A Rose by Any Other Name? The Potential Consequences of Microglial Heterogeneity During CNS Health and Disease

Microglial activation and macrophage infiltration into the CNS are common features of CNS autoimmune disease and of chronic neurodegenerative diseases. Because these cells largely express an overlapping set of common macrophage markers, it has been difficult to separate their respective contributions to disease onset and progression. This problem is further confounded by the many types of macrophages that have been termed microglia. Several approaches, ranging from molecular profiling of isolated cells to the generation of irradiation chimeric rodent models, are now beginning to generate rudimentary definitions distinguishing the various types of microglia and macrophages found within the CNS and the potential roles that these cells may play in health and disease.     

Neuroprotection in glaucoma

Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents’ efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.     

Simultaneous spectrophotometric estimation of Hydrochlorothiazide, Atenolol and Losartan potassium in tablet dosage form

Two simple, accurate and reproducible spectrophotometric methods have been developed for the simultaneous estimation of Hydrochlorothiazide (Hctz), Atenolol (Atn) and Losartan potassium (Los) in combined tablet dosage forms. The first method involves determination using the simultaneous equation method, the sampling wavelengths selected are, 272.5 nm, 224 nm and 250 nm over the concentration ranges of 0.5-30 microg/ml, 1-50 microg/ ml and 1-60 microg/ml for Hctz, Atn and Los respectively. The second method is the First order derivative method, the sampling wavelengths selected for estimation of Hctz, Atn and Los are 280.5 nm, 233 nm and 244 nm with linearity in the concentration ranges of 0.5-30 microg/ ml, 1-50 microg/ml and 1-60 microg/ml respectively. The results of the analysis were validated statistically and recovery studies were carried out as per ICH guidelines.     

RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration

Accumulating evidence suggests that presence of macrophages in the tumor microenvironment add to the invasive and tumor-promoting hallmarks of cancer cells by secreting angiogenic and growth factors. RKIP is a known metastasis suppressor and interferes with several steps of metastasis. However, the mechanistic underpinnings of its function as a broad metastasis suppressor remain poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of-function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of the CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as important negative regulator of tumor microenvironment.     

Boston Type 2 keratoprosthesis- mid term outcomes from a tertiary eye care centre in India

To analyse the anatomical and functional outcomes of Boston type II keratoprosthesis at a tertiary eye care centre in South India. Retrospective chart review of 10 patients operated with Boston keratoprosthesis Type 2 between Feb 2013 and June 2017 were analysed. Outcome measures analysed included, visual outcome, device retention and postoperative complications. The most common indication for surgery was SJS in 80% (8 of 10 eyes). Mean follow-up duration was 2.75 years (0.5–5 years, SD?-?1.71, median 32 months) Postoperative visual acuity improved to better than 20/200 in 7 eyes and better than 20/30 in 6 eyes with device retention in 9 eyes at last follow-up. Pre-existing glaucoma was noted in 1 eye. RPM was noted in 1 eye, retinal detachment in 1 eye, endophthalmitis in 1 eye and sterile melt requiring kpro replacement in 1 eye. No progression or development of glaucoma was noted postoperatively in any eye . Boston type 2 keratoprosthesis is a viable option to restore vision in patients with end stage ocular surface disorders. Though the procedure can be associated with complications, early as well as late, our midterm outcome appears to be encouraging.     

Novel dithranol phospholipid microemulsion for topical application: development, characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm2/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

In vitro activity of aztreonam–avibactam against Enterobacterales isolates collected in Latin America,Africa/Middle East,Asia, and Eurasia for the ATLAS Global Surveillance Program in 2019–2021

This study aimed to report reference method antimicrobial susceptibility results for 24,937 recent (2019–2021) clinical isolates of Enterobacterales from 27 countries in Latin America, Eurasia, Africa/Middle East, and Asia with a focus on the investigational combination aztreonam–avibactam against metallo-β-lactamase (MBL) isolates. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution methodology. Minimum inhibitory concentrations (MICs) were interpreted using the CLSI (2022) breakpoints for all agents except aztreonam–avibactam (provisional pharmacokinetic/pharmacodynamic susceptible breakpoint, ≤ 8 mg/L) and tigecycline (US-FDA). Molecular testing for β-lactamase genes was performed on isolates with meropenem MICs ≥ 2 mg/L, ceftazidime–avibactam MICs ≥ 16 mg/L, and/or aztreonam–avibactam MICs ≥ 16 mg/L, and 50% of isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs ≥ 2 mg/L. Aztreonam–avibactam inhibited 99.8% of all Enterobacterales at ≤ 8 mg/L (MIC₉₀, 0.25 mg/L) and maintained activity against phenotypically resistant subsets of multidrug-resistant (MDR) (99.5% susceptible), extensively drug-resistant (XDR) (98.7%), and carbapenem-resistant Enterobacterales (CRE) (99.1%) isolates. At ≤ 8 mg/L, aztreonam–avibactam inhibited 100%, 99.6%, 99.6%, and 98.8% of KPC-, OXA-48-like-, ESBL-, and MBL-carrying isolates, respectively. MBL-positive isolates were most prevalent in India (20.5%), Guatemala (13.8%), and Jordan (13.2%). No differences in the activity of aztreonam–avibactam were observed across the global regions evaluated. At a concentration of ≤ 8 mg/L, aztreonam–avibactam inhibited almost all Enterobacterales collected from developing countries, including MBL-producing isolates. The widespread dissemination of MBLs among Enterobacterales highlights the unmet need for new agents such as aztreonam–avibactam for the treatment of CRE infections.