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.     

Adverse Childhood Experiences are Associated with Miscarriage in Adulthood: The GROWH Study

Maternal and Child Health Journal - To investigate whether adverse childhood experiences are associated with miscarriage. The Gulf Resilience on Women’s Health Consortium recruited from...     

The effect of various media and probe angles on the power output of the Cyclo G6 Glaucoma Laser System

Lasers in Medical Science - To evaluate the effect of various media and Iridex MicroPulse P3 (MP3) probe angles on the power output from the Cyclo G6 Glaucoma Laser (G6) System. A laser power meter...     

Correction of pre-existing astigmatism by on-axis incision size modulation in manual small-incision cataract surgery

Purpose:To study the effect of wound size modulation on pre-existing astigmatism by on-axis placement of incision in manual small-incision cataract surgery (MSICS).Methods:In this prospective interventional study conducted at a tertiary care centre, 40 eyes of 40 consecutive senile cataract patients with 1.00–3.00 D corneal astigmatism were enrolled for the study. MSICS by modified Blumenthal’s technique was performed through 6.0, 6.5, and 7.0 mm on-axis incision in 1.0–1.49 D (group A), 1.50–1.99 D (group B), and 2.00–3.00 D (group C) astigmatism, respectively. Surgically induced astigmatism (SIA) was calculated by vector analysis and double angle plots (DAP) at 12 weeks postoperatively.Results:There were 22 males and 18 females with mean age of 58.12 ± 1.18 years. The mean SIA at 12 weeks was 0.85 ± 0.28 D in group A (17 eyes), 1.32 ± 0.65 D in group B (10 eyes), and 1.91 ± 0.69 D in group C (13 eyes). The overall median uncorrected visual acuity was 0.18 (IQR = 0 to 0.2). The mean astigmatism decreased from 1.95 ± 0.74 D to 1.04 + 0.57 D (P = 0.00) in superior incision and from 1.70 + 0.50 D to 0.92 ± 0.45 D (P = 0.00) in temporal incision group with central shift of centroid in all cases.Conclusion:The customization of on-axis external incision size can be used to manage pre-existing corneal astigmatism of less than 3.00 D using both temporal and superior incisions effectively.     

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.     

Complete and incomplete lower motor neuron facial palsy in post-COVID-19 mucormycosis

Purpose:To study facial nerve palsy (FNP) in post-COVID-19-mucormycosis patients and its ocular complications, report different presentations of FNP in such patients, and propose its etiopathogenesis based on presentation and clinico-radiologic localization.Methods:A prospective cohort study was carried out in patients of post-COVID-19-mucormycosis who presented at our tertiary center, over a period of 3 months. Motor and sensory examination of the facial nerve was done to diagnose FNP and localize the lesion clinically. Slit-lamp examination was done for grading corneal involvement. MRI brain, orbit, and paranasal sinuses (PNS) with contrast were studied to find involvement along the facial nerve. It was assessed whether this site of lesion corresponded with clinical localization. Data were analyzed using the percentage of total cases and Fisher’s test.Results:A total of 300 patients with post-COVID-19 mucormycosis were examined, of which 30 (10%) patients were found to have FNP. All were lower motor neuron (LMN) type and were associated with corneal complications. The most common site clinically was distal to the chorda tympani (66.66%) and radiologically was infratemporal (IT) fossa (63.4%). The clinical localization significantly correlated with the radiological findings (P = 0.012). Twenty percent of patients showed incomplete involvement of facial musclesConclusion:FNP was found to be of LMN type. The most common site of insult was IT fossa. There was a good clinico-radiological correspondence of lesions. Isolated lesions were also found along the peripheral nerve course, presenting as incomplete facial palsy. Recognition of FNP in post-COVID-19 mucormycosis, in all its variable forms, is important to manage corneal complications.     

Influence of copy number on the expression levels of pandemic influenza hemagglutinin recombinant protein in methylotrophic yeast Pichia pastoris

The hemagglutinin (HA) gene of novel Swine Origin Influenza A/California/04/2009 (H1N1) was engineered for expression in Pichia pastoris as a soluble secreted protein. The full length HA-synthetic gene having ?? secretory tag under the control of AOX1 promoter was integrated into P. pastoris genome through homologous recombination. The resultant Pichia clones having single and multiple copy integrants of the expression cassettes were screened for the expression of full length HA protein in the culture supernatant. In order to completely exploit the expression potential of the P. pastoris expression system, a systematic investigation on the influence of gene copy number on the expression of the recombinant protein was made. A panel of Pichia clones carrying increasing copies of the heterologous gene was selected based on Geneticin resistance and SYBR green-based quantitative real-time PCR approach. Using these strategies, recombinant Pichia transformants carrying up to a maximum of four to six copies of the transgene were identified. After optimising the expression conditions for shaker flask culture, the resultant clones demonstrated that the increase in copy number results in a proportional elevation in the expression level of H1N1HA recombinant protein. Our findings clearly suggest that the gene dosage effect play a vital role in high level expression of the pandemic Influenza HA protein in yeast system.     

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.     

Approaches for CNS delivery of drugs – nose to brain targeting of antiretroviral agents as a potential attempt for complete elimination of major reservoir site of HIV to aid AIDS treatment

Introduction: Human immune-deficiency virus (HIV) infection causing acquired immune-deficiency syndrome (AIDS) is one of the most life-threatening infections. The central nervous system (CNS) is reported to be the most important HIV reservoir site where the antiretroviral drugs are unable to reach.

Areas covered: This article includes the review about HIV infections, its pathogenesis, HIV infections in CNS, its consequences, current therapies, challenges associated with the existing therapies, approaches to overcome them, CNS delivery of drugs – barriers, transport routes, approaches for transporting drugs across the blood–brain barrier, nasal route of drug delivery, and nose to brain targeting of antiretroviral agents as a potential approach for complete cure of AIDS.

Expert opinion: Various approaches are exploited to enhance the drug delivery to the brain for various categories of drugs. However, very few have investigated on the delivery of antiretrovirals to the brain. Targeting antiretrovirals to CNS through oral/nasal routes along with oral/parenteral delivery of drug to the plasma can be a promising approach for an attempt to completely eradicate HIV reservoir and cure AIDS, after clinical trials. Further research is required to identify the exact location of the HIV reservoir in CNS and developing good animal models for evaluation of different newly developed formulations.