THE ROLE OF INTRAVITREAL METHOTREXATE AS AN ADJUNCT TO LOCAL OR SYSTEMIC CORTICOSTEROIDS IN VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT AND CHOROIDAL DETACHMENT: A Pilot Study.

PURPOSE: To evaluate the role of repeated intravitreal methotrexate as an adjunct to pars plana vitrectomy in the management of rhegmatogenous retinal detachment with choroidal detachment. METHOD: The authors compared anatomical and visual outcomes of rhegmatogenous retinal detachment with choroidal detachment eyes that underwent pars plana vitrectomy with (Group B) or without repeated intravitreal methotrexate (Group A). RESULTS: The study included 25 eyes of 25 patients, 16 eyes in Group A and nine in Group B. Both groups had similar baseline characteristics. In Group A, successful retinal attachment was achieved in 50% as compared with 89% in Group B; however, the difference was not statistically significant ( P = 0.08). Also, Group B had a significantly greater change in visual acuity from baseline to the last follow-up visit (1.6 + 1.5 logMAR units) compared with Group A (1.18 + 1 logMAR units) ( P = 0.05). There were no significant safety concerns with the use of intravitreal methotrexate. CONCLUSION: Repeated intravitreal methotrexate after vitrectomy for rhegmatogenous retinal detachment with choroidal detachment improves outcomes without posing major safety concerns. Nonetheless, further investigation is necessary to establish the optimal intravitreal methotrexate dosage and duration to prevent recurrence effectively.

MEDIUM-TERM PERFLUORO-N-OCTANE AS RESCUE POSTOPERATIVE TAMPONADE FOR VERY COMPLEX RETINAL DETACHMENTS: ANATOMICAL AND FUNCTIONAL OUTCOMES.

PURPOSE: To report the anatomical and functional outcomes of medium-term perfluoro-n-octane (PFO) tamponade as a rescue procedure in very complex retinal detachments (RDs). METHODS: We reviewed the case records of 35 consecutive patients who underwent vitrectomy for very complex RDs due to diverse etiologies. The surgical complexity was so graded because of the intraoperative failure to ascertain complete retinal reattachment; perfluoro-n-octane was used as rescue tamponade for 2 to 4 weeks. The second intervention included additional membrane peeling, retinectomy, endophotocoagulation, and gas/silicone oil tamponade. The minimum follow-up was 3 months after the final intervention: the primary outcome was retinal reattachment and the secondary outcome was change in best-corrected visual acuity (BCVA). RESULTS: The most common presentations were severe trauma with retinal incarceration, preretinal and subretinal hemorrhage, or chronic/recurrent RDs with anterior proliferative vitreoretinopathy. Preoperative BCVA was ≤counting fingers in 31 (88.6%) patients. Complete retinal attachment without any tamponade was achieved in 33 (94.3%) eyes. best-corrected visual acuity improved in 30 (85.7%) eyes: 16 (45.7%) had BCVA ≥20/200 and 21 (60%) regained ambulatory vision (≥5/200). Two eyes developed keratopathy, and four needed antiglaucoma medications. CONCLUSION: We achieved excellent anatomical outcomes and acceptable functional outcomes in nearly inoperable RDs with few side effects. Medium-term perfluoro-n-octane tamponade can be used as a salvage procedure in very complex RDs where intraoperative reattachment cannot be ensured.

Current Challenges for the Effective Management of the COVID-19 Pandemic.

INTRODUCTION: Within a short period, the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) spread all over the globe and became the first pandemic of the present century. Early diagnostic tools and effective drugs are urgently needed to effectively manage the COVID-19 pandemic. Based on current literature, we provide recent updates on SARS-CoV-2 biology, available diagnostic methods, and therapeutic options for the management of COVID-19 pandemic. METHODS: A literature survey was done using Google and PubMed and Web of Science to summarize the current updates on this topic. RESULTS: Current coronavirus diagnostic tests are reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR (qRT-PCR), and reverse transcription loop-mediated isothermal amplification (RT-LAMP) which detects the presence of specific genome sequence of virus. Existing antiviral drugs or new therapeutic options such as neutralizing antibody or plasma therapy are mostly used to restrict the virus growth with a limited success. CONCLUSION: As there is no specific treatment or vaccine available to limit the infection of SARS-CoV-2, we need to rely on the existing way to limit the disease. The first priority to fight COVID-19 is development of early diagnostic tools so that infected persons can be identified and further viral transmission can be blocked. Evaluation of existing drugs or identification of new therapeutic entities becomes the major challenge to deal with the present pandemic.

