Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

The distal femoral epiphysis in forensic age diagnostics: studies on the evaluation of the ossification process by means of T1- and PD/T2-weighted magnetic resonance imaging.

The age of majority, which corresponds to the age of 18 years in most European countries, plays a crucial role for a large number of legal decisions. Accordingly, an increasing number of requests by authorities to forensic age estimation experts comprise the question of whether the age of 18 years has been reached by an individual. In recent years, novel study data suggested that magnetic resonance imaging (MRI) of the knee might likewise allow for the determination of majority beyond reasonable doubt. However, the data basis, especially concerning the distal femoral epiphysis (DFE), is still poor. For this reason, 392 routine MRI cases of the knee (204 males and 188 females of a Western Caucasian population, aged between 12 and 25 years) were retrospectively analyzed. T1-weighted and water-selective fat-saturated PD/T2-weighted sequences, generated at 1.5 and 3.0 T clinical MR scanners, were available. Ossification stages of the DFE were determined by means of the classification system by Vieth et al. (Eur Radiol 2018; 28:3255-3262). Both the intra-observer agreement and inter-observer agreement were found to be "very good" (κ = 0.899 and κ = 0.830). The present study confirmed that MRI of the DFE is suitable to determine majority in both sexes when stage 6 is present as the study revealed minimum ages above the age of 18 years for this stage (20.40 years in males and 20.60 years in females). Accordingly, the data represent a strong support for the so far existing database. Hence, the investigation of the knee using routine MRI appears to become a realistic alternative for forensic age estimation practice in the near future.

Magnetic resonance imaging of the proximal tibial epiphysis is suitable for statements as to the question of majority: a validation study in forensic age diagnostics.

Determining majority plays a key role for forensic age diagnostics in living individuals. Recent data suggest that magnetic resonance imaging (MRI) of the proximal tibial epiphysis (PTE) may be a suitable alternative or at least an additional tool to clarify whether an individual has reached majority. However, the reference data situation is still sparse. Hence, the present dual center study retrospectively analyzed routine MRI of the knee in 413 cases (214 males and 199 females) of a Western Caucasian population aged between 12 and 25 years. MRI was performed at 1.5 and 3.0 T clinical scanners using T1- and T2-weighted sequences. The classification system by Vieth et al. (Eur Radiol 2018; 28:3255-3262) was applied for determining the ossification stages of the PTE. Intra-observer agreement was "very good" (κ = 0.931), and inter-observer agreement was "good" (κ = 0.798). Minimum ages above the age of 18 years were observed with the final stage (stage 6) in either sex (20.27 years in males and 18.55 years in females). The results are not in contradiction with the previous data and can be considered a strong and valuable support of the so far existing database. Therefore, the investigation of the PTE using routine MRI (either at 1.5 or 3.0 T) could be taken into consideration for application in forensic age estimation practice in near future.

Neuronal gamma oscillations and activity-dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue.

Microglial cells (resident macrophages) feature rapid activation in CNS disease and can acquire multiple phenotypes exerting neuroprotection or neurotoxicity. The functional impact of surveying ("resting") microglia on neural excitability and neurotransmission in physiology is widely unknown, however. We addressed this issue in male rat hippocampal slice cultures (in situ) by pharmacological microglial ablation within days and by characterizing neuronal gamma-band oscillations (30-70 Hz) that are highly sensitive to neuromodulators and disturbances in ion and energy regulation. Gamma oscillations support action potential timing and synaptic plasticity, associate with higher brain functions like perception and memory, and require precise communication between excitatory pyramidal cells and inhibitory (GABAergic) interneurons. The slice cultures featured well-preserved hippocampal cytoarchitecture and parvalbumin-positive interneuron networks, microglia with ramified morphology, and low basal levels of IL-6, TNF-α, and nitric oxide (NO). Stimulation of slice cultures with the pro-inflammatory cytokine IFN-γ or bacterial LPS serving as positive controls for microglial reactivity induced MHC-II expression and increased cytokine and NO release. Chronic exposure of slice cultures to liposome-encapsulated clodronate reduced the microglial cell population by about 96%, whereas neuronal structures, astrocyte GFAP expression, and basal levels of cytokines and NO were unchanged. Notably, the properties of gamma oscillations reflecting frequency, number and synchronization of synapse activity were regular after microglial depletion. Also, electrical stimulus-induced transients of the extracellular potassium concentration ([K+ ]o ) reflecting cellular K+ efflux, clearance and buffering were unchanged. This suggests that nonreactive microglia are dispensable for neuronal homeostasis and neuromodulation underlying network signaling and rhythm generation in cortical tissue.

Persistent increase in ventral hippocampal long-term potentiation by juvenile stress: A role for astrocytic glutamine synthetase.

A traumatic childhood is among the most important risk factors for developing stress-related psychopathologies such as posttraumatic stress disorder or depression later in life. However, despite the proven role of astrocytes in regulating transmitter release and synaptic plasticity, the contribution of astrocytic transmitter metabolism to such stress-induced psychopathologies is currently not understood. In rodents, childhood adversity can be modeled by juvenile stress exposure, resulting in increased anxiety, and impaired coping with stress in adulthood. We describe that such juvenile stress in rats, regardless of additional stress in adulthood, leads to reduced synaptic efficacy in the ventral CA1 (vCA1) Schaffer collaterals, but increased long-term potentiation (LTP) of synaptic transmission after high-frequency stimulation. We tested whether the glutamate-glutamine-cycle guides the lasting changes on plasticity observed after juvenile stress by blocking the astrocytic glutamate-degrading enzyme, glutamine synthetase (GS). Indeed, the pharmacological inhibition of GS by methionine sulfoximine in slices from naïve rats mimics the effect of juvenile stress on vCA1-LTP, while supplying glutamine is sufficient to normalize the LTP. Assessing steady-state mRNA levels in the vCA1 stratum radiatum reveals distinct shifts in the expression of GS, astrocytic glutamate, and glutamine transporters after stress in juvenility, adulthood, or combined juvenile/adult stress. While GS mRNA expression levels are lastingly reduced after juvenile stress, GS protein levels are maintained stable. Together our results suggest a critical role for astrocytes and the glutamate-glutamine cycle in mediating long-term effects of juvenile stress on plasticity in the vCA1, a region associated with anxiety and emotional memory processing.

Seizure-induced microvascular injury is associated with impaired neurovascular coupling and blood-brain barrier dysfunction.

OBJECTIVE: Blood-brain barrier (BBB) impairment, redistribution of pericytes, and disturbances in cerebral blood flow may contribute to the increased seizure propensity and neurological comorbidities associated with epilepsy. However, despite the growing evidence of postictal disturbances in microcirculation, it is not known how recurrent seizures influence pericytic membrane currents and subsequent vasodilation. METHODS: Here, we investigated successive changes in capillary neurovascular coupling and BBB integrity during recurrent seizures induced by 4-aminopyridine or low-Mg2+ conditions. To avoid the influence of arteriolar dilation and cerebral blood flow changes on the capillary response, we measured seizure-associated pericytic membrane currents, capillary motility, and permeability changes in a brain slice preparation. Arteriolar responses to 4-aminopyridine-induced seizures were further studied in anesthetized Sprague Dawley rats by using electrocorticography and tissue oxygen recordings simultaneously with intravital imaging of arteriolar diameter, BBB permeability, and cellular damage. RESULTS: Within the preserved vascular network in hippocampal slice cultures, pericytes regulated capillary diameter in response to vasoactive agents and neuronal activity. Seizures induced distinct patterns of membrane currents that contributed to the regulation of pericytic length. During the course of recurrent seizures, individual vasodilation responses eroded and BBB permeability increased, despite unaltered neurometabolic coupling. Reduced vascular responsiveness was associated with mitochondrial depolarization in pericytes. Subsequent capillary constriction preceded BBB opening, suggesting that pericyte injury mediates the breach in capillary integrity. In vivo findings were consistent with slice experiments, showing seizure-related neurovascular decoupling and BBB dysfunction in small cortical arterioles, accompanied by perivascular cellular injury despite normoxic conditions. SIGNIFICANCE: Our study presents a direct observation of gradually developing neurovascular decoupling during recurrent seizures and suggests pericytic injury as an inducer of vascular dysfunction in epilepsy.

