Tailoring Ag Electron Donating Ability for Organohalide Reduction: A Bilayer Electrode Design.

Electrochemical reduction of organohalides provides a green approach in the reduction of environmental pollutants, the synthesis of new organic molecules, and many other applications. The presence of a catalytic electrode can make the process more energetically efficient. Ag is known to be a very good electrode for the reduction of a wide range of organohalides. Herein, we examine the elementary adsorption and reaction steps that occur on Ag and the changes that result from changes in the Ag-coated metal, strain in Ag, solvent, and substrate geometry. The results are used to develop an electrode design strategy that can possibly be used to further increase the catalytic activity of pure Ag electrodes. We have shown how epitaxially depositing one to three layers of Ag on catalytically inert or less active support metal can increase the surface electron donating ability, thus increasing the adsorption of organic halide and the catalytic activity. Many factors, such as molecular geometry, lattice mismatches, work function, and solvents, contribute to the adsorption of organic halide molecules over the bilayer electrode surface. To isolate and rank these factors, we examined three model organic halides, namely, halothane, bromobenzene (BrBz), and benzyl bromide (BzBr) adsorption on Ag/metal (metal = Au, Bi, Pt, and Ti) bilayer electrodes in both vacuum and acetonitrile (ACN) solvent. The different metal supports offer a range of lattice mismatches and work function differences with Ag. Our calculations show that the surface of Ag becomes more electron donating and accessible to adsorption when it forms a bilayer with Ti as it has a lower work function and almost zero lattice mismatch with Ag. We believe this study will help to increase the electron donating ability of the Ag surface by choosing the right metal support, which in turn can improve the catalytic activity of the working electrode.

Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in Treatment of Insomnia.

Insomnia is one of the major challenges in medical science nowadays as it leads to great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression, and memory disturbance in affected individuals. Several important classes of drugs have been tried, including the BZDs and non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance, and cognitive impairment. In some instances, withdrawal symptoms have been observed upon the abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Treatment of insomnia with Daridorexant as a Dual Orexin Receptor Antagonist (DORA) has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown a promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from obstructive sleep apnoea, chronic obstructed airway disease (COAD), Alzheimer's disease (AD), hypertension, and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.

Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in the Treatment of Insomnia.

Insomnia is one of the major challenges in medical science nowadays as it leads to the great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression and memory disturbance in affected individuals. Several important classes of drugs have been tried including the BZDs and Non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance and cognitive impairments. In some instances, withdrawal symptoms have been observed on abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Daridorexant as a Dual Orexin Receptor Antagonists (DORA) in the treatment of insomnia has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from Obstructive sleep apnoea, Chronic Obstructive Airway Disease (COAD), Alzheimer's Disease (AD), hypertension and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer.

Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.

Knowledge, Attitude and Practice Survey Regarding High Alert Medication Among Resident Doctors in a Tertiary Care Teaching Hospital in Eastern India.

BACKGROUND: Medication errors are a reality in all settings where medicines are prescribed, dispensed, and used. High-alert medications (HAM) are those that bear a heightened risk of causing significant harm to the patient if used erroneously. Though mishaps with HAM may not be more common than with other drugs, the consequences of error with them can be especially serious. We conducted a survey on knowledge, attitude, and practice, among residents working in a teaching hospital to assess the ground situation regarding HAM awareness and handling. METHODS: We approached 492 residents among the approximately 600 currently working through purposive sampling. Residents in all disciplines (clinical, paraclinical, and preclinical) were targeted. A structured questionnaire with 54 questions, pilot-tested on 20 volunteer residents, was used for data collection. The questionnaire was administered to residents through face-to-face interviews by two raters while they were on duty, but not during rush hours. RESULTS: Of the total 261 responses received, 32.33% respondents correctly defined or explained the meaning of the term 'medication error'. Knowledge regarding the difference between medication error and adverse events did not get reflected in 68.38% of the participants, and only 16.86% were able to name the relevant group of medicines as HAM. Regarding attitude in dealing with HAM, the majority believed that taking the history of drug allergy and reconciling all prescription and over-the-counter (OTC) drugs already being used before prescribing or using medicine is important. In practice, most respondents followed protocols but not routinely. Several potential errors in practice were identified. CONCLUSION: The current situation requires corrective action. There is an urgent need for improving awareness regarding HAM for the sake of patient safety. The pharmacology department can take the lead in designing awareness campaigns with support from the hospital administration.

Cefiderocol: A new Antimicrobial for Complicated Urinary Tract Infection (CUTI) Caused by Carbapenem-resistant Enterobacteriaceae (CRE).