Clinical Characteristics and Remedy Profiles of Patients with COVID-19: A Retrospective Cohort Study.

OBJECTIVE: The aim of the study was to identify indicated homeopathic remedies based on the clinical characteristics of coronavirus disease 2019 (COVID-19) patients in India. METHODS: In this retrospective, cohort study, confirmed COVID-19 patients admitted at a COVID Health Centre in New Delhi between April 29 and June 17, 2020 were given conventional and homeopathic treatment. Patients were grouped into mild, moderate or severe categories of disease. Their symptomatologic profiles were analyzed to identify indicated homeopathic medicines. RESULTS: A total of 196 COVID-19 patients were admitted. One hundred and seventy-eight patients had mild symptoms; eighteen patients had moderate symptoms; no patients with severe symptoms were included as they were referred to tertiary care centers with ventilatory support. The mean age of patients with mild symptoms was significantly lower (38.6 years; standard deviation or SD ± 15.8) compared with patients in the moderate category (66.0 years; SD ± 9.09). The most important symptoms identified were fever (43.4%), cough (47.4%), sore throat (29.6%), headache (18.4%), myalgia (17.9%), fatigue (16.8%), chest discomfort (13.8%), chills (12.6%), shortness of breath (11.2%) and loss of taste (10.2%). Twenty-eight homeopathic medicines were prescribed, the most frequently indicated being Bryonia alba (33.3%), Arsenicum album (18.1%), Pulsatilla nigricans (13.8%), Nux vomica (8%), Rhus toxicodendron (7.2%) and Gelsemium sempervirens (5.8%), in 30C potency. CONCLUSION: Data from the current study reveal that Arsenicum album, Bryonia alba, Pulsatilla nigricans, Nux vomica, Rhus toxicodendron and Gelsemium sempervirens are the most frequently indicated homeopathic medicines. A randomized controlled clinical trial based on this finding is the next step.

Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1-mediated neutrophilic acute lung inflammation.

Neutrophil infiltration represents the early acute inflammatory response in acute lung injury. The recruitment of neutrophils from the peripheral blood across the endothelial-epithelial barrier into the alveolar airspace is highly regulated by the adhesion molecules on alveolar epithelial cells (AECs). Wnt/ß-catenin signaling is involved in the progression of inflammatory lung diseases including asthma, emphysema, and pulmonary fibrosis. However, the function of Wnt/ß-catenin signaling in acute lung inflammation is unknown. Here, we identified platelet-derived Dickkopf-1 (Dkk1) as the major Wnt antagonist contributing to the suppression of Wnt/ß-catenin signaling in AECs during acute lung inflammation. Intratracheal administration of Wnt3a or an antibody capable of neutralizing Dkk1 inhibited neutrophil influx into the alveolar airspace of injured lungs. Activation of Wnt/ß-catenin signaling in AECs attenuated intercellular adhesion molecule 1 (ICAM-1)/vascular cell adhesion molecule 1 (VCAM-1)-mediated adhesion of both macrophages and neutrophils to AECs. Our results suggest a role for Wnt/ß-catenin signaling in modulating the inflammatory response, and a functional communication between platelets and AECs during acute lung inflammation. Targeting Wnt/ß-catenin signaling and the communication between platelets and AECs therefore represents potential therapeutic strategies to limit the damage of acute pulmonary inflammation.

Role of microRNA-150 and glycoprotein nonmetastatic melanoma protein B in angiogenesis during hyperoxia-induced neonatal lung injury.

