Explore the vast range of titles available.

Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell–Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4 + regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.

Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age. Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20 weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20 weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex. IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20 weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1±2.3 vs 0.5±0.8; (mean±SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21±0.04 log number puncta/week vs 0.16±0.04, respectively; p=0.037). Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans.

Purpose The purpose of this investigation is to describe the clinical, imaging, histologic and flow dynamic characteristics of orbital cavernous haemangioma. Methods In this clinicopathologic series, clinical features were obtained from patient records. All imaging studies were reviewed. All specimens were reviewed with haematoxylin and eosin, and 10 were subject to a staining protocol including: Movat Pantachrome, periodic acid Schiff, D2-40, CD31, GLUT-1, Ki-67, vascular endothelial growth factor receptor 1 (VEGF-r1) (flt-1), VEGF-r2 (Flk-1), VEGF, anti-smooth muscle actin (SMA), CD20, CD4, CD8 and CD68. Imaging and pathology were reviewed in a systematic fashion. Results Clinically, lesions were more common in middle-aged females presenting with axial proptosis and pain. One-third demonstrated signs of optic nerve dysfunction. Dynamic imaging revealed focal early and diffuse late enhancement. Lesions demonstrated slow growth at 0.2 cm3/year. Histologically, all lesions demonstrated large vascular channels with mature-appearing endothelium and abundant stroma. Three salient features were noted and characterised: thrombosis, nests of perivascular hypercellularity and expanded stromal elements. Acute thrombosis was a feature of each specimen (<10% of channels). Fibrin clots were lined by a layer of CD31+ endothelium. Perivascular hypercellular areas stained uniformly with CD31 and less so with VEGFr2. Additionally, focal areas of Ki67+ and CD68+ cells were found in these regions. Expanded stroma contained CD31+ microcapillary networks and stained diffusely with anti-SMA. Conclusions Cavernous haemangioma demonstrate clinical features and growth characteristics of a benign mass. Dynamic imaging highlights their slow flow vascular nature. Histologically, the hypercellularity and stromal changes identified can be understood within the pathogenic context of thrombosis and recanalisation in an organised lesion.

Background Mouse models are commonly used to study central nervous system disorders, in which cerebrospinal fluid (CSF) drainage may be disturbed. However, mouse CSF drainage into lymphatics has not been thoroughly characterized. We aimed to image this using an in vivo approach that combined quantum dot fluorescent nanoparticles with hyperspectral imaging. Findings Quantum dot 655 was injected into the CSF of the cisterna magna in seven mice and visualized by in vivo hyperspectral imaging at time points 20 and 40 min, 1, 2, and 6 h after injection. In controls (n = 4), quantum dots were applied directly onto intact dura mater covering the cisterna magna. After imaging, lymph nodes in the neck were harvested and processed post-mortem for histological analysis. After injection into the CSF, quantum dot signal was detected in vivo in submandibular lymph nodes of all mice studied as early as 20 min, but not in controls. Post-mortem gross and histological examination of lymph nodes confirmed in vivo observations. Conclusions Non-invasive in vivo hyperspectral imaging is a useful tool to study CSF lymphatic drainage and is relevant to understanding this pathway in CNS disease models.

Thorough gross examination of breast cancer specimens is critical in order to sample relevant portions for subsequent microscopic examination. This task would benefit from an imaging tool which permits targeted and accurate block selection. Optical coherence tomography (OCT) is a non-destructive imaging technique that visualizes tissue architecture and has the potential to be an adjunct at the gross bench. Our objectives were: (1) to familiarize pathologists with the appearance of breast tissue entities on OCT; and (2) to evaluate the yield and quality of OCT images of unprocessed, formalin-fixed breast specimens for the purpose of learning and establishment of an OCT–histopathology library. Methods: Firstly, 175 samples from 40 formalin-fixed, unprocessed breast specimens with residual tissue after final diagnosis were imaged with OCT and then processed into histology slides. Histology findings were correlated with features on OCT. Results: Residual malignancy was seen in 30% of tissue samples. Corresponding OCT images demonstrated that tumor can be differentiated from fibrous stroma, based on features such as irregular boundary, heterogeneous texture and reduced penetration depth. Ductal carcinoma in situ can be subtle, and it is made more recognizable by the presence of comedo necrosis and calcifications. OCT features of benign and malignant breast entities were compiled in a granular but user-friendly reference tool. Conclusion: OCT images of fixed breast tissue were of sufficient quality to reproduce features of breast entities previously described in fresh tissue specimens. Our findings support the use of readily available unprocessed, fixed breast specimens for the establishment of an OCT–histopathology library.

