Neuropathological Features of Covid-19 Solomon, Isaac H; Normandin, Erica; Bhattacharyya, Shamik ...
The New England journal of medicine,
09/2020, Letnik:
383, Številka:
10
Journal Article
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Eighteen brains of patients who died 0 to 32 days after the onset of symptoms of SARS-CoV-2 infection showed hypoxic–ischemic changes but no encephalitis, meningitis, strokes, or changes in olfactory ...bulbs or tracts. Low viral counts were detected by quantitative RT-PCR in a few brain sections, and no virus was evident on immunohistochemical analysis.
Osteoarthritis is a debilitating joint disease affecting nearly 30 million people for which there are no disease-modifying therapies. Several drugs that have failed clinical trials have shown ...inefficient and inadequate delivery to target cells. Anabolic growth factors are one class of such drugs that could be disease-modifying if delivered directly to chondrocytes, which reside deep within dense, anionic cartilage tissue. To overcome this biological barrier, we conjugated a growth factor to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. The nanocarrier uses reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. Amine terminal polyamidoamine (PAMAM) dendrimers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. From this small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected. When conjugated to insulin-like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold for up to 30 days. In a surgical model of rat osteoarthritis, a single injection of dendrimer-IGF-1 rescued cartilage and bone more effectively than free IGF-1. Dendrimer-IGF-1 reduced width of cartilage degeneration by 60% and volumetric osteophyte burden by 80% relative to untreated rats at 4 weeks after surgery. These results suggest that PEGylated PAMAM dendrimer nanocarriers could improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.
Two dry surfaces can instantly adhere upon contact with each other through intermolecular forces such as hydrogen bonds, electrostatic interactions and van der Waals interactions
. However, such ...instant adhesion is challenging when wet surfaces such as body tissues are involved, because water separates the molecules of the two surfaces, preventing interactions
. Although tissue adhesives have potential advantages over suturing or stapling
, existing liquid or hydrogel tissue adhesives suffer from several limitations: weak bonding, low biological compatibility, poor mechanical match with tissues, and slow adhesion formation
. Here we propose an alternative tissue adhesive in the form of a dry double-sided tape (DST) made from a combination of a biopolymer (gelatin or chitosan) and crosslinked poly(acrylic acid) grafted with N-hydrosuccinimide ester. The adhesion mechanism of this DST relies on the removal of interfacial water from the tissue surface, resulting in fast temporary crosslinking to the surface. Subsequent covalent crosslinking with amine groups on the tissue surface further improves the adhesion stability and strength of the DST. In vitro mouse, in vivo rat and ex vivo porcine models show that the DST can achieve strong adhesion between diverse wet dynamic tissues and engineering solids within five seconds. The DST may be useful as a tissue adhesive and sealant, and in adhering wearable and implantable devices to wet tissues.
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem ...thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
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•Germinal centers are lost in lymph nodes and spleens in acute COVID-19•Bcl-6+ GC B cells and Bcl-6+ T follicular helper cells are markedly diminished•Abundant TH1 cells and aberrant TNF-α production are seen in COVID-19 lymph nodes•SARS-CoV-2-specific activated B cells accumulate in the blood of patients
Shiv Pillai and colleagues show that in acute COVID-19, there is a striking loss of germinal centers in lymph nodes and spleens and depletion of Bcl-6+ B cells but preservation of AID+ B cells. A specific block in germinal center type Bcl-6+ T follicular helper cell differentiation may explain the loss of germinal centers and the accumulation of non-germinal-center-derived activated B cells. These data suggest an underlying basis for the lower quality and lack of durability of humoral immune responses observed during natural infection with SARS-CoV-2 and have significant implications for expectations of herd immunity.
This letter describes an immunocompromised patient who had persistent infection with SARS-CoV-2 over a period of months, despite several courses of remdesivir. Phylogenetic analysis showed ...accelerated viral evolution.