The incidence of carbapenem-resistant gram-negative (CRGNB) bacterial infections has increased globally. The wide diversity of strains, multiplicity of infections, and rapid development and spread of resistance are a matter of great concern both in community and hospital settings. Cefiderocol is a novel injectable siderophore containing cephalosporin with potent microbicidal activity against most carbapenem-resistant Enterobacteriaceae (CRE). It has recently been approved by USFDA for the treatment of complicated urinary tract infections (cUTI) caused by susceptible gram-negative microorganisms. This review focuses on the salient pharmacological profile of the drug and the clinical studies that were undertaken. Cefiderocol is first in class injectable siderophore cephalosporin showing potency against carbapenem- resistant Enterobacteriaceae. It has recently been approved by US FDA for the treatment of adult patients with complicated urinary tract infections (cUTI) caused by susceptible Gram-negative microorganisms, where there are limited or no alternative treatment options.

Hypertension Clinical Practice Guidelines (ISH, 2020): What Is New?

OBJECTIVE: In May 2020, the International Society of Hypertension (ISH) published "Practice Guidelines for the Management of Hypertension." The ISH 2020 guidelines were developed based on evidence criteria (i) to be used globally, (ii) to be fit for application in low-middle-income and high-income settings, and (iii) to be concise, simple, and easy to use by clinicians, nurses, and community health workers, as appropriate. The defined purpose was to adhere to the current evidence and develop a balanced proposal for global use in line with the ISH mission. METHODOLOGY: Multiple novel approaches have been included keeping in mind about lifestyle modification and flexibility in treatment options. RESULTS AND CONCLUSIONS: The ISH 2020 guidelines are practical and physician friendly. It also proves immensely helpful for low-resource countries without national guidelines on the management of hypertension.

Transcriptional regulation of VEGFA expression in T-regulatory cells from breast cancer patients.

The initiation of new blood vessel formation (neo-angiogenesis) is one of the primary requirements for the establishment of tumor. As the tumor grows beyond a certain size, a hypoxic-condition arises in the inner core of tumor, triggering the release of chemokines, which attract T-regulatory (Treg) cells in the tumor-site. The presence of FOXP3, a lineage-specific transcription factor, expressing Treg cells in various types of tumor implements immunosuppressive and tumor-promoting strategies. One such strategy is the invitation of endothelial cells for neo-vascularization in the tumor site. Here we report that as the disease progresses, Treg cells from breast cancer patients are capable of secreting high-amount of VEGFA. The VEGFA promoter lacks Treg-specific transcription factor FOXP3 binding site. FOXP3 in association with locus-specific transcription factor STAT3 binds to VEGFA promoter to induce its transcription in Treg cells obtained from breast cancer patients. Treg cell-secreted VEGFA induces neo-angiogenesis from endothelial cells under in-vitro conditions. Targeting Tregs in mice with breast tumor reduces tumor growth as well as the level of neo-angiogenesis in the tumor tissue.

Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times.

In the current COVID-19 pandemic, evidence to justify the use of any specific antiviral drug with proven efficacy is not yet available. Antiviral drug development always remains a challenge to the scientists. Remdesivir has emerged as a promising molecule, based on results of clinical trials and observational studies and has receieved marketing approval for COVID-19 treatment under "emergency use authorization" in countries such as United States. Remdesivir is a newer antiviral drug that acts as an RNA-dependent RNA polymerase (RdRp) inhibitor targeting the viral genome replication process. Therapeutic efficacy was first demonstrated by suppressing viral replication in Ebola-infected rhesus monkeys. It is available for parenteral use with reasonable safety and tolerability profile. Multiple clinical trials are going on in many countries to evaluate its safety, efficacy and tolerability. Positive outcome will make the drug capable of meeting the demand generated by both the current pandemic and future outbreak. HOW TO CITE THIS ARTICLE: Choudhury S, Chakraborty DS, Lahiry S, Chatterjee S. Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times. Indian J Crit Care Med 2020;24(7):570-574.

Will controlled release mebeverine be able to surpass placebo in treatment of diarrhoea predominant irritable bowel syndrome?