Evaluation of an optimized metal artifact reduction algorithm for flat-detector angiography compared to DSA imaging in follow-up after neurovascular procedures.

BACKGROUND: Flat detector CT - angiography (FDCTA) has become a valuable imaging tool in post- and peri-interventional imaging after neurovascular procedures. Metal artifacts produced by radiopaque implants like clips or coils still impair image quality. METHODS: FDCTA was performed in periprocedural or follow-up imaging of 21 patients, who had received neurovascular treatment. Raw data was sent to a dedicated workstation and subsequently a metal artifact reduction algorithm (MARA) was applied. Two neuroradiologists examined the images. RESULTS: Application of MARA improved image appearance and led to a significant reduction of metal artifacts. After application of MARA only 8 datasets (34% of the images) were rated as having many or extensive artifacts, before MARA 15 (65%) of the images had extensive or many artifacts. Twenty percent more cases of reperfusion were diagnosed after application of MARA, congruent to the results of digital subtraction angiography (DSA) imaging. Also 3 (13% of datasets) images, which could not be evaluated before application of MARA, could be analyzed after metal artifact reduction and reperfusion could be excluded. CONCLUSION: Application of MARA improved image evaluation, reduced the extent of metal artifacts, and more cases of reperfusion could be detected or excluded, congruent to DSA imaging.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ.

Microglia (tissue-resident macrophages) represent the main cell type of the innate immune system in the CNS; however, the mechanisms that control the activation of microglia are widely unknown. We systematically explored microglial activation and functional microglia-neuron interactions in organotypic hippocampal slice cultures, i.e., postnatal cortical tissue that lacks adaptive immunity. We applied electrophysiological recordings of local field potential and extracellular K(+) concentration, immunohistochemistry, design-based stereology, morphometry, Sholl analysis, and biochemical analyses. We show that chronic activation with either bacterial lipopolysaccharide through Toll-like receptor 4 (TLR4) or leukocyte cytokine IFN-γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, CD11b and CD68 up-regulation, and proinflammatory cytokine (IL-1ß, TNF-α, IL-6) and nitric oxide (NO) release. Notably, these reactive phenotypes only moderately alter intrinsic neuronal excitability and gamma oscillations (30-100 Hz), which emerge from precise synaptic communication of glutamatergic pyramidal cells and fast-spiking, parvalbumin-positive GABAergic interneurons, in local hippocampal networks. Short-term synaptic plasticity and extracellular potassium homeostasis during neural excitation, also reflecting astrocyte function, are unaffected. In contrast, the coactivation of TLR4 and IFN-γ receptors results in neuronal dysfunction and death, caused mainly by enhanced microglial inducible nitric oxide synthase (iNOS) expression and NO release, because iNOS inhibition is neuroprotective. Thus, activation of TLR4 in microglia in situ requires concomitant IFN-γ receptor signaling from peripheral immune cells, such as T helper type 1 and natural killer cells, to unleash neurotoxicity and inflammation-induced neurodegeneration. Our findings provide crucial mechanistic insight into the complex process of microglia activation, with relevance to several neurologic and psychiatric disorders.

Computer-Aided Detection of Pulmonary Nodules in Computed Tomography Using ClearReadCT.

