Junctional adhesion molecule-A deficient mice are protected from severe experimental autoimmune encephalomyelitis.

In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood-brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule-A (JAM-A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM-A expression at the blood-brain barrier and its luminal redistribution during aEAE. JAM-A deficient (JAM-A-/-) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein-specific CD4+ T-cell priming. While JAM-A absence influenced macrophage behavior on primary mouse brain microvascular endothelial cells (pMBMECs) under flow in vitro, it did not impact T-cell extravasation across primary mouse brain microvascular endothelial cells. At aEAE onset, we observed reduced lymphocyte and CCR2+ macrophage infiltration into the spinal cord of JAM-A-/- mice compared to control littermates. This correlated with increased CD3+ T-cell accumulation in spinal cord perivascular spaces and brain leptomeninges, suggesting JAM-A absence leads to T-cell trapping in central nervous system border compartments. In summary, JAM-A plays a role in immune cell infiltration and clinical disease progression in aEAE.

Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes.

Oligodendrocytes (ODCs) are myelinating cells of the central nervous system (CNS) supporting neuronal survival. Oxidants and mitochondrial dysfunction have been suggested as the main causes of ODC damage during neuroinflammation as observed in multiple sclerosis (MS). Nonetheless, the dynamics of this process remain unclear, thus hindering the design of neuroprotective therapeutic strategies. To decipher the spatio-temporal pattern of oxidative damage and dysfunction of ODC mitochondria in vivo, we created a novel mouse model in which ODCs selectively express the ratiometric H2 O2 biosensor mito-roGFP2-Orp1 allowing for quantification of redox changes in their mitochondria. Using 2-photon imaging of the exposed spinal cord, we observed significant mitochondrial oxidation in ODCs upon induction of the MS model experimental autoimmune encephalomyelitis (EAE). This redox change became already apparent during the preclinical phase of EAE prior to CNS infiltration of inflammatory cells. Upon clinical EAE development, mitochondria oxidation remained detectable and was associated with a significant impairment in organelle density and morphology. These alterations correlated with the proximity of ODCs to inflammatory lesions containing activated microglia/macrophages. During the chronic progression of EAE, ODC mitochondria maintained an altered morphology, but their oxidant levels decreased to levels observed in healthy mice. Taken together, our study implicates oxidative stress in ODC mitochondria as a novel pre-clinical sign of MS-like inflammation and demonstrates that evolving redox and morphological changes in mitochondria accompany ODC dysfunction during neuroinflammation.

Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer's disease mouse model.

Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer's disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this. We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid ß (Aß) pathology at an early (4month old) and at a more advanced pathological (10month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Aß neuropathology. ES exposure resulted in a reduction of cell-associated amyloid in 4month old APP/PS1 mice, but in an exacerbation of Aß plaque load at 10months of age, demonstrating that ES affects Aß load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Aß neuropathology. In WT mice, immediately following ES exposure (P9), Iba1-immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1ß expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4months, while these changes resolved by 10months of age. Finally, Aß neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4months, which was further enhanced by ES, whereas the microglial response to Aß neuropathology, as measured by Iba1 and CD11b, was less prominent after ES at 10months of age. Finally, the hippocampus appears to be more vulnerable for these ES-induced effects, since ES did not affect Aß neuropathology and neuroinflammation in the entorhinal cortex of adult ES exposed mice. Overall, our results demonstrate that ES exposure has both immediate and lasting effects on the neuroinflammatory response. In the context of AD, such alterations in neuroinflammation might contribute to aggravated neuropathology in ES exposed mice, hence altering disease progression. This indicates that, at least in a genetic context, ES could aggravate AD pathology.

Emergency medicine in the general practice internship in Finnmark county. / Akuttmedisinsk turnusarbeid i Finnmark.