Microgravity-induced headward fluid shifts are one of the mechanisms implicated in spaceflight-associated eye conditions, including intraocular pressure (IOP) and retinal nerve fiber layer (RNFL) thickness changes. In this longitudinal study, we investigated IOP and RNFL thickness changes over time in a mouse model of microgravity-induced headward fluid shifts. The study involved 20 adult male B6(Cg)- /J mice, randomly assigned to two groups: the hindlimb unloading (HU) mice, unloaded for 21 days followed by 14 days of release, and control mice kept under the same conditions except HU for 35 days. IOP and RNFL thickness in peripapillary and peripheral rings of right and left eyes were measured before and once a week after HU. Our analysis utilized mixed linear models to compare the estimated marginal means of IOP and RNFL thickness on each day with baseline values for each eye. Post hoc splined mixed linear models with a knot at day 14 were employed to assess the rate of IOP change in each segment. IOP was significantly elevated in both eyes of the HU mice on day 14 compared to baseline. The splined analysis revealed a bilateral positive rate of IOP change up to day 14, followed by a negative rate of change thereafter. In contrast, control mice displayed no significant differences in IOP at any timepoint. RNFL thicknesses of right eye peripapillary and peripheral rings were reduced after 1 week and 2 weeks, respectively. In contrast, left eye RNFL thickness measurements did not show any significant change compared to baseline. The HU mouse model displays a distinct ocular phenotype that may be useful for understanding IOP and RNFL changes in microgravity and their relevance to Spaceflight-Associated Neuro-ocular Syndrome.

ObjectiveOne of the most important risk factors for developing a glaucomatous optic neuropathy is elevated intraocular pressure. Moreover, mechanisms such as altered perfusion have been postulated to injure the optical path. In a mouse model, we compare first negative effects of cerebral perfusion/reperfusion on the optic nerve structure versus alterations by elevated intraocular pressure. Second, we compare the alterations by isolated hypoperfusion-reperfusion and isolated intraocular pressure to the combination of both.Methods and analysisMice were divided in four groups: (1) controls; (2) perfusion altered mice that underwent transient bi-common carotid artery occlusion (BCCAO) for 40 min; (3) glaucoma group (DBA/2J mice); (4) combined glaucoma and altered perfusion (DBA/2J mice with transient BCCAO). Optic nerve sections were stereologically examined 10–12 weeks after intervention.ResultsAll experimental groups showed a decreased total axon number per optic nerve compared with controls. In DBA/2J and combined DBA/2J & BCCAO mice the significant decrease was roughly 50%, while BCCAO leaded to a 23% reduction of axon number, however reaching significance only in the direct t-test. The difference in axon number between BCCAO and both DBA/2J mice was almost 30%, lacking statistical significance due to a remarkably high variation in both DBA/2J groups.ConclusionElevated intraocular pressure in the DBA/2J mouse model of glaucoma leads to a much more pronounced optic nerve atrophy compared with transient forebrain hypoperfusion and reperfusion by BCCAO. A supposed worsening effect of an altered perfusion added to the pressure-related damage could not be detected.

Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na+,K+-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that Myshkin mice carrying an inactivating mutation in the neuron-specific Na+,K+-ATPase α3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state. Myshkin mice show increased Ca2+ signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na+,K+-ATPase α3 protein rescue the mania-like phenotype of Myshkin mice. These findings establish Myshkin mice as a unique model of mania, reveal an important role for Na+,K+-ATPase α3 in the control of mania-like behavior, and identify Na+,K+-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.

Long-duration human spaceflight can lead to changes in both the eye and the brain, which have been referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). These changes may manifest as a constellation of symptoms, which can include optic disc edema, optic nerve sheath distension, choroidal folds, globe flattening, hyperopic shift, and cotton wool spots. Although the underpinning mechanisms for SANS are not yet known, contributors may include intracranial interstitial fluid accumulation following microgravity induced headward fluid shift. Development and validation of SANS countermeasures contribute to our understanding of etiology and accelerate new technology including exercise modalities, Lower Body Negative Pressure suits, venous thigh cuffs, and Impedance Threshold Devices. However, significant knowledge gaps remain including biomarkers, a full set of countermeasures and/or treatment regimes, and finally reliable ground based analogs to accelerate the research. This review from the European Space Agency SANS expert group summarizes past research and current knowledge on SANS, potential countermeasures, and key knowledge gaps, to further our understanding, prevention, and treatment of SANS both during human spaceflight and future extraterrestrial surface exploration.

Purpose: Like motor neurons, retinal ganglion cells (RGCs) have long axons and high metabolic demands, making them vulnerable to disruption of axonal transport. Unlike motor neurons, the RGC axons are accessible to high-resolution non-invasive optical imaging in their intraocular portion. A non-invasive in vivo retinal imaging biomarker can be valuable for amyotrophic lateral sclerosis (ALS) diagnosis and monitoring. We aim to assess the presence of inner retinal pathology in a mouse model of ALS and its possible progression with age. Methods: Transgenic SOD1G93A mice (n=8, 4M/4F) and age-matched controls (n=8, 4M/4F) underwent in vivo retinal imaging with confocal scanning laser ophthalmoscopy (cSLO) coupled with optical coherence tomography (OCT) at 20 weeks of age. Another group of SOD1G93A mice (n=20, 6M/14F) and age-matched controls (n=20, 6M/14F) underwent longitudinal in vivo retinal imaging with the same device. Each retinal imaging session included infrared reflectance (IR) and blue reflectance (BR) cSLO coupled with OCT. Hyperreflective puncta located in the retinal nerve fiber layer (RNFL) were counted in a blinded fashion in ALS and control mice. The number of puncta at 20 weeks of age in ALS mice was compared with controls using Wilcoxon test. The rates of increase of puncta number were analyzed using a Generalized Linear Mixed-Effect Model (GLMM) for genotype, time, and sex. Results: IR-cSLO coupled with OCT revealed hyperreflective puncta located in the RNFL of ALS mice. IR-cSLO fundus imaging at the age of 20 weeks showed ALS mice had significantly higher number of puncta compared to controls (2.1[+ or -]2.3 vs 0.5[+ or -]0.8; (mean [+ or -]SD), respectively, p=0.036). GLMM analysis showed both ALS mutation and age were significantly associated with the rate of increase of puncta number (p=0.000232 and p=0.000366, respectively). In addition, female ALS mice had a steeper increase of puncta compared to male ALS mice (0.21[+ or -]0.04 log number puncta/week vs 0.16[+ or -]0.04, respectively; p=0.037). Conclusion: Our findings demonstrate distinct inner retinal nerve fiber layer pathology, detected using cSLO coupled with OCT, which worsens over time. These findings support the potential of retinal imaging as a translationally relevant, non-invasive biomarker for ALS diagnosis or disease monitoring in humans. Keywords: amyotrophic lateral sclerosis, retinal nerve fiber layer, superoxide dismutase, mouse, eye imaging, optical coherence tomography, sex, spheroids, pathology, hyperreflective, puncta