This study evaluates the accuracy of a computer-aided detection (CAD) application for pulmonary nodular lesions (PNL) in computed tomography (CT) scans, the ClearReadCT (Riverain Technologies). The study was retrospective for 106 biopsied PNLs from 100 patients. Seventy-five scans were Contrast-Enhanced (CECT) and 25 received no enhancer (NECT). Axial reconstructions in soft-tissue and lung kernel were applied at three different slice thicknesses, 0.75 mm (CECT/NECT n = 25/6), 1.5 mm (n = 18/9) and 3.0 mm (n = 43/18). We questioned the effect of (1) enhancer, (2) kernel and (3) slice thickness on the CAD performance. Our main findings are: (1) Vessel suppression is effective and specific in both NECT and CECT. (2) Contrast enhancement significantly increased the CAD sensitivity from 60% in NECT to 80% in CECT, P = 0.025 Fischer's exact test. (3) The CAD sensitivity was 84% in 3 mm slices compared to 68% in 0.75 mm slices, P > 0.2 Fischer's exact test. (4) Small lesions of low attenuation were detected with higher sensitivity. (5) Lung kernel reconstructions increased the false positive rate without affecting the sensitivity (P > 0.05 McNemar's test). In conclusion, ClearReadCT showed an optimized sensitivity of 84% and a positive predictive value of 67% in enhanced lung scans with thick, soft kernel reconstructions. NECT, thin slices and lung kernel reconstruction were associated with inferior performance.

Astrocytic glutamine synthetase is expressed in the neuronal somatic layers and down-regulated proportionally to neuronal loss in the human epileptic hippocampus.

Human mesial temporal lobe epilepsy (MTLE) features subregion-specific hippocampal neurodegeneration and reactive astrogliosis, including up-regulation of the glial fibrillary acidic protein (GFAP) and down-regulation of glutamine synthetase (GS). However, the regional astrocytic expression pattern of GFAP and GS upon MTLE-associated neurodegeneration still remains elusive. We assessed GFAP and GS expression in strict correlation with the local neuronal number in cortical and hippocampal surgical specimens from 16 MTLE patients using immunohistochemistry, stereology and high-resolution image analysis for digital pathology and whole-slide imaging. In the cortex, GS-positive (GS+) astrocytes are dominant in all neuronal layers, with a neuron to GS+ cell ratio of 2:1. GFAP-positive (GFAP+) cells are widely spaced, with a GS+ to GFAP+ cell ratio of 3:1-5:1. White matter astrocytes, on the contrary, express mainly GFAP and, to a lesser extent, GS. In the hippocampus, the neuron to GS+ cell ratio is approximately 1:1. Hippocampal degeneration is associated with a reduction of GS+ astrocytes, which is proportional to the degree of neuronal loss and primarily present in the hilus. Up-regulation of GFAP as a classical hallmark of reactive astrogliosis does not follow the GS-pattern and is prominent in the CA1. Reactive alterations were proportional to the neuronal loss in the neuronal somatic layers (stratum pyramidale and hilus), while observed to a lesser extent in the axonal/dendritic layers (stratum radiatum, molecular layer). We conclude that astrocytic GS is expressed in the neuronal somatic layers and, upon neurodegeneration, is down-regulated proportionally to the degree of neuronal loss.

Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Voltage-Gated Calcium Channels.

