White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Differential atrophy along the longitudinal hippocampal axis in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers. This study included structural brain MRI data of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitively normal (CN) subjects, mild cognitively impaired (MCI) subjects and AD patients were conveniently selected considering the age and sex match between clinical groups. Structural MRI acquisitions were pre-processed and analysed with a new longitudinal axis segmentation method, dividing the hippocampus in three subdivisions (anterior, intermediate, and posterior). When normalizing the volume of hippocampal sub-divisions to total hippocampus, the posterior hippocampus negatively correlates with age only in CN subjects (r = -.31). The longitudinal ratio of hippocampal atrophy (anterior sub-division divided by the posterior one) shows a significant increase with age only in CN (r = .25). Overall, in AD, the posterior hippocampus is predominantly atrophied early on. Consequently, the anterior/posterior hippocampal ratio is an AD differentiating metric at early disease stages with potential for diagnostic and prognostic applications.

Interleukin 33 supports squamous cell carcinoma growth via a dual effect on tumour proliferation, migration and invasion, and T cell activation.

Interleukin (IL)-33 is an important cytokine in the tumour microenvironment; it is known to promote the growth and metastasis of solid cancers, such as gastric, colorectal, ovarian and breast cancer. Our group demonstrated that the IL-33/ST2 pathway enhances the development of squamous cell carcinoma (SCC). Conversely, other researchers have reported that IL-33 inhibits tumour progression. In addition, the crosstalk between IL-33, cancer cells and immune cells in SCC remains unknown. The aim of this study was to investigate the effect of IL-33 on the biology of head and neck SCC lines and to evaluate the impact of IL-33 neutralisation on the T cell response in a preclinical model of SCC. First, we identified epithelial and peritumoural cells as a major local source of IL-33 in human SCC samples. Next, in vitro experiments demonstrated that the addition of IL-33 significantly increased the proliferative index, motility and invasiveness of SCC-25 cells, and downregulated MYC gene expression in SCC cell lines. Finally, IL-33 blockade significantly delayed SCC growth and led to a marked decrease in the severity of skin lesions. Importantly, anti-IL-33 monoclonal antibody therapy increase the percentage of CD4+IFNγ+ T cells and decreased CD4+ and CD8+ T cells secreting IL-4 in tumour-draining lymph nodes. Together, these data suggest that the IL-33/ST2 pathway may be involved in the crosstalk between the tumour and immune cells by modulating the phenotype of head and neck SCC and T cell activity. IL-33 neutralisation may offer a novel therapeutic strategy for SCC.

Combining Advanced Analytical Methodologies to Uncover Suspect PFAS and Fluorinated Pharmaceutical Contributions to Extractable Organic Fluorine in Human Serum (Tromsø Study).

A growing number of studies have reported that routinely monitored per- and polyfluoroalkyl substances (PFAS) are not sufficient to explain the extractable organic fluorine (EOF) measured in human blood. In this study, we address this gap by screening pooled human serum collected over 3 decades (1986-2015) in Tromsø (Norway) for >5000 PFAS and >300 fluorinated pharmaceuticals. We combined multiple analytical techniques (direct infusion Fourier transform ion cyclotron resonance mass spectrometry, liquid chromatography-Orbitrap-high-resolution mass spectrometry, and total oxidizable precursors assay) in a three-step suspect screening process which aimed at unequivocal suspect identification. This approach uncovered the presence of one PFAS and eight fluorinated pharmaceuticals (including some metabolites) in human serum. While the PFAS suspect only accounted for 2-4% of the EOF, fluorinated pharmaceuticals accounted for 0-63% of the EOF, and their contribution increased in recent years. Although fluorinated pharmaceuticals often contain only 1-3 fluorine atoms, our results indicate that they can contribute significantly to the EOF. Indeed, the contribution from fluorinated pharmaceuticals allowed us to close the organofluorine mass balance in pooled serum from 2015, indicating a good understanding of organofluorine compounds in humans. However, a portion of the EOF in human serum from 1986 and 2007 still remained unexplained.

Isolation and characterisation of Leishmania (Leishmania) infantum from cutaneous leishmaniasis patients in northeast Brazil.