Glycoprotein nonmetastatic melanoma protein B (GPNMB), a transmembrane protein, has been reported to have an important role in tissue repair and angiogenesis. Recently, we have demonstrated that hyperoxia exposure down-regulates microRNA (miR)-150 expression and concurrent induction of its target gene, GPNMB, in neonatal rat lungs. This study aimed to test the hypothesis that soluble GPNMB (sGPNMB) promotes angiogenesis in the hyperoxic neonatal lungs. Wild-type (WT) or miR-150 knockout (KO) neonates, exposed to 95% O2 for 3, 6, and 10 days, were evaluated for lung phenotypes, GPNMB protein expression in the lungs, and sGPNMB levels in the bronchoalveolar lavage. Angiogenic effects of sGPNMB were examined both in vitro and in vivo. After a 6-day exposure, similar analyses were performed in WT and miR-150 KO neonates during recovery at 7, 14, and 21 days. miR-150 KO neonates displayed an increased capillary network, decreased inflammation, and less alveolar damage compared with WT neonates after hyperoxia exposure. The early induction of GPNMB and sGPNMB were found in miR-150 KO neonates. The recombinant GPNMB, which contained a soluble portion of GPNMB, promoted endothelial tube formation in vitro and enhanced angiogenesis in vivo. The increased capillaries in the hyperoxic lungs of miR-150 KO neonates appeared dysmorphic. They were abnormally enlarged in size and occasionally laid at subepithelial regions in the alveoli. However, the lung architecture returned to normal during recovery, suggesting that abnormal vascularity during hyperoxia does not affect postnatal lung development. GPNMB plays an important role in angiogenesis during hyperoxia injury. Treatment with GPNMB may offer a novel therapeutic approach in reducing pathologic complications in bronchopulmonary dysplasia.

Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels.

Polyphosphate (polyP), a polymer of orthophosphate moieties released from the dense granules of activated platelets, is a procoagulant agent. Inositol pyrophosphates, another group of phosphate-rich molecules, consist of mono- and diphosphates substituted on an inositol ring. Diphosphoinositol pentakisphosphate (IP7), the most abundant inositol pyrophosphate, is synthesized on phosphorylation of inositol hexakisphosphate (IP6) by IP6 kinases, of which there are 3 mammalian isoforms (IP6K1/2/3) and a single yeast isoform. Yeast lacking IP6 kinase are devoid of polyP, suggesting a role for IP6 kinase in maintaining polyP levels. We theorized that the molecular link between IP6 kinase and polyP is conserved in mammals and investigated whether polyP-dependent platelet function is altered in IP6K1 knockout (Ip6k1(-/-)) mice. We observe a significant reduction in platelet polyP levels in Ip6k1(-/-) mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots was reduced in Ip6k1(-/-) mice, thereby altering clot ultrastructure, which was rescued on the addition of exogenous polyP. In vivo assays revealed longer tail bleeding time and resistance to thromboembolism in Ip6k1(-/-) mice. Taken together, our data suggest a novel role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels.

Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers.

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.

Management of rhegmatogenous retinal detachment with coexisting macular hole: a comparison of vitrectomy with and without internal limiting membrane peeling.