UNLABELLED: Acute cerebral ischemia and chronic neurovascular diseases share various common mechanisms with neurodegenerative diseases, such as disturbed cellular calcium and energy homeostasis and accumulation of toxic metabolites. A link between these conditions may be constituted by amyloid precursor protein (APP), which plays a pivotal role in the pathogenesis of Alzheimer's disease, but has also been associated with the response to acute hypoxia and regulation of calcium homeostasis. We therefore studied hypoxia-induced loss of function and recovery upon reoxygenation in hippocampal slices of mice lacking APP (APP(-/-)) or selectively expressing its soluble extracellular domain (APPsα-KI). Transient hypoxia disrupted electrical activity at the network and cellular level. In mice lacking APP, these impairments were significantly more severe, showing increased rise of intracellular calcium, faster loss of function, and higher incidence of spreading depression. Likewise, functional recovery upon reoxygenation was much slower and less complete than in controls. Most of these deficits were rescued by selective expression of the soluble extracellular fragment APPsα, or by pharmacological block of L-type calcium channels. We conclude that APP supports neuronal resistance toward acute hypoxia. This effect is mediated by the secreted APPsα-domain and involves L-type calcium channels. SIGNIFICANCE STATEMENT: Amyloid precursor protein (APP) is involved in the pathophysiology of Alzheimer's disease, but its normal function in the brain remains elusive. Here, we describe a neuroprotective role of the protein in acute hypoxia. Functional recovery of mouse hippocampal networks after transient reduction of oxygen supply was strongly impaired in animals lacking APP. Most protective effects are mediated by the soluble extracellular fragment APPsα and involve L-type calcium channels. Thus, APP contributes to calcium homeostasis in situations of metabolic stress. This finding may shed light on the physiological function of APP and may be important for understanding mechanisms of neurodegenerative diseases.

Shifts in excitatory/inhibitory balance by juvenile stress: A role for neuron-astrocyte interaction in the dentate gyrus.

Childhood trauma is a well-described risk factor for the development of stress-related psychopathology such as posttraumatic stress disorder or depression later in life. Childhood adversity can be modeled in rodents by juvenile stress (JS) protocols, resulting in impaired coping with stressful challenges in adulthood. In the current study, we investigated the long-lasting impact of JS on the expression of molecular factors for glutamate and γ-aminobutyric acid (GABA) uptake and turnover in sublayers of the dentate gyrus (DG) using laser microdissection and quantitative real-time polymerase chain reaction. We observed reduced mRNA expression levels after JS for factors mediating astrocytic glutamate and GABA uptake and degradation. These alterations were prominently observed in the dorsal but not ventral DG granule cell layer, indicating a lasting change in astrocytic GABA and glutamate metabolism that may affect dorsal DG network activity. Indeed, we observed increased inhibition and a lack of facilitation in response to paired-pulse stimulation at short interstimulus intervals in the dorsal DG after JS, while no alterations were evident in basal synaptic transmission or forms of long-term plasticity. The shift in paired-pulse response was mimicked by pharmacologically blocking the astrocytic GABA transporter GAT-3 in naïve animals. Accordingly, reduced expression levels of GAT-3 were confirmed at the protein level in the dorsal granule cell layer of rats stressed in juvenility. Together, these data demonstrate a lasting shift in the excitatory/inhibitory balance of dorsal DG network activity by JS that appears to be mediated by decreased GABA uptake into astrocytes.

A reliable model for gamma oscillations in hippocampal tissue.

Gamma oscillations (30-100 Hz) reflect a fast brain rhythm that provides a fundamental mechanism of complex neuronal information processing in the hippocampus and in the neocortex in vivo. Gamma oscillations have been implicated in higher brain functions, such as sensory perception, motor activity, and memory formation. Experimental studies on synaptic transmission and bioenergetics underlying gamma oscillations have primarily used acute slices of the hippocampus. This study tests whether organotypic hippocampal slice cultures of the rat provide an alternative model for cortical gamma oscillations in vitro. Our findings are that 1) slice cultures feature well-preserved laminated architecture and neuronal morphology; 2) slice cultures of different maturation stages (7-28 days in vitro) reliably express gamma oscillations at about 40 Hz as induced by cholinergic (acetylcholine) or glutamatergic (kainate) receptor agonists; 3) the peak frequency of gamma oscillations depends on the temperature, with an increase of ∼ 3.5 Hz per degree Celsius for the range of 28-36 °C; 4) most slice cultures show persistent gamma oscillations for ∼ 1 hr during electrophysiological local field potential recordings, and later alterations may occur; and 5) in slice cultures, glucose at a concentration of 5 mM in the recording solution is sufficient to power gamma oscillations, and additional energy substrate supply with monocarboxylate metabolite lactate (2 mM) exclusively increases the peak frequency by ∼ 4 Hz. This study shows that organotypic hippocampal slice cultures provide a reliable model to study agonist-induced gamma oscillations at glucose levels near the physiological range.