BACKGROUND: In Brazil, Leishmania (Leishmania) infantum is a widely distributed protozoan parasite. The human leishmaniasis caused by this species is often associated with visceral form. Tegumentary leishmaniasis (TL) cases due to L. (L.) infantum in the country are considered rare but may be underestimated. Although probably uncommon, these cases represent a new challenge to the prevention and control of leishmaniasis. OBJECTIVES: Here, we describe two distinct cases of TL with atypical clinical presentations caused by L. (L.) infantum. METHODS AND FINDINGS: Parasites were isolated from cutaneous lesions of the two patients and typed as L. (L.) infantum after sequencing of the ribosomal DNA internal transcribed spacer. The dermotropic L. (L.) infantum isolates were compared in terms of growth culture patterns, metacyclogenesis and in vitro infectivity in macrophages. MAIN CONCLUSIONS: This study addresses the emergence of L. (L.) infantum as a causative agent of cutaneous disease in a visceral leishmaniasis hotspot located in northeast Brazil. The data presented provides novel information about the presence of dermotropic L. (L.) infantum in the country and demonstrates the infectivity potential of theses isolates.

Acute generalized exanthematous pustulosis triggered by COVID-19.

Acute generalized exanthematous pustulosis is a severe adverse skin reaction, usually caused by drugs, but in rare cases it can be associated with infections. Several cases related to COVID-19 have been reported, however, almost all were drug-related. Here we report a case of acute generalized exanthematous pustulosis associated with COVID-19 in a previously healthy 64-year-old woman, with no culprit drugs.

Effects of Mannosylerythritol-Lipids-B on Cutibacterium acnes ATCC 6919.

Mannosylerythritol-lipids-B (MEL-B) are microbial-produced glycolipids with skincare properties, notably moisturizing, antimelanogenic, antimicrobial, and antiaging. Thus, there is a potential use of MEL-B in a formulation for treating acne-prone skin. This study investigated the antimicrobial effect of MEL-B against the Gram-positive bacteria Cutibacterium acnes. The broth macro dilution method was used to evaluate the growth of C. acnes (3-4 CFU/mL), in the absence (positive control) or presence of MEL-B (128, 192, 256, and 512 µg/mL). Additionally, the leakage of genetic materials was used to determine the potential drug-induced membrane disruption of glycolipids. The amount of DNA and RNA release was quantified spectrophotometrically at 260 nm. Macro dilution technique and membrane integrity experiments showed that MEL-B does not have antimicrobial activity against C. acnes. Indeed, MEL-B assisted C. acnes growth. Ultimately, MEL-B has been reported as a remarkably active compound for skincare formulations; however, preliminarily, it should be avoided for acneic skin.

Ehrlichia canis and Rickettsia conorii Infections in Shelter Dogs: Seropositivity and Implications for Public Health.

A cross-sectional study was conducted to gain insight into the epidemiology of canine ehrlichiosis and rickettsiosis in northern Portugal. Specific IgG antibodies to Ehrlichia canis were analysed using a commercial enzyme-linked immunosorbent assay (ELISA), and antibodies to Rickettsia conorii were analysed using a commercial indirect immunofluorescence antibody test (IFAT). A total of 113 dogs from two different shelters were sampled, and seroprevalence values of 0.9% (95% confidence (CI): 0.2-4.8%) for E. canis and 9.7 (95% CI: 5.5-16.6%) for R. conorii were found. Multiple logistic regression investigated risk factors for seropositivity. The odds ratios (ORs) of R. conorii seropositivity were higher for female dogs (OR = 6.429; 95% CI: 1.201-34.407). Dogs seropositive for co-infection (E. canis + R. conorii) were more frequently observed among females (OR = 7.606; CI 95%: 1.478-39.132) and in Shelter 2 (OR = 18.229; 95% CI: 2.190-151.756). These findings show that shelter dogs in northern Portugal are exposed to E. canis and R. conorii, which can affect both canines and humans. It is imperative to adopt a One Health approach to educate the public about the hazards of canine zoonoses and develop legislation and procedures to control their spread and preserve public health.

Shoulder Pain - Don't Forget First Rib Fractures.