PURPOSE: To compare the outcomes of vitrectomy with or without internal limiting membrane peeling for rhegmatogenous retinal detachment and coexisting macular hole. METHODS: Thirty-one consecutive patients (31 eyes) with macula-off retinal detachment, peripheral breaks and a coexisting macular hole were prospectively enrolled over a 3-year period. All patients underwent vitrectomy with encirclage and gas or silicone oil tamponade. The 17 patients who underwent internal limiting membrane peeling for macular hole constituted Group A and the remaining 14 patients constituted Group B. The main outcome measures were change in best-corrected visual acuity, retinal reattachment, macular hole closure, and type of macular hole closure. RESULTS: The two groups were comparable in preoperative demographics and clinical parameters. The retinal reattachment rate was 100% in both the groups. Macular hole closed in 14 of 17 eyes (82.4%) in Group A and 13 of 14 eyes (92.9%) in Group B (P = 0.607). A flat-open configuration of macular hole closure was observed in 8 of 14 eyes (57%) in Group A and 3 of 13 eyes (27.5%) in Group B (P = 0.188). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved to 1.0 ± 0.3 (20/200; range, 0.8-1.7) in Group A and 0.6 ± 0.2 (20/80; range, 0.3-1.1) in Group B (P < 0.0001). Ten patients achieved best-corrected visual acuity of ≥ 20/80 in Group B and none in Group A (P < 0.0001). CONCLUSION: The anatomical and visual outcomes of vitrectomy without internal limiting membrane peeling in macular hole in retinal detachment were similar to or better than the outcomes obtained with internal limiting membrane peeling.

Diagnostic significance of dysregulated miRNAs in T-cell malignancies and their metabolic roles.

T-cell malignancy is a broad term used for a diverse group of disease subtypes representing dysfunctional malignant T cells transformed at various stages of their clonal evolution. Despite having similar clinical manifestations, these disease groups have different disease progressions and diagnostic parameters. The effective diagnosis and prognosis of such a diverse disease group demands testing of molecular entities that capture footprints of the disease physiology in its entirety. MicroRNAs (miRNAs) are a group of noncoding RNA molecules that regulate the expression of genes and, while doing so, leave behind specific miRNA signatures corresponding to cellular expression status in an altered stage of a disease. Using miRNAs as a diagnostic tool is justified, as they can effectively distinguish expressional diversity between various tumors and within subtypes of T-cell malignancies. As global attention for cancer diagnosis shifts toward liquid biopsy, diagnosis using miRNAs is more relevant in blood cancers than in solid tumors. We also lay forward the diagnostic significance of miRNAs that are indicative of subtype, progression, severity, therapy response, and relapse. This review discusses the potential use and the role of miRNAs, miRNA signatures, or classifiers in the diagnosis of major groups of T-cell malignancies like T-cell acute lymphoblastic lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), extranodal NK/T-cell lymphoma (ENKTCL), and cutaneous T-cell lymphoma (CTCL). The review also briefly discusses major diagnostic miRNAs having prominent metabolic roles in these malignancies to highlight their importance among other dysregulated miRNAs.

Orchestral role of lipid metabolic reprogramming in T-cell malignancy.

The immune function of normal T cells partially depends on the maneuvering of lipid metabolism through various stages and subsets. Interestingly, T-cell malignancies also reprogram their lipid metabolism to fulfill bioenergetic demand for rapid division. The rewiring of lipid metabolism in T-cell malignancies not only provides survival benefits but also contributes to their stemness, invasion, metastasis, and angiogenesis. Owing to distinctive lipid metabolic programming in T-cell cancer, quantitative, qualitative, and spatial enrichment of specific lipid molecules occur. The formation of lipid rafts rich in cholesterol confers physical strength and sustains survival signals. The accumulation of lipids through de novo synthesis and uptake of free lipids contribute to the bioenergetic reserve required for robust demand during migration and metastasis. Lipid storage in cells leads to the formation of specialized structures known as lipid droplets. The inimitable changes in fatty acid synthesis (FAS) and fatty acid oxidation (FAO) are in dynamic balance in T-cell malignancies. FAO fuels the molecular pumps causing chemoresistance, while FAS offers structural and signaling lipids for rapid division. Lipid metabolism in T-cell cancer provides molecules having immunosuppressive abilities. Moreover, the distinctive composition of membrane lipids has implications for immune evasion by malignant cells of T-cell origin. Lipid droplets and lipid rafts are contributors to maintaining hallmarks of cancer in malignancies of T cells. In preclinical settings, molecular targeting of lipid metabolism in T-cell cancer potentiates the antitumor immunity and chemotherapeutic response. Thus, the direct and adjunct benefit of lipid metabolic targeting is expected to improve the clinical management of T-cell malignancies.

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.

T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.