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IntroductionEarly focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional gray matter growth in childhood and adolescence, while accounting for lesion characteristics.MethodsWe relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at ages 7 and 16 were compared to age-matched controls. Non-lesioned volumes of gray matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F; Controls: 17 M, 18 F) and 16 (Patients: 18 M, 11 F; Controls: 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics.ResultsWhole hemisphere volumes were reduced at both ages in patients compared to controls (gray matter volume: −16% in males, −10% in females). In ipsilesional hemisphere, cortical gray matter and thalamic volume losses (average −13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in gray matter volumes, as only male volumes were smaller than in male controls (average −7.5%), mostly in territories mirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of female controls. Similar sex differences were found in both cerebellar hemispheres.DiscussionThese results suggest sex-dependent growth trajectories after an early brain lesion with a contralesional growth deficit in males only. The similarity of patterns at ages 7 and 16 suggests that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well-described perinatal vulnerability of the male brain, and with no compensation thereafter.

Introduction: Early focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional gray matter growth in childhood and adolescence, while accounting for lesion characteristics. Methods: We relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at ages 7 and 16 were compared to age-matched controls. Non-lesioned volumes of gray matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F; Controls: 17 M, 18 F) and 16 (Patients: 18 M, 11 F; Controls: 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics. Results: Whole hemisphere volumes were reduced at both ages in patients compared to controls (gray matter volume: -16% in males, -10% in females). In ipsilesional hemisphere, cortical gray matter and thalamic volume losses (average -13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in gray matter volumes, as only male volumes were smaller than inmale controls (average-7.5%), mostly in territoriesmirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of female controls. Similar sex differences were found in both cerebellar hemispheres. Discussion: These results suggest sex-dependent growth trajectories after an early brain lesion with a contralesional growth deficit in males only. The similarity of patterns at ages 7 and 16 suggests that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well-described perinatal vulnerability of themale brain, and with no compensation thereafter. [ABSTRACT FROM AUTHOR]

Abstract Background Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). Methods Mammary fibroblasts from either female 8 weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test. Results We show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors. Conclusions These data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer.

Background. Cardiogenic shock caries high mortality and morbidity. Myocarditis patients developing cardiogenic shock refractory to medical treatment might benefit from extracorporeal membrane oxygenation or mechanical ventricular assist devices. Methods. A retrospective, single center observational study to assess the rate and outcomes of mechanical circulatory support of patients with fulminant myocarditis related cardiogenic shock. Short-term outcomes were evaluated. The primary endpoint of the study was hospital survival. Results. Two hundred ninetyone patient were supported with short-term mechanical assist devices at our institution during 12 year period. Among them, 4 (1.4%) were treated for myocarditis related cardiogenic shock. All patients were female, with a mean age of 34±4 years. In one case surgically implantable short-term mechanical assist device was used, in other three cases – extracorporeal membrane oxygenation. The mean duration of the support was 364±273 hours, mean intensive care unit stay – 35±29 days. Three of four patients were successfully weaned from the support and discharged from the hospital with complete heart function recovery. Conclusion. Patient with fulminant myocarditis, who would have died without the initiation of mechanical circulatory, had favorable short-term outcome with 75% survival rate.

Non-obese diabetic (NOD) mice are well-established models of independently developing spontaneous autoimmune diseases, Sjögren's syndrome (SS) and type 1 diabetes (T1D). The key determining factor for T1D is the strong association with particular MHCII molecule and recognition by diabetogenic T cell receptor (TCR) of an insulin peptide presented in the context of I-Ag7 molecule. For SS the association with MHCII polymorphism is weaker and TCR diversity involved in the onset of the autoimmune phase of SS remains poorly understood. To compare the impact of TCR diversity reduction on the development of both diseases we generated two lines of TCR transgenic NOD mice. One line expresses transgenic TCRβ chain originated from a pathogenically irrelevant TCR, and the second line additionally expresses transgenic TCRαmini locus. Analysis of TCR sequences on NOD background reveals lower TCR diversity on Treg cells not only in the thymus, but also in the periphery. This reduction in diversity does not affect conventional CD4+ T cells, as compared to the TCRmini repertoire on B6 background. Interestingly, neither transgenic TCRβ nor TCRmini mice develop diabetes, which we show is due to lack of insulin B:9-23 specific T cells in the periphery. Conversely SS develops in both lines, with full glandular infiltration, production of autoantibodies and hyposalivation. It shows that SS development is not as sensitive to limited availability of TCR specificities as T1D, which suggests wider range of possible TCR/peptide/MHC interactions driving autoimmunity in SS.

Pregnenolone is a steroid with specific characteristics, being the first steroid to be synthesised from cholesterol at all sites of steroidogenesis, including the brain. For many years, pregnenolone was defined as an inactive precursor of all steroids because no specific target had been discovered. However, over the last decade, it has become a steroid of interest because it has been recognised as being a biomarker for brain‐related disorders through the development of metabolomic approaches and advanced analytical methods. In addition, physiological roles for pregnenolone emerged when specific targets were discovered. In this review, we highlight the discovery of the selective interaction of pregnenolone with the type‐1 cannabinoid receptor (CB1R). After describing the specific characteristic of CB1Rs, we discuss the newly discovered mechanisms of their regulation by pregnenolone. In particular, we describe the action of pregnenolone as a negative allosteric modulator and a specific signalling inhibitor of the CB1R. These particular characteristics of pregnenolone provide a great strategic opportunity for therapeutic development in CB1‐related disorders. Finally, we outline new perspectives using innovative genetic tools for the discovery of original regulatory mechanisms of pregnenolone on CB1‐related functions. [ABSTRACT FROM AUTHOR]