BACKGROUND: It is preferred that duty doctors in municipal health services participate in call-outs in emergency situations. The frequency of participation has previously been shown to vary. We wanted to examine the newly qualified doctors' expectations and experiences ­ both before and after the general practice internship ­ of emergency medicine and ambulance call-outs. MATERIAL AND METHOD: All 23 of the interns who were to undertake their general practice internship in Finnmark county in the period 2015­16 answered a questionnaire and participated in a focus group interview before the start of the internship. Twenty-one of the interns participated in the focus group interview after completing the internship. Each doctor took part in two interviews. We analysed the transcripts from the focus group interviews using the grounded theory method. RESULTS: The responses from the questionnaire before the general practice internship showed that the interns felt they needed more training in intravenous cannulation and in teamwork. Their expectations in connection with the challenges of call-outs are best characterised by the core category 'Can I do anything useful?' from the focus groups before the internship. After the internship, however, the core category 'It all went well in the end', was the best fit. Due to short transport times and their knowledge of certain patients, some of the doctors chose not to take part in call-outs. INTERPRETATION: During the general practice internship, the interns were initially anxious about whether they might be superfluous in call-outs, but eventually found their footing in the call-out role. The study shows that there is a need for more practice in certain practical procedures, and that doctors' non-technical skills need to be improved. This can be done through training in team leader roles before the general practice internship.

Insulin-like growth factor-1 receptor controls the function of CNS-resident macrophages and their contribution to neuroinflammation.

Signaling by insulin-like growth factor-1 (IGF-1) is essential for the development of the central nervous system (CNS) and regulates neuronal survival and myelination in the adult CNS. In neuroinflammatory conditions including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), IGF-1 can regulate cellular survival and activation in a context-dependent and cell-specific manner. Notwithstanding its importance, the functional outcome of IGF-1 signaling in microglia/macrophages, which maintain CNS homeostasis and regulate neuroinflammation, remains undefined. As a result, contradictory reports on the disease-ameliorating efficacy of IGF-1 are difficult to interpret, together precluding its potential use as a therapeutic agent. To fill this gap, we here investigated the role of IGF-1 signaling in CNS-resident microglia and border associated macrophages (BAMs) by conditional genetic deletion of the receptor Igf1r in these cell types. Using a series of techniques including histology, bulk RNA sequencing, flow cytometry and intravital imaging, we show that absence of IGF-1R significantly impacted the morphology of both BAMs and microglia. RNA analysis revealed minor changes in microglia. In BAMs however, we detected an upregulation of functional pathways associated with cellular activation and a decreased expression of adhesion molecules. Notably, genetic deletion of Igf1r from CNS-resident macrophages led to a significant weight gain in mice, suggesting that absence of IGF-1R from CNS-resident myeloid cells indirectly impacts the somatotropic axis. Lastly, we observed a more severe EAE disease course upon Igf1r genetic ablation, thus highlighting an important immunomodulatory role of this signaling pathway in BAMs/microglia. Taken together, our work shows that IGF-1R signaling in CNS-resident macrophages regulates the morphology and transcriptome of these cells while significantly decreasing the severity of autoimmune CNS inflammation.

Gender differences in work-life balance of European neurosurgeons.

Introduction: Neurosurgery is one of the most demanding medical specialties. For neurosurgeons, balancing professional activity with personal life can be challenging. Research question: To evaluate gender differences in contribution of neurosurgeons in the household and child-rearing, as well as their impact on personal life and career. Material and methods: An anonymous, electronic, 59-item web-based survey was administered to National Neurosurgical Societies of Europe, and European Member Societies of the European Association of Neurosurgical Societies (June-October 2021). Results: A total of 205 European neurosurgeons (87 females and 118 males, mean age 40.7) are included in our survey. In neurosurgery, females are significantly more likely to be alone (37.9%), while males are significantly more likely to have children (66.9%). In terms of household efforts, females spend more time than males on the same tasks. Most participants (71.2%) view gender issues as a disadvantage in career pursuing. Women feel less accepted (54.3%) and having fewer opportunities (58.6%), while men believe that pregnancy/child-rearing (65.8%) and having many roles (51.3%) are the main obstacles. Both genders (77.6%) favor more convenient working conditions for young parents.Discussion and Conclusion. In our study we found that, women neurosurgeons take more responsibilities at home, especially in the child-rearing years. Female neurosurgeons are more likely to live alone or stay childless more often compared to their male colleagues. Supportive facilities, flexible programs, universal life policies and presumably curbing of the social stereotypes are of importance to overcome gender inequities that women are still facing in neurosurgery.

