Opacification of Array SA40N silicone multifocal intraocular lens

We report opacification of 2 multifocal intraocular lenses (IOLs). Patients with these IOLs may be more likely to require IOL explantation than those with monofocal IOLs.     

CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells

Journal of Neuroimmune Pharmacology - Microglial cells are brain specific professional phagocytic immune cells that play a crucial role in the inflammation- mediated neurodegeneration especially in...     

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders

Journal of Neuroimmune Pharmacology - Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular...     

Altered Macrophage Phenotype Transition Impairs Skeletal Muscle Regeneration

Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11b-diphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b⁺(CD90/B220/CD49b/NK1.1/Ly6G)⁻(F4/80/I-Ab/CD11c)⁻Ly6C^+/−] accumulation occurred; interestingly, Ly6C⁺ and Ly6C⁻ monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C⁺ macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b⁺F4/80⁺ cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b⁺F4/80⁺Ly6C⁻CD301⁻ macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of anti-inflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C⁻ macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration.Skeletal muscle has a remarkable capacity for regeneration with a complex injury/repair process that includes inflammation, myofiber regeneration, and angiogenesis. The careful orchestration of inflammatory cells and resident muscle stem cells, also known as satellite cells, is vital to skeletal muscle regenerative capacity.^1,2Macrophages are unique effector cells in innate immunity that play critical roles in the maintenance of tissue homeostasis. Monocytes/macrophages are major inflammatory cell populations recruited into injured skeletal muscle. Mouse monocytes comprise two phenotypically distinct subsets in blood: Ly6C^hi/+ cells and Ly6C^lo/− cells.^3–5 Although some groups suggest that Ly6C^hi/+ monocytes are solely recruited into injured tissue and further become Ly6C^lo/− monocytes within the tissue,^3,4,6,7 others have suggested that Ly6C^lo/− monocytes can also be recruited as a second wave to the injury site after the immediate response by Ly6C^hi/+ cells.^8,9 Swirski et al⁵ further characterized and expanded the definition of Ly6C^hi and Ly6C^lo monocyte subsets in the blood [specifically, CD11b⁺(F480, I-Ab, CD11c)^lo(CD90, B220, CD49b, NK1.1, Ly6G)^loLy6C^hi/lo], which were shown to be derived from splenic reserves and recruited to injured myocardium following a myocardial infarction. However, the propensity of Ly6C^hi/+ and Ly6C^lo/− monocytes to differentiate into specific macrophage polarization states (ie, M1 or M2) has not been established. Ramachandran et al⁶ provided evidence that Ly6C^hi monocytes were recruited to injured liver and further differentiated into both Ly6C^hi and Ly6C^lo macrophages. Interestingly, many groups have characterized the Ly6C^hi/+ monocytes/macrophages as proinflammatory, primarily by their production/expression of proinflammatory cytokines/chemokines such as chemokine ligand-2 [Ccl2, also known as monocyte chemoattractant protein-1 (Mcp-1)],^5,6 Cxcl10 [interferon-γ–induced protein 10 (Ip-10)],⁶ inducible nitric oxide synthase (iNOS),¹⁰ tumor necrosis factor-α (TNF-α)^7,8,10,11, IL-12,¹⁰ Cxcl2 [macrophage inflammatory protein-2 (Mip-2)],³ Il-1β,^3,7 and vascular endothelial growth factor (VEGF).⁵ These groups have also characterized Ly6C^lo/− monocytes/macrophages as anti-inflammatory by their production/expression of anti-inflammatory cytokine/chemokines, growth factors, or other markers such as Ccl22 (Mdc),³ Ccl17 (Tarc),³ Il-4,⁵ IL-10,^5,7 transforming growth factor-β (Tgf-β),⁷ arginase-1 (Arg1),^6,12 resistin-like alpha [Retnla, also known as found in inflammatory zone-1 (Fizz-1)],⁶ insulin-like growth factor-1 (Igf-1),^3,6 and platelet-derived growth factor-β (Pdgf-β).³ Whereas Ly6C⁺ cells have a short half-life during tissue damage,⁴ Ly6C⁻ cells remain in the circulation for longer periods and traffic into peripheral tissues under noninflammatory conditions.^4,13 The dynamics of Ly6C^hi/+ and Ly6C^lo/− monocyte infiltration into injured skeletal muscle and their propensity to contribute to proinflammatory and anti-inflammatory macrophages in this tissue remain to be fully explored.Although monocytes are recruited to injured tissues, resident macrophages also exist in tissue and play a role in inflammation. Brigitte et al¹⁴ found that resident macrophages form a centripetal migration pathway for recruited leukocytes by producing two chemokines, KC and MCP-1. Two studies selectively ablated resident macrophages using the human diphtheria toxin receptor (DTR) present on CD11b-expressing cells (ie, monocytes/macrophages/neutrophils). One study showed that the intraperitoneal injection of diphtheria toxin (DT) in a CD11b-DTR mouse could ablate resident macrophages in the kidney and ovary, but not the hepatic sinusoidal nor alveolar macrophages.