First rib fractures are uncommon, mainly in paediatric population, considering its anatomic features and their skeleton plasticity. Traditional teaching usually characterizes it as a hallmark of severe trauma. Herein, to unfold awareness to an unnoticed diagnosis, we describe two paediatric cases of isolated first rib fracture in adolescents without a clear identifiable cause nor an underlining trauma mechanism. Neurovascular injuries should always be investigated, as fracture of the first rib with ensuing callus formation is a rare but fearing cause of thoracic outlet syndrome. We highlight the scarcity of reports on isolated first rib fractures outside of sports medicine, as well as the importance of considering this otherwise easily missed diagnosis in a common complaint in children.

A study of knowledge, attitudes, and practices on ticks and tick-borne diseases of cattle among breeders of two bovine Portuguese autochthonous breeds.

Beef cattle production in Portugal is an important sector of national agricultural production, with half of the herd being in the Alentejo region. Despite this, animal health is essential for its productivity, which may be compromised by ticks and tick-borne diseases. So far, no study has been conducted in Portugal to assess knowledge, attitudes, and practices (KAP) on ticks and tick-borne diseases in cattle, which the authors are aware of. This type of questionnaire is a very useful tool in the development and application of effective and sustainable prevention and control measures. Therefore, a KAP questionnaire was applied to 44 cattle breeders of autochthonous Portuguese breeds, namely 14 breeders of the Alentejana breed and 30 of the Mertolenga breed, between January 1 and May 9, 2023. Based on the analysis criteria of these surveys, 64% of the Alentejana breeders and 63% of the Mertolenga breeders have an average level of knowledge about ticks and tick-borne diseases, and 21% of the Alentejana breeders and 33% of the Mertolenga breeders have a high level of knowledge. Although only 21.4% of the Alentejana and 36.7% of the Mertolenga breeders consider tick infestation as a major animal health problem, 71.4% of the Alentejana and 63.3% of breeders of the Mertolenga state that one of the main reasons for veterinary consultations on their farm is deworming of animals, and 92.9% of breeders of the Alentejana and 96.7% of breeders of the Mertolenga refer the use of dewormers as a strategy to control tick infestation. The results of this study contribute to highlighting the importance of correcting some identified knowledge gaps and improving knowledge, especially on the life cycle of this parasite, its local distribution and seasonality, resistance to acaricides, and alternative control strategies.

Redox Regulation of LAT Enhances T Cell-Mediated Inflammation.

The positional cloning of single nucleotide polymorphisms (SNPs) of the neutrophil cytosolic factor 1 (Ncf1) gene, advocating that a low oxidative burst drives autoimmune disease, demands an understanding of the underlying molecular causes. A cellular target could be T cells, which have been shown to be regulated by reactive oxygen species (ROS). However, the pathways by which ROS mediate T cell signaling remain unclear. The adaptor molecule linker for activation of T cells (LAT) is essential for coupling T cell receptor-mediated antigen recognition to downstream responses, and it contains several cysteine residues that have previously been suggested to be involved in redox regulation. To address the possibility that ROS regulate T cell-dependent inflammation through LAT, we established a mouse strain with cysteine-to-serine mutations at positions 120 and 172 (LATSS). We found that redox regulation of LAT through C120 and C172 mediate its localization and phosphorylation. LATSS mice had reduced numbers of double-positive thymocytes and naïve peripheral T cells. Importantly, redox insensitivity of LAT enhanced T cell-dependent autoimmune inflammation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). This effect was reversed on an NCF1-mutated (NCF1m1j), ROS-deficient, background. Overall, our data show that LAT is redox-regulated, acts to repress T cell activation, and is targeted by ROS induced by NCF1 in antigen-presenting cells (APCs).

Noradrenergic Pathways Involved in Micturition in an Animal Model of Hydrocephalus-Implications for Urinary Dysfunction.