Central Nervous System Barriers Impact Distribution and Expression of iNOS and Arginase-1 in Infiltrating Macrophages During Neuroinflammation.

In multiple sclerosis (MS) and other neuroinflammatory diseases, monocyte-derived cells (MoCs) traffic through distinct central nervous system (CNS) barriers and gain access to the organ parenchyma exerting detrimental or beneficial functions. How and where these MoCs acquire their different functional commitments during CNS invasion remains however unclear, thus hindering the design of MS treatments specifically blocking detrimental MoC actions. To clarify this issue, we investigated the distribution of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory MoCs at the distinct border regions of the CNS in a mouse model of MS. Interestingly, MoCs within perivascular parenchymal spaces displayed a predominant pro-inflammatory phenotype compared to MoCs accumulating at the leptomeninges and at the intraventricular choroid plexus (ChP). Furthermore, in an in vitro model, we could observe the general ability of functionally-polarized MoCs to migrate through the ChP epithelial barrier, together indicating the ChP as a potential CNS entry and polarization site for MoCs. Thus, pro- and anti-inflammatory MoCs differentially accumulate at distinct CNS barriers before reaching the parenchyma, but the mechanism for their phenotype acquisition remains undefined. Shedding light on this process, we observed that endothelial (BBB) and epithelial (ChP) CNS barrier cells can directly regulate transcription of Nos2 (coding for iNOS) and Arg1 (coding for arginase-1) in interacting MoCs. More specifically, while TNF-α+IFN-γ stimulated BBB cells induced Nos2 expression in MoCs, IL-1ß driven activation of endothelial BBB cells led to a significant upregulation of Arg1 in MoCs. Supporting this latter finding, less pro-inflammatory MoCs could be found nearby IL1R1+ vessels in the mouse spinal cord upon neuroinflammation. Taken together, our data indicate differential distribution of pro- and anti-inflammatory MoCs at CNS borders and highlight how the interaction of MoCs with CNS barriers can significantly affect the functional activation of these CNS-invading MoCs during autoimmune inflammation.

Four Athenas - Europe's first female neurosurgeons.

In the early 20th century, a tumultuous era was yielding geopolitical and social change. Europe at large was undergoing redefinition of borders, political structures, and economies, while rebuilding societies after World War I. At the same time, neurosurgery was emerging as a new specialty, and women were allowed to study medicine for the first time in many European countries. These factors created a synergy, setting the stage for Europe's four first female neurosurgeons to emerge. In 1924, Germany's Alice Rosenstein began her neurosurgical career and contributed to the refinement of pneumoencephalography. Due to her Jewish background, she was forced to flee Europe, emigrating to the United States, where she did not continue to practice neurosurgery. In 1929, Russia's Serafima Bryusova began her neurosurgical training. She studied intracranial pressure in trephined patients and wrote the first Russian monograph on cerebral angiography before she was immobilized by severe arthritis. England's Diana Beck began her neurosurgical career in 1939. She contributed to the surgical treatment of intracerebral hemorrhage and researched idiopathic intracranial hypertension, even though many believed she could not be a successful surgeon due to her myasthenia gravis. In 1943, Romania's Sofia Ionescu started a prolific academic neurosurgical career. She developed a minimally-invasive technique to treat intracerebral hematomas and worked tirelessly to bring neurosurgery to all corners of her country. Europe's first women in neurosurgery were marked by war and adversity. Their stories carry within them a spirit of resilience, fortitude, and tenacity that continues to characterize women in neurosurgery today.

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System.

The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.