¹⁵ By using a chimeric mouse, CD11b-DTR host with green fluorescent protein (GFP) donor bone marrow (BM), another group¹⁴ demonstrated a reduction in the resident macrophage population in skeletal muscle with intravenous DT treatment. Consequently, a reduction in the recruited GFP⁺ population 1 day after muscle injury compared to control was observed.¹⁴ However, as the transplanted BM was GFP⁺, it is unclear whether this recruitment deficit was present in the neutrophil population (the primary myeloid cell recruited at day 1), whether this affected macrophage recruitment at any time points along muscle regeneration, or whether this had any effect on the regeneration of the muscle. Regardless, the essential role of ablation of resident macrophages in skeletal muscle regeneration remains elusive.The concept that macrophages are crucial in muscle regeneration is supported by growing experimental evidence. Firstly, several different methods have been used to deplete monocytes/macrophages to investigate their role in skeletal muscle regeneration. This includes injecting antibodies against F4/80,¹⁶ CD11b,^17,18 macrophage colony-stimulating factor (M-CSF) receptor,¹⁹ or clodronate-containing liposomes¹; all of these experiments demonstrated that monocyte/macrophage depletion impaired skeletal muscle regeneration. Secondly, mice deficient in Mcp-1 (also known as Ccl2) or the MCP-1 receptor, CC chemokine receptor 2 (Ccr2), demonstrated a remarkable decrease in monocyte/macrophage infiltration in association with impaired skeletal muscle regeneration.^20–24 Most importantly, the poor capacity of skeletal muscle regeneration in Ccr2^−/− mice was restored by transplantation with BM-derived cells from wild-type mice.²⁵ Thus, Ccr2 expression by BM-derived cells is critical in skeletal muscle regeneration, an observation that strongly supports the essential role for monocytes/macrophages in this dynamic process.Macrophages exhibit remarkable plasticity and are physiologically diverse in response to environmental cues. Extensive in vitro studies defined two phenotypically different macrophage subsets by activation state.^26–29 Classically activated, or M1 macrophages, obtained by lipopolysaccharide treatment alone or in combination with IFN-γ, secrete proinflammatory cytokines, such as TNF-α, and increased iNOS activity, resulting in the production of reactive oxygen species. Alternatively activated, or M2 macrophages, are activated by IL-4 treatment. M2 macrophages express high Arg1, Ym1, Fizz1,¹² the mannose receptor (CD206), and CD301.^2,30,31 Multiple variants based on different stimuli have been described and designated as M2a, M2b, and M2c,^26,27 or as wound healing and regulatory macrophages.²⁸Monocyte and macrophage subsets also exist in injured skeletal muscle. Following injury, proinflammatory and anti-inflammatory monocytes/macrophages sequentially accumulated in muscle. Initial monocyte/macrophage populations were associated with the production of proinflammatory cytokines and removal of necrotic tissue. These initial populations were replaced by monocytes/macrophages that were associated with the production of anti-inflammatory cytokines and tissue repair.^7,32 In rats, M1 and M2 subsets were defined as ED1⁺ and ED2⁺ macrophages, respectively.^33,34 Although these studies suggest that different monocyte/macrophage subsets are associated with different stages of skeletal muscle regeneration, the kinetics and influence of different monocyte/macrophage subsets in skeletal muscle regeneration remain to be determined.DTR transgenic mice have been used to study the effects of monocyte/macrophage ablation on tissue injury and repair.^7,15,35,36 DT binds to the heparin-binding epidermal growth factor–like growth factor (hbEGF) receptor (also known as DTR) followed by internalization, rapidly inducing apoptosis in both dividing and terminally differentiated cells.³⁷ DT exhibits 1 × 10⁴ less affinity in normal mouse cells compared to human cells.³⁸ Thus, tissue-specific transgenic expression of human hbEGF (DTR) confers DT sensitivity to murine cells, such as dendritic cells, vascular smooth muscle cells, or monocytes/macrophages.^15,39,40 CD11b-DTR mice express a transgene containing a human DTR under the control of the CD11b promoter that is constitutively expressed in monocytes and macrophages. Ablation studies in peritoneal populations revealed specific ablation of F4/80⁺ populations in CD11b-DTR mice that were not affected when DT was injected into wild-type mice. Additionally, other population cell numbers such as of T cells, B cells, and granulocytes in the spleen and peritoneal cavity were not affected by DT administration in CD11b-DTR mice.⁴¹ Therefore, monocytes/macrophages can be transiently and specifically ablated by treatment with a single dose of DT.In this study, we used DTR transgenic mice on a FVB background (CD11b-DTR) to transiently ablate monocytes/macrophages at different time points following injury to investigate the effect of monocyte and macrophage subsets on skeletal muscle regeneration. Ablating early infiltrating monocytes/macrophages impaired skeletal muscle regeneration, whereas later ablation had a minimal effect on this tissue response to injury.     

Nontargeted Hepatitis C Screening in an Urban Emergency Department in New York City

BackgroundPreviously the Centers for Disease Control and Prevention (CDC) recommended targeted hepatitis C virus (HCV) screening for adults born between 1945 and 1965 and individuals with HCV risk factors. In April 2020, the CDC updated their recommendations to now include all individuals 18 years of age and older in settings with HCV prevalence > 0.1%. Few emergency departments (EDs) currently employ this nontargeted screening approach.ObjectivesWe examined how a shift from targeted to nontargeted screening might affect HCV case identification. We hypothesized that nontargeted screening could improve HCV case identification in our ED.MethodsRetrospective review of prospectively collected nontargeted screening data from June 6, 2018 to June 5, 2019 in a large urban academic ED. Patients 18 years of age and older, triaged to the adult or pediatric ED and able to provide consent for HCV testing, were eligible for study inclusion.ResultsThere were 83,864 ED visits and 40,282 unique patients deemed eligible for HCV testing. Testing occurred in 10,630 (26.4%) patients, of which 638 (6%) had positive HCV antibody (Ab+) tests and 214 (2%) had a positive viral load (VL+). Birth cohort-targeted screening would have identified 48% of the patients with Ab+ tests and 47% of those who were VL+. Risk-based targeted screening would increase the number of Ab+ patients to 67% and VL+ to 72%.ConclusionsNontargeted ED-based HCV screening can identify a large number of patients with HCV infection. A shift from targeted to nontargeted screening may result in fewer missed infections but requires further study.     