Quantitative Assessment of Breast-Tumor Stiffness Using Shear-Wave Elastography Histograms.

Purpose: Shear-wave elastography (SWE) measures tissue elasticity using ultrasound waves. This study proposes a histogram-based SWE analysis to improve breast malignancy detection. Methods: N = 22/32 (patients/tumors) benign and n = 51/64 malignant breast tumors with histological ground truth. Colored SWE heatmaps were adjusted to a 0−180 kPa scale. Normalized, 250-binned RGB histograms were used as image descriptors based on skewness and area under curve (AUC). The histogram method was compared to conventional SWE metrics, such as (1) the qualitative 5-point scale classification and (2) average stiffness (SWEavg)/maximal tumor stiffness (SWEmax) within the tumor B-mode boundaries. Results: The SWEavg and SWEmax did not discriminate malignant lesions in this database, p > 0.05, rank sum test. RGB histograms, however, differed between malignant and benign tumors, p < 0.001, Kolmogorov−Smirnoff test. The AUC analysis of histograms revealed the reduction of soft-tissue components as a significant SWE biomarker (p = 0.03, rank sum). The diagnostic accuracy of the suggested method is still low (Se = 0.30 for Se = 0.90) and a subject for improvement in future studies. Conclusions: Histogram-based SWE quantitation improved the diagnostic accuracy for malignancy compared to conventional average SWE metrics. The sensitivity is a subject for improvement in future studies.

Microglia Activation in the Midbrain of the Human Neonate: The Effect of Perinatal Hypoxic-Ischemic Injury.

Perinatal hypoxia-ischemia (PHI) is a major risk factor for the development of neuropsychiatric deficits later in life. We previously reported that after prolonged PHI, the dopaminergic neurons of the human neonate showed a dramatic reduction of tyrosine hydroxylase (TH) in the substantia nigra, without important signs of neuronal degeneration despite the significant reduction in their cell size. Since microglia activation could precede neuronal death, we now investigated 2 microglia activation markers, ionized calcium-binding adapter molecule 1 (Iba1), and the phagocytosis marker Cd68. The highest Iba1 immunoreactivity was found in neonates with neuropathological lesions of severe/abrupt PHI, while the lowest in subjects with moderate/prolonged or older PHI. Subjects with very severe/prolonged or chronic PHI showed an increased Iba1 expression and very activated microglial morphology. Heavy attachment of microglia on TH neurons and remarkable expression of Cd68 were also observed indicating phagocytosis in this group. Females appear to express more Iba1 than males, suggesting a gender difference in microglia maturation and immune reactivity after PHI insult. PHI-induced microglial "priming" during the sensitive for brain development perinatal/neonatal period, in combination with genetic or other epigenetic factors, could predispose the survivors to neuropsychiatric disorders later in life, possibly through a sexually dimorphic way.

Redistribution of astrocytic glutamine synthetase in the hippocampus of chronic epileptic rats.

