. Results indicate that the schema of independent happiness was more coherent in more WEIRD countries. In contrast, the coherence of interdependent happiness was unrelated to a country's "WEIRD-ness." Reliabilities of both happiness measures were lowest in African and Middle Eastern countries, suggesting these two conceptualizations of happiness may not be globally comprehensive. Overall, while the two measures had many similar correlates and properties, the self-focused concept of independent happiness is "WEIRD-er" than interdependent happiness, suggesting cross-cultural researchers should attend to both conceptualizations

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity