Clinical presentation and treatment outcomes of an algorithmic approach to uveal effusion syndrome

Purpose:To describe the clinical features and treatment outcomes in spontaneous uveal effusion syndrome (UES).Methods:A 10-year retrospective chart review of UES patients from a tertiary eye center was carried out. Optical coherence tomography (OCT), fundus fluorescein angiography, and ultrasound biomicroscopy (UBM) scans were performed. UES was managed based on presenting best-corrected visual acuity (BCVA), symptoms, and fundus findings. Patients with secondary causes of uveal effusion were excluded.Results:Twenty-five eyes of 16 patients were included. Of the 16 patients, 14 (88%) were male and 9 (56%) had bilateral disease. Fifteen of 25 affected eyes had nanophthalmos (axial length (AL) <20.5 mm) and 6 had hyperopia with AL >20.5 mm. The presenting mean distance BCVA was 0.74 ± 0.64 logMAR (mean Snellen: 20/100). Eleven eyes had exudative retinal detachment, and 4 also had exudative choroidal detachment (CD). Choroidal thickness (CT) was increased in 11 eyes on B-scan ultrasonography, and the mean CT was 1.74 ± 0.38 mm. Sub-retinal fluid (SRF) and retinal folds were the most common OCT findings. UBM findings included shallow angles, peripheral CD, and supra-ciliary effusion. A combination of local and systemic corticosteroids was used to successfully treat 12 eyes, 6 needed surgery, and 7 were observed. Partial sclerectomy with anterior chamber maintainer-assisted SRF drainage was the favored surgery. The median period of follow-up was 6.5 months (0.1–76 months), and the mean distance BCVA at the last follow-up was 0.58 ± 0.42 logMAR (mean Snellen: 20/80).Conclusion:UES can be suitably managed both medically and surgically based on clinical presentation.     

Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

Comparative Evaluation of Tensile Bond Strength between Silicon Soft Liners and Processed Denture Base Resin Conditioned by Three Modes of Surface Treatment: An Invitro Study

Soft denture liners act as a cushion for the denture bearing mucosa through even distribution of functional load, avoiding local stress concentrations and improving retention of dentures there by providing comfort to the patient. The objective of the present study was to compare and evaluate the tensile bond strengths of silicone-based soft lining materials (Ufi Gel P and GC Reline soft) with different surface pre treatments of heat cure PMMA denture base acrylic resin. Stainless steel dies measuring 40 mm in length; 10 mm in width and 10 mm in height (40 × 10 × 10) were machined to prepare standardized for the polymethyl methacrylate resin blocks. Stainless steel dies (spacer for resilient liner) measuring 3 mm thick; 10 mm long and 10 mm wide were prepared as spacers to ensure uniformity of the soft liner being tested. Two types of Addition silicone-based soft lining materials (room temperature polymerised soft lining materials (RTPSLM): Ufi Gel P and GC Reline soft) were selected. Ufi Gel P (VOCO, Germany), GC Reline soft (GC America) are resilient, chairside vinyl polysiloxane denture reliners of two different manufacturers. A total of 80 test samples were prepared of which 40 specimens were prepared for Group A (Ufi Gel P) and 40 specimens for Group B (GC Reline soft). In these groups, based on Pre-treatment of acrylic resin specimens each group was subdivided into four sub groups of 10 samples each. Sub-group I—without any surface treatment. Sub-group II—sand blasted Sub-group III—treated with Methyl Methacrylate monomer Sub-group IV-treated with chemical etchant Acetone. The results were statistically analysed by Kruscal Wallis test, Mann–Whitney U test, and Independent t test. The specimens treated with MMA monomer wetting showed superior and significant bond strength than those obtained by other surface treatments. The samples belonging to subgroups of GC Reline soft exhibit superior tensile bond strength than subgroups of Ufi Gel P. The modes of failure of all specimens were mostly adhesive in nature. Surface pre treatments by chemical means improved the bond strength between the silicone liners and denture base.     

ProDisc–C versus anterior cervical discectomy and fusion for the surgical treatment of symptomatic cervical disc disease: two-year outcomes of Asian prospective randomized controlled multicentre study

European Spine Journal - Our study aimed to evaluate non-inferiority of ProDisc-C to anterior cervical discectomy and fusion (ACDF) in terms of clinical outcomes and incidence of adjacent segment...     

Stress granule formation,disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity

While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The alphavirus virulence factor nonstructural protein 3 (nsP3) suppresses the formation of stress granules (SGs)—a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-binding proteins. Expression of ADP-ribosylhydrolase–deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-binding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during alphavirus infection.

Biomolecular condensates are prevalent in cells and critical for a range of cellular functions, including RNA metabolism, embryonic cell fate specification, and neuronal activity (1–3). While condensates often dynamically exchange components with the surrounding milieu, the overall composition of these cellular structures remains distinct (4). How cells control the specific composition of these condensates remains unclear. Stress granules (SGs), one of the best characterized biomolecular condensates, are RNA–protein assemblies formed in response to a variety of environmental cues (1). While SG composition can vary with the type of stress cue (5), certain common components, such as Ras GTP-activating protein-binding proteins G3BP1/2, are essential for formation of SGs (6, 7). Dysregulation of SG formation and disassembly is implicated in the pathogenesis of diseases, including viral infection, cancer, and neurodegeneration (2, 8–10).SG formation and disassembly are tightly regulated during viral infection, often reflecting cellular translation status (11–14). In the early phase of many viral infections, the presence of double-stranded viral RNAs (vRNAs) activate protein kinase R (PKR), resulting in eIF2α phosphorylation, messenger RNA (mRNA) translation inhibition, and formation of SGs enriched with translation initiation factors such as eIF3b. However, in later infection stages, many viruses instead suppress SG formation or disassemble SGs altogether. The mechanisms underlying this switch, and its physiological function, remain unclear.SG formation and disassembly are regulated by posttranslational modifications of proteins, including those that conjugate simple chemical groups, attach polypeptides, and add nucleotides as in the case of ADP-ribosylation (15–21). ADP-ribosylation refers to the addition of one or more ADP-ribose units onto proteins (22–24). In humans, ADP-ribosylation is accomplished primarily by a family of 17 ADP-ribosyltransferases, commonly known as poly(ADP-ribose) polymerases (PARPs). SG components are specifically ADP-ribosylated, and ADP-ribose polymers [i.e., poly(ADP-ribose) or PAR], five PARPs and two isoforms of the degradative enzyme PAR glycohydrolase (PARG) have been localized to these condensates (17, 25–27). Overexpression of these PARPs and PARG isoforms induces and suppresses SG formation, respectively, while PARG knockdown delays SG disassembly (17, 26). The noncovalent interaction between PAR and proteins facilitates SG targeting (25–27). For example, PAR-mediated targeting regulates TDP-43 localization to SGs and prevents the formation of pathological aggregates in amyotrophic lateral sclerosis (26, 27).The mosquito-borne alphaviruses, which cause a range of diseases from rashes and arthritis to encephalitis, induce SG formation early in infection and later initiate SG disassembly (11, 14, 28, 29). Previous studies have identified the alphaviral nonstructural protein 3 (nsP3), a key factor for virus replication and virulence (30–32), as able to suppress SG formation (28, 33–35). The alphaviral nsP3 is a tripartite protein composed of a highly conserved macrodomain (MD) in the N terminus, a central zinc-binding domain (ZBD), and a C-terminal hypervariable domain (HVD; ref. 30). Recent studies indicate that the HVD, which is of low complexity, directs alphaviral nsP3 binding to host SG proteins (30, 36). For example, the HVD of chikungunya virus (CHIKV) binds the essential SG components G3BP1 and G3BP2 (33, 37). Given that nsP3 expression increases over the course of viral infection, it has been proposed that nsP3 sequesters G3BP1/2, resulting in the suppression of SG formation during the late phase of infection (28, 29, 34).Here, we report that the expression of the G3BP-binding HVD alone does not suppress SG formation; rather, expression of the N-terminal MD alone can trigger the suppression of this biomolecular condensate. The structural integrity of SGs is dependent on ADP-ribosylation (17), and we and others recently found that the viral MD can remove single ADP-ribose groups, and possibly PAR, from ADP-ribosylated proteins (31, 38–40). We therefore hypothesized that MD ADP-ribosylhydrolase activity is required to suppress SG formation across stress conditions, with G3BP1 being a key target substrate. Indeed, we find that MD ADP-ribosylhydrolase activity is critical for disassembling SGs formed by G3BP1 expression and during viral infection. Consistent with this premise, live cell imaging revealed that SGs persist in cells infected with a hydrolase-deficient recombinant CHIKV. ADP-ribosylhydrolase activity is required for altering the composition of biomolecular condensates in nsP3-expressing or virus-infected cells and specifically regulates translation factor localization. Together, these data argue that nsP3 ADP-ribosylhydrolase activity modulates SG formation, disassembly, and composition.     

RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype

Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re‐expression. Furthermore, relapse‐free survival of non‐inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.