Glutamine synthetase (GS) is an astrocytic enzyme, which catalyzes the synthesis of glutamine from glutamate and ammonia. In the central nervous system, GS prevents glutamate-dependent excitotoxicity and detoxifies nitrogen. Reduction in both expression and activity of GS was reported in the hippocampus of patients with temporal lobe epilepsy (TLE), and this reduction has been suggested to contribute to epileptogenesis. In this study, we characterized hippocampal GS expression in the pilocarpine model of TLE in Wistar rats by means of stereology and morphometric analysis. Neither the GS positive cell number nor the GS containing cell volume was found to be altered in different hippocampal subregions of chronic epileptic rats when compared with controls. Instead, redistribution of the enzyme at both intracellular and tissue levels was observed in the epileptic hippocampus; GS was expressed more in proximal astrocytic branches, and GS expressing astrocytic somata was located in closer proximity to vascular walls. These effects were not due to shrinkage of astrocytic processes, as revealed by glial fibrillary acidic protein staining. Our results argue for GS redistribution rather than downregulation in the rat pilocarpine model of TLE. The potential contribution of increased GS perivascular affinity to the pathogenesis of epilepsy is discussed as well.

Reliability of a Risk-Factor Questionnaire for Osteoporosis: A Primary Care Survey Study with Dual Energy X-ray Absorptiometry Ground Truth.

(1) Purpose: Predisposing factors to osteoporosis (OP) as well as dual-source x-ray densitometry (DXA) steer therapeutic decisions by determining the FRAX index. This study examines the reliability of a standard risk factor questionnaire in OP-screening. (2) Methods: n = 553 eligible questionnaires encompassed 24 OP-predisposing factors. Reliability was assessed using DXA as a gold standard. Multiple logistic regression and Spearman's correlations, as well as the confounding influence of age and body mass index, were analyzed in SPSS (IBM Corporation, Armonk, NY, USA). (3) Results: Our study revealed low patient self-awareness regarding OP and its risk factors. One out of every four patients reported a positive history for osteoporosis not confirmed by DXA. The extraordinarily high incidence of rheumatoid arthritis and thyroid disorders likely reflect confusion with other diseases or health anxiety. FRAX-determining risk factors such as malnutrition, liver insufficiency, prior fracture without trauma, and glucocorticoid therapy did not correlate with increased OP incidence, altogether demonstrating how inaccurate survey information could influence therapeutic decisions on osteoporosis. (4) Conclusions: Contradictive results and a low level of patient self-awareness suggest a high degree of uncertainty and low reliability of the current OP risk factor survey.

Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus.

Cortical information processing comprises various activity states emerging from timed synaptic excitation and inhibition. However, the underlying energy metabolism is widely unknown. We determined the cerebral metabolic rate of oxygen (CMRO2) along a tissue depth of <0.3 mm in the hippocampal CA3 region during various network activities, including gamma oscillations and sharp wave-ripples that occur during wakefulness and sleep. These physiological states associate with sensory perception and memory formation, and critically depend on perisomatic GABA inhibition. Moreover, we modelled vascular oxygen delivery based on quantitative microvasculature analysis. (1) Local CMRO2 was highest during gamma oscillations (3.4 mM/min), medium during sharp wave-ripples, asynchronous activity and isoflurane application (2.0-1.6 mM/min), and lowest during tetrodotoxin application (1.4 mM/min). (2) Energy expenditure of axonal and synaptic signaling accounted for >50% during gamma oscillations. (3) CMRO2 positively correlated with number and synchronisation of activated synapses, and neural multi-unit activity. (4) The median capillary distance was 44 µm. (5) The vascular oxygen partial pressure of 33 mmHg was needed to sustain oxidative phosphorylation during gamma oscillations. We conclude that gamma oscillations featuring high energetics require a hemodynamic response to match oxygen consumption of respiring mitochondria, and that perisomatic inhibition significantly contributes to the brain energy budget.

The role of gadolinium in magnetic resonance imaging for early prostate cancer diagnosis: A diagnostic accuracy study.