Tumors Metastatic to the Heart Goldberg, Aaron D; Blankstein, Ron; Padera, Robert F
Circulation (New York, N.Y.),
2013-October-15, Letnik:
128, Številka:
16
Journal Article
Abstract Drug eluting coatings that can direct the host tissue response to implanted medical devices have the potential to ameliorate both the medical and financial burden of complications from ...implantation. However, because many drugs useful in this arena are biologic in nature, a paucity of delivery strategies for biologics, including growth factors, currently limits the control that can be exerted on the implantation environment. Layer-by-Layer (LbL) polyelectrolyte multilayer films are highly attractive as ultrathin biologic reservoirs, due to the capability to conformally coat difficult geometries, the use of aqueous processing likely to preserve fragile protein function, and the tunability of incorporation and release profiles. Herein, we describe the first LbL films capable of microgram-scale release of the biologic Bone Morphogenetic Protein 2 (BMP-2), which is capable of directing the host tissue response to create bone from native progenitor cells. Ten micrograms of BMP-2 are released over a period of two weeks in vitro; less than 1% is released in the first 3 h (compared with commercial collagen matrices which can release up to 60% of BMP-2, too quickly to induce differentiation). BMP-2 released from LbL films retains its ability to induce bone differentiation in MC3T3 E1S4 pre-osteoblasts, as measured by induction of alkaline phosphatase and stains for calcium (via Alizarin Red) and calcium matrix (via Von Kossa). In vivo , BMP-2 film coated scaffolds were compared with film coated scaffolds lacking BMP-2. BMP-2 coatings implanted intramuscularly were able to initiate host progenitor cells to differentiate into bone, which matured and expanded from four to 9 weeks as measured by MicroCT and histology. Such LbL films represent new steps towards controlling and tuning host response to implanted medical devices, which may ultimately increase the success of implanted devices, provide alternative new approaches toward bone wound healing, and lay the foundation for development of a multi-therapeutic release coating.
Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6–8 week ...period of joint immobilization exists as today’s gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we demonstrate that a single-stage revision using prostheses coated with self-assembled, hydrolytically degradable multilayers that sequentially deliver the antibiotic (gentamicin) and the osteoinductive growth factor (BMP-2) in a time-staggered manner enables both eradication of established biofilms and complete and rapid bone tissue repair around the implant in rats with induced osteomyelitis. The nanolayered construct allows precise independent control of release kinetics and loading for each therapeutic agent in an infected implant environment. Antibiotics contained in top layers can be tuned to provide a rapid release at early times sufficient to eliminate infection, followed by sustained release for several weeks, and the underlying BMP-2 component enables a long-term sustained release of BMP-2, which induced more significant and mechanically competent bone formation than a short-term burst release. The successful growth factor-mediated osteointegration of the multilayered implants with the host tissue improved bone-implant interfacial strength 15-fold when compared with the uncoated one. These findings demonstrate the potential of this layered release strategy to introduce a durable next-generation implant solution, ultimately an important step forward to future large animal models toward the clinic.
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has led to a global public health crisis. In elderly individuals and those with comorbidities, COVID-19 is associated with high mortality, ...frequently caused by acute respiratory distress syndrome. We examine in situ expression of SARS-CoV-2 in airways and lung obtained at autopsy of individuals with confirmed COVID-19 infection. Seven autopsy cases (male, N = 5; female, N = 2) with reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection and a median age of 66 years (range, 50–77 years) were evaluated using a rabbit polyclonal antibody against SARS Nucleocapsid protein in correlation with clinical parameters. The median time from symptom onset to death was 9 days (range, 6–31 days), from hospitalization 7 days (range, 1–21 days), from positive RT-PCR 7 days (range, 0–18 days), and from intensive care unit admission defining onset of respiratory failure 3 days (range, 1–18 days). Chest imaging identified diffuse airspace disease in all patients corresponding to acute and (N = 5) or organizing (N = 2) diffuse alveolar damage (DAD) on histologic examination. Among five patients with acute-phase DAD (≤7 days from onset of respiratory failure), SARS-CoV-2 was detected in pulmonary pneumocytes and ciliated airway cells (N = 5), and in upper airway epithelium (N = 2). In two patients with organizing DAD (>14 days from onset of respiratory failure), no virus was detected in lungs or airways. No endothelial cell infection was observed. The findings suggest that SARS-CoV-2 infection of epithelial cells in lungs and airways of patients with COVID-19 who developed respiratory failure can be detected during the acute phase of lung injury and is absent in the organizing phase.
Abstract
Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in ...diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year.
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