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a chronic relapsing disorder characterized by abdominal pain-discomfort and altered bowel habits. The IBS-diarrhoea predominant subtype (IBS-D) is defined as >25% of bowel movements representing type 6 or 7 of the Bristol Stool Form Scale. Management of IBS-D is mainly symptomatic, including lifestyle modification. Due to absence of standard treatment, multiple drugs are used. A controlled release (CR) form of mebeverine, recommended for spasmodic gastrointestinal disorders (including IBS) has recently been introduced in Indian market. We have conducted a placebo-controlled double blind randomized controlled trial [CTRI/2018/03/012897] to evaluate the effectiveness and safety of this product. METHODS: 40 patients of IBS-D were recruited from medicine out-patient department (OPD) of a tertiary care hospital and randomized to two parallel groups. One received mebeverine 200 mg CR tablets twice daily for 8 weeks, while other received matching placebo. Outcome parameters were number of bowel movements per day over past 7 days (NoBM7d), severity of abdominal cramps and IBS quality of life (IBSQoL) score. Medication adherence record and treatment emergent adverse events were captured. RESULTS: Mebeverine group showed modest but statistically significant improvement in NoBM7d, cramps and IBSQoL from baseline to 4 and 8 weeks. The changes within the placebo group were not statistically significant. Also, the intergroup differences at both 4 and 8 weeks were not statistically significant. Adherence was better in mebeverine group and both interventions were well tolerated. CONCLUSIONS: Mebeverine 200 mg CR twice daily has modest effect in IBS-D and therefore will not be a good choice for patients with severe symptoms.

Advances in Vasodilatory Shock: A Concise Review.

Vasodilatory shock is a critical manifestation of cardiovascular failure. There is uncontrolled vasodilation and vascular hyporesponsiveness to endogenous vasoconstrictors, causing the failure of physiologic vasoregulatory mechanisms. Unfortunately, only few randomized studies exist to guide clinical management and hemodynamic stabilization in patients who do not respond to the standard approach of managing vasodilatory shock. The present review offers the latest updates in management of this important clinical entity and a guidance framework for future research. HOW TO CITE THIS ARTICLE: Lahiry S, Thakur S, Chakraborty DS. Advances in Vasodilatory Shock: A Concise Review. Indian J Crit Care Med 2019;23(10):475-480.

Control of Functionalities in GO: Effect of Bronsted Acids as Supported by Ab Initio Simulations and Experiments.

Graphene oxide (GO) is an attractive precursor for graphene, provided by the well-known wet-chemical oxidative process. The intercalation of acid in graphite is considered as a crucial step, and its subsequent oxidation holds special relevance in synthesis. So far, the above chemistry is dominated by usage of H2SO4. Recently, H3PO4 appeared as a suitable intercalant for graphite. However, its role is not well understood in the formation of GO, especially when present as a co-acid with H2SO4. Additionally, a relatively lower toxicity of H3PO4 as compared to H2SO4, elimination of toxic NaNO3 usage, and a facile purification protocol are encouraging in terms of low-cost production of GO with a reduced environmental impact. Here, we report the systematic synthesis and characterization of GOs prepared with the variation in the ratio of H2SO4 and H3PO4. Ab initio simulations revealed that intercalation is primarily affected because of the usage of a mixture of co-acids. Interestingly, the ratio of the acids dictated the nature of the functionalities, extent of the defects, and morphology of the GOs, accounting for a pronounced effect on thermal stability, contact angle, zeta potential, and hydrodynamic size. The oxidation mechanism showed a predominance of H2SO4 content, whereas H3PO4 is found to mainly govern the intercalation of graphite, thereby affecting the acid-based intercalation-oxidation chemistry of graphite. The as-prepared GO suspension exhibited a high adsorption capacity for methylene blue dye removal in water, suggesting its potential as an adsorbent material in water treatment. The utility of the two acids affects the acid-based intercalation-oxidation chemistry of graphite and simultaneously may open up new opportunities for synthesized GOs, on tenets of green chemistry, in a wide arena of applications.

Effect of 1,25 dihydroxy vitamin D3 supplementation on pain relief in early rheumatoid arthritis.

BACKGROUND: To assess effect of 1,25 dihydroxy vitamin D3 supplementation on pain relief in early rheumatoid arthritis (RA). MATERIALS AND METHODS: An open-labeled randomized trial was conducted comparing 60,000 IU 1,25 dihydroxy vitamin D3 + calcium (1000 mg/day) combination [Group A] versus calcium (1000 mg/day) only [Group B], as supplement to existing treatment regimen in early RA. Primary outcome included (i) minimum time required for onset of pain relief (Tm) assessed through patients' visual analog scale (VAS); (ii) % change in VAS score from onset of pain relief to end of 8 weeks. Secondary outcome included change in disease activity score (DAS-28). RESULTS: At the end of 8-weeks, Group A reported 50% higher median pain relief scores (80% vs. 30%; P < 0.001) and DAS-28 scores (2.9 ± 0.6 vs. 3.1 ± 0.4; P = 0.012) compared to Group B; however, Tm remained comparable (19 ± 2 vs. 20 ± 2 days; P = 0.419). Occurrence of hypovitaminosis-D was lower (23.3%) compared to Indian prevalence rates and was a risk factor for developing active disease (Odds Ratio (OR) = 7.52 [95% Confidence Interval (CI) 2.67-21.16], P < 0.0001). Vitamin D deficiency was significantly (P < 0.001) more common in female gender, active disease, and shorter mean disease duration. Vitamin D levels were inversely correlated to disease activity as assessed by DAS-28 (r = -0.604; P < 0.001). CONCLUSIONS: Vitamin-D deficiency is a risk factor for developing active disease in RA. Weekly supplementation of 60,000 IU of 1,25 dihydroxy vitamin D3 in early RA results in greater pain relief. The number needed to treat for this additional pain relief was 2. IDENTIFIER: CTRI/2018/01/011532 (www.ctri.nic.in).

Andrographolide binds to ATP-binding pocket of VEGFR2 to impede VEGFA-mediated tumor-angiogenesis.

Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.

Emended description of the family Chromatiaceae, phylogenetic analyses of the genera Alishewanella, Rheinheimera and Arsukibacterium, transfer of Rheinheimera longhuensis LH2-2T to the genus Alishewanella and description of Alishewanella alkalitolerans sp. nov. from Lonar Lake, India.

Phylogenetic analyses were performed for members of the family Chromatiaceae, signature nucleotides deduced and the genus Alishewanella transferred to Chromatiaceae. Phylogenetic analyses were executed for the genera Alishewanella, Arsukibacterium and Rheinheimera and the genus Rheinheimera is proposed to be split, with the creation of the Pararheinheimera gen. nov. Furthermore, the species Rheinheimera longhuensis, is transferred to the genus Alishewanella as Alishewanella longhuensis comb. nov. Besides, the genera Alishewanella and Rheinheimera are also emended. Strain LNK-7.1T was isolated from a water sample from the Lonar Lake, India. Cells were Gram-negative, motile rods, positive for catalase, oxidase, phosphatase, contained C16:0, C17:1ω8c, summed feature3 (C16:1ω6c and/or C16:1ω7c) and summed feature 8 (C18:1ω7c) as major fatty acids, PE and PG as the major lipids and Q-8 as the sole respiratory quinone. Phylogenetic analyses using NJ, ME, ML and Maximum parsimony, based on 16S rRNA gene sequences, identified Alishewanella tabrizica RCRI4T as the closely related species of strain LNK-7.1T with a 16S rRNA gene sequence similarity of 98.13%. The DNA-DNA similarity between LNK-7.1T and the closely related species (A. tabrizica) was only 12.0% and, therefore, strain LNK-7.1T was identified as a novel species of the genus Alishewanella with the proposed name Alishewanella alkalitolerans sp. nov. In addition phenotypic characteristics confirmed the species status to strain LNK-7.1T. The type strain of A. alkalitolerans is LNK-7.1T (LMG 29592T = KCTC 52279T), isolated from a water sample collected from the Lonar lake, India.

New insights into therapeutic activity and anticancer properties of curcumin.

Natural compounds obtained from plants are capable of garnering considerable attention from the scientific community, primarily due to their ability to check and prevent the onset and progress of cancer. These natural compounds are primarily used due to their nontoxic nature and the fewer side effects they cause compared to chemotherapeutic drugs. Furthermore, such natural products perform even better when given as an adjuvant along with traditional chemotherapeutic drugs, thereby enhancing the potential of chemotherapeutics and simultaneously reducing their undesired side effects. Curcumin, a naturally occurring polyphenol compound found in the plant Curcuma longa, is used as an Indian spice. It regulates not only the various pathways of the immune system, cell cycle checkpoints, apoptosis, and antioxidant response but also numerous intracellular targets, including pathways and protein molecules controlling tumor progression. Many recent studies conducted by major research groups around the globe suggest the use of curcumin as a chemopreventive adjuvant molecule to maximize and minimize the desired effects and side effects of chemotherapeutic drugs. However, low bioavailability of a curcumin molecule is the primary challenge encountered in adjuvant therapy. This review explores different therapeutic interactions of curcumin along with its targeted pathways and molecules that are involved in the regulation of onset and progression of different types of cancers, cancer treatment, and the strategies to overcome bioavailability issues and new targets of curcumin in the ever-growing field of cancer.