OBJECTIVE: Prostate lesions detected with multiparametric magnetic resonance imaging (mpMRI) are classified for their malignant potential according to the Prostate Imaging-Reporting And Data System (PI-RADS™2). In this study, we evaluate the diagnostic accuracy of the mpMRI with and without gadolinium, with emphasis on the added diagnostic value of the dynamic contrast enhancement (DCE). MATERIALS AND METHODS: The study was retrospective for 286 prostate lesions / 213 eligible patients, n = 116/170, and 49/59% malignant for the peripheral (Pz) and transitional zone (Tz), respectively. A stereotactic MRI-guided prostate biopsy served as the histological ground truth. All patients received a mpMRI with DCE. The influence of DCE in the prediction of malignancy was analyzed by blinded assessment of the imaging protocol without DCE and the DCE separately. RESULTS: Significant (CSPca) and insignificant (IPca) prostate cancers were evaluated separately to enhance the potential effects of the DCE in the detection of CSPca. The Receiver Operating Characteristics Area Under Curve (ROC-AUC), sensitivity (Se) and specificity (Spe) of PIRADS-without-DCE in the Pz was 0.70/0.47/0.86 for all cancers (IPca and CSPca merged) and 0.73/0.54/0.82 for CSPca. PIRADS-with-DCE for the same patients showed ROC-AUC/Se/Spe of 0.70/0.49/0.86 for all Pz cancers and 0.69/0.54/0.81 for CSPca in the Pz, respectively, p>0.05 chi-squared test. Similar results for the Tz, AUC/Se/Spe for PIRADS-without-DCE was 0.75/0.61/0.79 all cancers and 0.67/0.54/0.71 for CSPca, not influenced by DCE (0.66/0.47/0.81 for all Tz cancers and 0.61/0.39/0.75 for CSPca in Tz). The added Se and Spe of DCE for the detection of CSPca was 88/34% and 78/33% in the Pz and Tz, respectively. CONCLUSION: DCE showed no significant added diagnostic value and lower specificity for the prediction of CSPca compared to the non-enhanced sequences. Our results support that gadolinium might be omitted without mitigating the diagnostic accuracy of the mpMRI for prostate cancer.

One-Stop Management of 230 Consecutive Acute Stroke Patients: Report of Procedural Times and Clinical Outcome.

BACKGROUND AND PURPOSE: Rapid thrombectomy for acute ischemic stroke caused by large vessel occlusion leads to improved outcome. Optimizing intrahospital management might diminish treatment delays. To examine if one-stop management reduces intrahospital treatment delays and improves functional outcome of acute stroke patients with large vessel occlusion. METHODS: We performed a single center, observational study from June 2016 to November 2018. Imaging was acquired with the latest generation angiography suite at a comprehensive stroke center. Two-hundred-thirty consecutive adults with suspected acute stroke presenting within 6 h after symptom onset with a moderate to severe National Institutes of Health Stroke Scale (≥10 in 2016; ≥7 since January 2017) were directly transported to the angiography suite by bypassing multidetector CT. Noncontrast flat-detector CT and biphasic flat-detector CT angiography were acquired with an angiography system. In case of a large vessel occlusion patients remained in the angiography suite, received intravenous rtPA therapy and underwent thrombectomy. As primary endpoints, door-to-reperfusion times and functional outcome at 90 days were recorded and compared in a case-control analysis with matched prior patients receiving standard management. RESULTS: A total of 230 patients (123 women, median age of 78 years (Interquartile Range (IQR) 69-84)) were included. Median symptom-to-door time was 130 min (IQR 70-195). Large vessel occlusion was diagnosed in 166/230 (72%) patients; 64/230 (28%) had conditions not suitable for thrombectomy. Median door-to-reperfusion time for M1 occlusions was 64 min (IQR 56-87). Compared to 43 case-matched patients triaged with multidetector CT, median door-to-reperfusion time was reduced from 102 (IQR 85-117) to 68 min (IQR 53-89; p < 0.001). Rate of good functional outcome was significantly better in the one-stop management group (p = 0.029). Safety parameters (mortality, sICH, any hemorrhage) did not differ significantly between groups. CONCLUSIONS: One-stop management for stroke triage reduces intrahospital time delays in our specific hospital setting.