Hydrocephalus is characterized by enlargement of the cerebral ventricles, accompanied by distortion of the periventricular tissue. Patients with hydrocephalus usually experience urinary impairments. Although the underlying etiology is not fully described, the effects of hydrocephalus in the neuronal network responsible for the control of urination, which involves periventricular areas, including the periaqueductal gray (PAG) and the noradrenergic locus coeruleus (LC). In this study, we aimed to investigate the mechanisms behind urinary dysfunction in rats with kaolin-induced hydrocephalus. For that purpose, we used a validated model of hydrocephalus-the rat injected with kaolin in the cisterna magna-also presents urinary impairments in order to investigate the putative involvement of noradrenergic control from the brain to the spinal cord Onuf's nucleus, a key area in the motor control of micturition. We first evaluated bladder contraction capacity using cystometry. Since our previous characterization of the LC in hydrocephalic animals showed increased levels of noradrenaline, we then evaluated the noradrenergic innervation of the spinal cord's Onuf's nucleus by measuring levels of dopamine ß-hydroxylase (DBH). We also evaluated the expression of the c-Fos protooncogene, the most widely used marker of neuronal activation, in the ventrolateral PAG (vlPAG), an area that plays a major role in the control of urination by its indirect control of the LC via pontine micturition center. Hydrocephalic rats showed an increased frequency of bladder contractions and lower minimum pressure. These animals also presented increased DBH levels at the Onuf´s nucleus, along with decreased c-Fos expression in the vlPAG. The present findings suggest that impairments in urinary function during hydrocephalus may be due to alterations in descending noradrenergic modulation. We propose that the effects of hydrocephalus in the decrease of vlPAG neuronal activation lead to a decrease in the control over the LC. The increased availability of noradrenaline production at the LC probably causes an exaggerated micturition reflex due to the increased innervation of the Onuf´s nucleus, accounting for the urinary impairments detected in hydrocephalic animals. The results of the study provide new insights into the neuronal underlying mechanisms of urinary dysfunction in hydrocephalus. Further research is needed to fully evaluate the translational perspectives of the current findings.

A Genome-Wide Association Study for Resistance to Tropical Theileriosis in Two Bovine Portuguese Autochthonous Breeds.

The control of Tropical Theileriosis, a tick-borne disease with a strong impact on cattle breeding, can be facilitated using marker-assisted selection in breeding programs. Genome-wide association studies (GWAS) using high-density arrays are extremely important for the ongoing process of identifying genomic variants associated with resistance to Theileria annulata infection. In this work, single-nucleotide polymorphisms (SNPs) were analyzed in the Portuguese autochthonous cattle breeds Alentejana and Mertolenga. In total, 24 SNPs suggestive of significance (p ≤ 10-4) were identified for Alentejana cattle and 20 SNPs were identified for Mertolenga cattle. The genomic regions around these SNPs were further investigated for annotated genes and quantitative trait loci (QTLs) previously described by other authors. Regarding the Alentejana breed, the MAP3K1, CMTM7, SSFA2, and ATG13 genes are located near suggestive SNPs and appear as candidate genes for resistance to Tropical Theileriosis, considering its action in the immune response and resistance to other diseases. On the other hand, in the Mertolenga breed, the UOX gene is also a candidate gene due to its apparent link to the pathogenesis of the disease. These results may represent a first step toward the possibility of including genetic markers for resistance to Tropical Theileriosis in current breed selection programs.

Caveolin scaffolding domain (CSD) peptide LTI-2355 modulates the phagocytic and synthetic activity of lung derived myeloid cells in Idiopathic Pulmonary Fibrosis (IPF) and Post-acute sequelae of COVID-fibrosis (PASC-F).

Rationale: The role of the innate immune system in Idiopathic Pulmonary Fibrosis (IPF) remains poorly understood. However, a functional myeloid compartment is required to remove dying cells and cellular debris, and to mediate innate immune responses against pathogens. Aberrant macrophage activity has been described in patients with Post-acute sequelae of COVID fibrosis (PASC-F). Therefore, we examined the functional and synthetic properties of myeloid cells isolated from normal donor lung and lung explant tissue from both IPF and PASC-F patients and explored the effect of LTI-2355, a Caveolin Scaffolding Domain (CSD) peptide, on these cells. Methods & Results: CD45 + myeloid cells isolated from lung explant tissue from IPF and PASC-F patients exhibited an impaired capacity to clear autologous dead cells and cellular debris. Uptake of pathogen-coated bioparticles was impaired in myeloid cells from both fibrotic patient groups independent of type of pathogen highlighting a cell intrinsic functional impairment. LTI-2355 improved the phagocytic activity of both IPF and PASC-F myeloid cells, and this improvement was paired with decreased pro-inflammatory and pro-fibrotic synthetic activity. LTI-2355 was also shown to primarily target CD206-expressing IPF and PASC-F myeloid cells. Conclusions: Primary myeloid cells from IPF and PASC-F patients exhibit dysfunctional phagocytic and synthetic properties that are reversed by LTI-2355. Thus, these studies highlight an additional mechanism of action of a CSD peptide in the treatment of IPF and progressive fibrotic lung disease.

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-neutrophil (PN) index in locally advanced rectal cancer patients: a retrospective cohort study.

Introduction: In locally advanced rectal cancers (LARC), tumour node metastasis (TNM) staging is far from optimal. The authors aimed to investigate the value of previously described circulating biomarkers as predictors of prognosis. Methods: Retrospective analysis of 245 LARC patients diagnosed between January 2010 and December 2022, who underwent neoadjuvant chemoradiotherapy and surgery at two centres. A Cox regression and Kaplan-Meier analysis were performed. Results: Post-treatment platelet-to-lymphocyte ratio (PLR) predicted pathological complete response. The neutrophil-to-lymphocyte ratio (NLR) in two timepoints of the treatment significantly predicted overall survival, whereas the platelet-neutrophil (PN) index significantly predicted disease-free survival. In pathological stage II, the PN index predicted patients with a higher risk of disease-free survival. Conclusion: Blood parameters might allow the definition of subgroups of risk beyond TNM for the application of different therapeutic strategies.

Mycobacterium avium subsp. paratuberculosis in Wild Boar (Sus scrofa) in Portugal.

Paratuberculosis, or Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis affecting both domestic and wild ruminants. The agent was also found in wild mammals such as wild boar (Sus scrofa); however, the role of wild mammals in the epidemiology of MAP is unclear. During the research period, 941 free-ranging wild boar (S. scrofa) legally hunted in two locations in the central-eastern region of Portugal were examined. Ninety-seven wild boars exhibited one or more gross lesions and were tested for the presence of Mycobacterium avium subsp. paratuberculosis using acid-fast staining, mycobacterial culture, polymerase chain reaction (PCR), and histopathological examination. Forty-five animals (46.4%, 95% CI: 36.5-56.3%) were identified as infected, as indicated by positive results in culture and/or PCR. The findings revealed that the most significant risk factor was being a juvenile compared to yearlings and adults (OR = 10.2, 95% CI: 2.2-48.0). Based on our results, 37.9% (n = 11) of the infected animals were considered suitable for human consumption. Our findings offer novel insights into mycobacterial infections in wild boar populations in Portugal and suggest that wild boar could be a source of human infection if zoonotic potential is considered.

Pre-clinical proof-of-concept of anti-fibrotic activity of caveolin-1 scaffolding domain peptide LTI-03 in ex vivo precision cut lung slices from patients with Idiopathic Pulmonary Fibrosis.

Rationale: While rodent lung fibrosis models are routinely used to evaluate novel antifibrotics, these models have largely failed to predict clinical efficacy of novel drug candidates for Idiopathic Pulmonary Fibrosis (IPF). Moreover, single target therapeutic strategies for IPF have failed and current multi-target standard of care drugs are not curative. Caveolin-1 (CAV-1) is an integral membrane protein, which, via its caveolin scaffolding domain (CSD), interacts with caveolin binding domains (CBD). CAV-1 regulates homeostasis, and its expression is decreased in IPF lungs. LTI-03 is a seven amino acid peptide derived from the CSD and formulated for dry powder inhalation; it was well tolerated in normal volunteers ( NCT04233814 ) and a safety trial is underway in IPF patients ( NCT05954988 ). Objectives: Anti-fibrotic efficacy of LTI-03 and other CSD peptides has been observed in IPF lung monocultures, and rodent pulmonary, dermal, and heart fibrosis models. This study aimed to characterize progressive fibrotic activity in IPF PCLS explants and to evaluate the antifibrotic effects of LTI-03 and nintedanib in this model. Methods: First, CBD regions were identified in IPF signaling proteins using in silico analysis. Then, IPF PCLS (n=8) were characterized by COL1A1 immunostaining, multiplex immunoassays, and bulk RNA sequencing following treatment every 12hrs with LTI-03 at 0.5, 3.0, or 10 µM; nintedanib at 0.1 µM or 1 µM; or control peptide (CP) at 10 µM. Measurements and Main Results: CBDs were present in proteins implicated in IPF, including VEGFR, FGFR and PDGFR. Increased expression of profibrotic mediators indicated active fibrotic activity in IPF PCLS over five days. LTI-03 dose dependently decreased COL1A1 staining, and like nintedanib, decreased profibrotic proteins and transcripts. Unlike nintedanib, LTI-03 did not induce cellular necrosis signals. Conclusion: IPF PCLS explants demonstrate molecular activity indicative of fibrosis during 5 days in culture and LTI-03 broadly attenuated pro-fibrotic proteins and pathways, further supporting the potential therapeutic effectiveness of LTI-03 for IPF.

HR/MS-based lipidome analysis of rat brain modulated by tolcapone.

Lipids play key roles in the body, influencing cellular regulation, function, and signalling. Tolcapone, a potent catechol-O-methyltransferase (COMT) inhibitor described to enhance cognitive performance in healthy subjects, was previously shown to impact fatty acid ß-oxidation and oxidative phosphorylation. However, its impact on the brain lipidome remains unexplored. Hence, this study aimed to assess how tolcapone affects the lipidome of the rat pre-frontal cortex (PFC), a region of the brain highly relevant to tolcapone therapeutic effect, while evaluating its influence on operant behaviour. Tolcapone at 20 mg/kg was chronically administered to Wistar rats during a behavioural task and an untargeted liquid chromatography high-resolution mass spectrometry (LC-HR/MS) approach was employed to profile lipid species. The untargeted analysis identified 7227 features, of which only 33% underwent statistical analysis following data pre-processing. The results revealed an improved cognitive performance and a lipidome remodelling promoted by tolcapone. The lipidomic analysis showed 32 differentially expressed lipid species in tolcapone-treated animals (FC ≥ 1.2, p-value ≤ 0.1), and among these several triacylglycerols, cardiolipins and N-acylethanolamine (NAE 16:2) were found upregulated whereas fatty acids, hexosylceramides, and several phospholipids including phosphatidylcholines and phosphatidylethanolamines were downregulated. These preliminary findings shed light on tolcapone impact on lipid pathways within the brain. Although tolcapone improved cognitive performance and literature suggests the significance of lipids in cognition, this study did not conclusively establish that lipids directly drove or contributed to this outcome. Nevertheless, it underscores the importance of lipid modulation and encourages further exploration of tolcapone-associated mechanisms in the central nervous system (CNS).

Septic Shock: LPS tolerance protects mitochondrial biogenesis and respiration.

ABSTRACT: Mitochondrial dysfunction is a recognized feature of sepsis, characterized by ultrastructural damage, diminished oxidative phosphorylation, and depletion of mitochondrial antioxidant capacity observed in deceased septic patients. Lipopolysaccharide (LPS) tolerance induces a controlled response to sepsis. This study aimed to evaluate the function of tolerant mitochondria after cecal ligation and puncture (CLP)-induced sepsis. Mytochondrial oxygen consumption was determined using polarography. Extraction and quantification of RNA for the expression of Tfam, Nrf-1 and Ppargc-1α; and Respiratory complex activity were measured. CLP-tolerant animals presented preserved respiratory rates of S3 and S4 and a ratio of respiratory control (RCR) compared to CLP non-tolerant animals with reduced oxidative phosphorylation and increased uncoupled respiration. Complex I Vmax was reduced in septic animals; however, CLP animals sustained normal Vmax. Mitochondrial biogenesis was preserved in CLP-tolerant animals compared to the CLP-nontolerant group, likely due to increased TFAM expression. LPS tolerance protected septic animals from mitochondrial dysfunction, favoring mitochondrial biogenesis and preserving mitochondrial respiration and respiratory complex I activity.