Prevalence of unsuspected thyroid nodules in adults on contrast enhanced 16- and 64-MDCT of the chest

AIM: To determine the prevalence of unsuspected thyroid nodules on contrast enhanced 16and 64-modified discrete cosine transform (MDCT) of the chest, in a population of adult outpatients imaged for indications other than thyroid disease. METHODS: This retrospective study involved review of intravascular contrast-enhanced MDCT scans of the chest from 3077 consecutive adult outpatients, to identify unsuspected thyroid nodules. Exclusion criteria included history of thyroid cancer, known thyroid nodules or thyroid disease and risk factors for thyroid cancer, as evidenced by their medical records. One of 9 radiologists recorded number of nodules, location and bidirectional measurement of largest nodule, as well as amount of thyroid visualized on the chest computed tomography (CT). Presence of nodule was correlated with age, gender, race and percentage of thyroid imaged. RESULTS: A total of 2510 (2510/3077 or 81.6%) study subjects were included in the data analysis; among them,one or more nodules were identified in 629 subjects (629/2510 or 25.1%), with 242 (242/629 or 38.5%) having multiple nodules. Patients with nodule(s) were significantly older than those without (64 ± 13 years vs 58 ± 14 years, P < 0.0001), and female gender was associated with presence of nodule(s) (373/1222 or 30.5% vs 256/1288 or 19.9%, P < 0.0001). Women were also more likely having multiple nodules (167/373 or 44.8%) compared to men (75/256 or 29.3%, P < 0.0001). The majority of nodules (427/629 or 67.9%) were less than 1 cm. CONCLUSION: This retrospective review revealed a prevalence of 25.1% for unsuspected thyroid nodules on contrast-enhanced chest CT.     

Spontaneous Regression of Small Cell Carcinoma of Lung Associated with Severe Neuropathy

This is a case report of small cell lung cancer (SCLC) that underwent spontuneous regression. This was associated with severe neuropathy, which was unresponsive to therapy, including corticosteroids andplasmapheresis. We present here the case report and a brief review of the literature.     

Brain CT and MRI Findings in 100 Consecutive Patients with Intracranial Tuberculoma

OBJECTIVE: The characteristics of intracranial tuberculoma on computed tomography (CT) and magnetic resonance imaging (MRI) are not well known. The authors reviewed the features of tuberculoma on CT scans and MRI. The authors also correlated the MRI characteristics on various pulse sequences with neuropathological findings. METHODS: The charts of patients with intracranial tuberculoma were consecutively reviewed during the period from 1988 to 1999. The diagnosis of tuberculoma was based on pathology (n = 19), clinical or neuroimaging response to tuberculous chemotherapy (n = 57), or evidence of systemic tuberculosis (n = 24). Neuropathological specimens of tuberculoma were graded for the amount of fibrosis, gliosis, necrosis, and cell types (lymphocytes, macrophages, plasma cells). RESULTS: One hundred patients (43 men) were identified. The age range was 1 to 75 years (mean = 30 y). The number of lesions ranged from 1 to > 100 (mean = 4.5 lesions/patient). Thirty-one patients had solitary lesions, whereas 69 had multiple lesions. Thirty-seven patients had hydrocephalus. After contrast administration, > 450 lesions were seen on CT and MRI images in all 100 scans. The diameter of these enhancing lesions ranged from 1 mm to 5 cm. Lesions > 1 cm showed varied enhancement, including irregular shapes, ringlike shapes, open rings, and lobular patterns. Targetlike lesions were seen in only 2 patients. Other features included cortical and subcortical infarcts (12 patients), calcification (10% of lesions), edema (33 patients), meningeal enhancement (12 patients), mass effect, and/or midline shift (18 patients). A hypointense core with a hyperintense rim was the most common signal characteristic on T2-weighted MRI. The central hypointensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images reflected extensive necrosis and hypercellularity. CONCLUSION: Multiple tuberculomas and infratentorial locations were more common in the authors' patient population than in previous reports. The MRI signal characteristics of intracranial tuberculoma are extremely diverse. An isointense or hypointense core with a hyperintense rim on T2-weighted and FLAIR images is the most common presentation. Core hypointensity of lesions on these images is related to necrosis and the large number of cells.