Adrenal failure followed by status epilepticus and hemolytic anemia in primary antiphospholipid syndrome

We report on a 14 year old boy who presented with the symptoms abdominal pain, fever and proteinuria. A hematoma in the region of the right pararenal space was diagnosed. Prothrombin time and activated partial thromboplastin time were prolonged, lupus anticoagulant and anticardiolipin antibodies were positive and serum cortisol was normal. Ten days after admission the boy suddenly suffered generalized seizures due to low serum sodium. As well, the patient developed hemolytic anemia, acute elevated liver enzymes, hematuria and increased proteinuria. At this time a second hemorrhage of the left adrenal gland was documented. Adrenal function tests revealed adrenal insufficiency. We suspected microthromboses in the adrenals and secondary bleeding and treated the boy with hydrocortisone, fludrocortisone and phenprocoumon. CONCLUSION: Adrenal failure is a rare complication of APS in children with only five cases reported to date. As shown in our patient, this syndrome can manifest in a diverse set of simultaneously occurring symptoms

Neuroprotective strategies for ischemic stroke—Future perspectives

Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from “traditional” neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota–gut–brain axis that may serve as a potential target for future neuroprotective therapies

Preconditioning concepts for the therapeutic use of extracellular vesicles against stroke

Various preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke

Peak Troponin I Levels Are Associated with Functional Outcome in Intracerebral Hemorrhage

Background: Troponin I is a widely used and reliable marker of myocardial damage and its levels are routinely measured in acute stroke care. So far, the influence of troponin I elevations during hospital stay on functional outcome in patients with atraumatic intracerebral hemorrhage (ICH) is unknown. Methods: Observational single-center study including conservatively treated ICH patients over a 9-year period. Patients were categorized according to peak troponin I level during hospital stay (≤0.040, 0.041–0.500, > 0.500 ng/mL) and compared regarding baseline and hematoma characteristics. Multivariable analyses were performed to investigate independent associations of troponin levels during hospital stay with functional outcome – assessed using the modified Rankin Scale (mRS; favorable 0–3/unfavorable 4–6) – and mortality after 3 and 12 months. To account for possible confounding propensity score (PS)-matching (1: 1; caliper 0.1) was performed accounting for imbalances in baseline characteristics to investigate the impact of troponin I values on outcome. Results: Troponin elevations (> 0.040 ng/mL) during hospital stay were observed in 308 out of 745 (41.3%) patients and associated with poorer status on admission (Glasgow Coma Scale/National Institute of Health Stroke Scale). Multivariable analysis revealed troponin I levels during hospital stay to be independently associated with unfavorable outcome after 12 months (risk ratio [95% CI]: 1.030 [1.009–1.051] per increment of 1.0 ng/mL; p = 0.005), but not with mortality. After PS-matching, patients with troponin I elevation (≥0.040 ng/mL) versus those without had a significant higher rate of ­unfavorable outcome after 3 and 12 months (mRS 4–6 at 3 months: < 0.04 ng/mL: 159/265 [60.0%] versus ≥0.04 ng/mL: 199/266 [74.8%]; p < 0.001; at 12 months: < 0.04 ng/mL: 141/248 [56.9%] versus ≥0.04 ng/mL: 179/251 [71.3%]; p = 0.001). Conclusions: Troponin I elevations during hospital stay occur frequently in ICH patients and are independently associated with functional outcome after 3 and 12 months but not with mortality

Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype

Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker’s hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases

TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality ; China Scholarship Counci

Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial

Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep–wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150 mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150 mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10 days of caffeine intake compared with 10 days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes

Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial

Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep-wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150 mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150 mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10 days of caffeine intake compared with 10 days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes