Unforeseen effects: Hiccups unveiled by high-dose steroids in demyelination.

Background: Intractable hiccups, persisting beyond 48 h, pose a clinical challenge, particularly in demyelinating diseases like Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS). Understanding the complex neural pathways of the hiccup reflex and the impact of high-dose steroid therapy is crucial for managing this rare but distressing symptom. The hiccup reflex involves afferents from the vagus, phrenic, and sympathetic nerves, with the reflex center in the anterior horns at the C3 to 5 level and the medulla oblongata. The potential interplay between demyelination and corticosteroid therapy in triggering persistent hiccups requires exploration. Case report: This case report details a 21-year-old male with undiagnosed demyelinating disorder, presenting persistent hiccups following high-dose steroid therapy for an acute disease flare. The patient's history included vertigo and progressive neurological symptoms, leading to an MS diagnosis with significant brain and spinal lesions. Persistent hiccups, initiated by steroid administration, were recurrent but responsive to metoclopramide after other measures failed. Discussion: The discussion centers on investigating the cause of hiccups in a patient with demyelination following steroid administration. Steroids' impact on neurological systems, including neurotransmitter function, and the potential disruption of neurological pathways due to demyelination may contribute to hiccups. Successful hiccup resolution with metoclopramide suggests a potential pharmacological approach for corticosteroid-induced hiccups in demyelinating diseases. This case emphasizes the need for further research into the intricate relationship between demyelination, steroid therapy, and hiccups to enhance management strategies for this uncommon yet impactful symptom.

A Systematic Review Unraveling the Intricate Neurological Spectrum of COVID-19: Manifestations, Complications, and Transformative Insights for Patient Care.

The coronavirus disease 2019 (COVID-19) pandemic has strained global healthcare and financial infrastructures. Neurological manifestations of COVID-19 have gained recognition, emphasizing the need for comprehensive research in this area. This systematic review aims to comprehensively examine the neurological manifestations and complications associated with COVID-19 and assess their prevalence, impact on patient outcomes, and potential relationships with comorbidities, while emphasizing the significance of ongoing research in this field. We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 guidelines. A comprehensive search of PubMed, Google Scholar, Science Direct, and ResearchGate databases was conducted to identify eligible studies focusing on COVID-19 patients, reporting neurological symptoms or complications, and published between 2020 and 2022 in English. The data extracted is performed in a Microsoft Excel spreadsheet. Two independent reviewers assessed study quality and bias using the AMSTAR 2 scale before inclusion. This systematic includes 12 systematic reviews and meta-analysis with 191,412 participants and average age of 60 years. Neurological symptoms included headaches, dizziness, anosmia, and ageusia. Complications ranged from cerebrovascular events to Guillain-Barré syndrome. Comorbidities, such as hypertension and diabetes, exacerbated severity. Mortality rates associated with neurological manifestations varied from 29.1% to 84.8%. The study underscores the complex neurological impact of COVID-19, affecting patients across age groups. Ongoing research is vital to understand mechanisms and develop targeted interventions, improving patient care and addressing pandemic consequences. This review provides a holistic view of COVID-19's neurological effects, emphasizing the need for sustained research efforts and collaborative endeavors to combat the neurological issues.

Adding a chapter to the literature: A rare encounter of unilateral Moyamoya disease with ipsilateral persistent trigeminal artery.

Background: The coexistence of persistent trigeminal artery (PTA) and Moyamoya disease (MMD) has been reported. If their pathogenesis is related and if PTA is protective or harmful in MMD remains unknown as these are rare cerebrovascular anomalies. Case presentation: A 35-year-old woman with sudden global aphasia whose CT head and CT angiography of head and neck showed a hypodensity in the left posterior middle cerebral artery (MCA), a possible left proximal internal carotid artery occlusion, and a left PTA with hypoplasia of vertebral and basilar arteries. Digital subtraction angiography showed chronic MMD in the left MCA with extensive pial collateralization from anterior cerebral artery (ACA). The patient was initiated on single antiplatelet therapy and later she underwent direct bypass surgical intervention and rehabilitation. Discussion: Our case report brings attention to the infrequent coexistence of ipsilateral MMD and PTA suggesting a potential congenital pathogenesis based on embryologic development and hemodynamics. Also, we propose a protective role of PTA in MMD in case of large anterior vessel occlusion. This case contributes to the scarce literature on the intriguing relationship between MMD and PTA.

Efficacy of Rituximab in CANOMAD: A Systematic Review.

CANOMAD, characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M (IgM) paraprotein, cold agglutinins, and disialosyl antibodies, encompasses a clinical, radiological, and laboratory diagnosis. CANOMAD is a rare condition, with fewer than 100 cases reported in the literature. The understanding and diagnosis of the disease have improved in the last few years, but the treatment of CANOMAD is mainly unknown, and there is not a clear consensus about it. We conducted a systematic review regarding the efficacy of rituximab in CANOMAD's treatment to investigate the clinical and biological response of CANOMAD in patients treated with rituximab. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines for this systematic review. To analyze the bias of the study, we used the Joanna Briggs Institute's (JBI) Critical Appraisal Checklist to analyze the bias of the case reports, and we used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for the observational studies. We only included case reports, case series, and observational studies written in English with patients formally diagnosed with CANOMAD and treated with rituximab. We excluded systematic reviews, literature reviews, and meta-analyses. We investigated the clinical and biological responses of the patients to rituximab. The clinical response was classified as complete recovery (CR), partial response (PR), stable disease (SD), and non-response (NR). We gathered 34 patients. The literature uses a modified Rankin score to define complete improvement (CR), partial response (PR), stable disease (SD), and progression. Clinically, there were three patients with CR, five with PR, 15 with SD, and 11 with progression. The biological response was assessed by measuring the decrease in antibody titers in 27 patients. Among those, six patients had CR, 12 had PR, eight had SD, and one had progression. Among 15 patients with neurological evaluation, 10 had ocular symptoms, and two presented with bulbar symptoms. Seven of the ten patients with ocular symptoms had SD, two had PR, and one had progression. Only 14 patients had a report of demyelinating features. Three had an axonal pattern, six had a demyelinating pattern, and five had a mixed pattern. Among patients with an axonal pattern, three had an SD. Among patients with a demyelinating pattern, three had a PR, two had an SD, and one had progression. Among patients with a mixed pattern, four had SD, and one had progression. We concluded that patients with CR have a shorter disease duration than patients with PR, SD, or progression. In addition, patients with CR had longer follow-ups than the other groups, suggesting that being treated early with rituximab improves the clinical outcome and has a sustained effect. There were no differences in the frequency of ocular and bulbar symptoms among patients with CANOMAD. The axonal pattern is more common in patients with SD, suggesting that axonal and mixed patterns could be markers of a bad prognosis.

Post-Hemorrhagic Hydrocephalus and Outcomes Amongst Neonates With Intraventricular Hemorrhage: A Systematic Review and Pooled Analysis.

Introduction Intraventricular hemorrhage (IVH) is a common cause of morbidity and mortality in preterm neonates. IVH leads to complications such as posthemorrhagic hydrocephalus (PHH), which commonly occurs in neonates with a more severe degree of IVH. Hence, we aimed to evaluate the characteristics and outcomes of PHH in neonates with IVH. Methods We performed a systematic review of cases reported from January 1978 to December 2020 through the PubMed database, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the keywords 'intraventricular hemorrhage,' 'cerebral intraventricular hemorrhage,' and 'newborn.' A total of 79 articles were considered for analysis, and data on neonatal and maternal characteristics and outcomes were collected. The analysis was performed by using the χ2 test, Wilcoxon rank-sum test, and multivariate logistic regression model. Results We analyzed a total of 101 IVH cases, 54.5% were male and 62.4% preterm. Thirteen point nine percent (13.9%) presented with grade I, 35.6% grade II, and grade III respectively, and 8% grade IV IVH. Among the 59 (58.4%) neonates with PHH, 33.6% had resolved PHH and 24.8% had unresolved. In adjusted regression analysis, we found that neonates with resolved PHH have lower odds of having neurodevelopmental delay (OR:0.15, 95%CI:0.03-0.74; p=0.02) and death (OR:0.9;95%CI:0.01-0.99; p=0.049) as compared to unresolved PHH. Conclusion Our study showed that neonates with resolved PHH have a statistically significant lower risk of neurodevelopmental delay (NDD) and mortality. Future studies should be planned to evaluate the role of treatment and its effect on outcomes in IVH neonates with PHH as a complication.

Synthesis, In vitro, and Docking Analysis of C-3 Substituted Coumarin Analogues as Anticancer Agents.

BACKGROUND: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effects along with multidrug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. OBJECTIVES: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking. METHODS: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. RESULTS: Among the synthesized analogues, 12 and 13 show good antiproliferative activity with IC50 values 1 and 1.3 µM, respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit a docking score of -4.10 kcal/mol and -4.38 kcal/mol, respectively. CONCLUSION: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

Risk factors and outcomes of intravenous tissue plasminogen activator and endovascular thrombectomy utilization amongst pediatrics acute ischemic stroke.

BACKGROUND: Pediatric stroke is a debilitating disease. There are several risk factors predisposing children to this life-threatening disease. Although, published literature estimates a relatively high incidence of pediatric stroke, treatment guidelines on intravenous tissue plasminogen activator and endovascular thrombectomy utilization remain a dilemma. There is a lack of large population-based studies and clinical trials evaluating the efficacy and safety outcomes associated with these treatments in this unique population. AIM: We sought to determine the prevalence of risk factors, concurrent utilization of intravenous tissue plasminogen activator and endovascular thrombectomy, and associated outcomes in pediatric stroke hospitalizations. METHODS: We performed a retrospective analysis of the Nationwide Inpatient Sample data (2003-2014) in pediatric (1-21 years of age) acute ischemic stroke hospitalizations using ICD-9-CM codes. The multivariable survey logistic regression model was weighted to account for sampling strategy, evaluate predictors of hemorrhagic conversion, and treatment outcomes (mortality, morbidity, and discharge disposition) amongst pediatric stroke hospitalizations. RESULTS: In this analysis, 9109 patients between 1 and 21 years of age were admitted during 2003-2014 for acute ischemic stroke. Of these 9109 patients, 119 (1.30%) received endovascular thrombectomy alone, 256 (2.82%) intravenous recombinant tissue plasminogen activator, and 69 (0.75%) both endovascular thrombectomy and intravenous recombinant tissue plasminogen activator. We found overall high prevalence of conditions like epilepsy (19.59%), atrial septal defect (11.76%), sickle cell disease (8.63%), and moyamoya disease (5.41%) in pediatric acute ischemic stroke patients. Unadjusted analysis showed high prevalence of all-cause in-hospital mortality in combined endovascular thrombectomy and intravenous recombinant tissue plasminogen activator utilization group, and higher prevalence of hemorrhagic conversion and morbidity in endovascular thrombectomy utilization group compared to other groups (p < 0.0001). Multivariate adjusted analysis showed that children with endovascular thrombectomy utilization (aOR: 19.19; 95% CI: 2.50-147.29, p = 0.005), intravenous recombinant tissue plasminogen activator utilization (aOR: 8.85; 95% CI: 1.92-40.76, p = 0.005), and both (endovascular thrombectomy and intravenous recombinant tissue plasminogen activator) utilization (aOR: 7.55; 95% CI: 1.16-49.31, p = 0.035) had higher odds of hemorrhagic conversion compared to no-treatment group. CONCLUSION: We found various risk factors associated with pediatric stroke. The early identification can be useful to formulate preventive strategies and influence the incidence of pediatric stroke. Our study results showed that use of intravenous recombinant tissue plasminogen activator and endovascular thrombectomy increase risk of mortality and hemorrhagic conversion, but we suggest to have more clinical studies to evaluate the idea candidates for utilization of intravenous recombinant tissue plasminogen activator and endovascular thrombectomy based on risk: benefit ratio.

Stevia rebaudiana targeting α-amylase: An in-vitro and in-silico mechanistic study.

Diabetes mellitus (DM) is the fastest growing metabolic disorder in the world. Recently, more attention is paid to the study of natural products due to side effects of synthetic drugs. Stevia rebaudiana (Bertoni) is considered an encouraging starting point for the antidiabetic lead development. In the present study, the in vitro α-amylase inhibitory activity of the extracts of S. rebaudiana is investigated. In order to understand the molecular mechanism and future pharmacophore development, in silico study of secondary metabolites isolated from S. rebaudiana was carried out. Results indicated that water extract shows highest α-amylase inhibitory activity as compared to other extracts. Moreover, compound 20 (rebaudioside A) which has been previously reported and isolated from water extract showed the impressive binding profile with α-amylase. Therefore, our study suggests that S. rebaudiana could be used in the development of therapeutic drugs for the treatment of diabetes.

Identification of novel indole based heterocycles as selective estrogen receptor modulator.

In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC.

Design, synthesis and biological evaluation of novel indole-benzimidazole hybrids targeting estrogen receptor alpha (ER-α).

In the course of efforts to develop novel selective estrogen receptor modulators (SERMs), indole-benzimidazole hybrids were designed and synthesised by fusing the indole nucleus with benzimidazole. All the compounds were first inspected for anti-proliferative activity using ER-α responsive T47D breast cancer cell lines and ER-α binding assay. From this study, two representative bromo substituted compounds 5f and 8f were found to be most active and thus were escalated for gene expression studies for targeting ER-α. Cell imaging experiment clearly suggest that compounds were able to cross cell membrane and accumulate thus causing cytotoxicity. RT-PCR and Western blotting experiments further supported that both compounds altered the expression of mRNA and receptor protein of ER-α, thereby preventing the further transactivation and signalling pathway in T47D cells lines. Structural investigation from induced fit simulation study suggest that compound 5f and 8f bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these results strongly indicate that compound 5f and 8f represents a novel potent ER-α antagonist properties and will proved promising in the discovery of SERM for the management of breast cancer.

Coumarin Derivatives as Anticancer Agents for Lung Cancer Therapy: A Review.

BACKGROUND: The prevalence of lung cancer is 14% among the newly diagnosed cancer cases worldwide. Currently, the number of drugs that are in clinical practice is having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. OBJECTIVE: Extensive exploration of Coumarin derivatives as a potent inhibitor of variety of proteins including EGFR, tyrosine kinase, ERK1/2, PI3K, HSP 90, Bax, STAT proteins, NF-κB and telomerase which have been associated with lung cancer. METHOD: The recent literature was surveyed utilizing the online resources and databases including scifinder, pubchem, EMBL, scopus and google scholar. RESULTS: Upon analyzing the structure-activity relationship, it was found that N-aryl carboxamide, phenyl substitution at the C-3 position and 1,2,3- triazolyl, trihydroxystilbene, amino substitution at the C-4 position of the coumarin nucleus were the most effective in targeting lung cancer. CONCLUSION: This review is a collaborative and extensive compilation of synthetic strategies, mechanism of action, and the structure-activity relationship thereof for the management of lung carcinoma.

Design, synthesis and biological evaluation of novel indole-xanthendione hybrids as selective estrogen receptor modulators.

Ground breaking clinical therapeutic advances in the treatment of breast cancer (BC) is the introduction of selective estrogen receptor modulators (SERMs). We have expeditiously designed and synthesized indole-xanthendione hybrids by coalescing the indole nucleus with xanthendione. All the compounds were first screened for anti-proliferative activity, cytotoxicity and ER-α binding affinity by utilizing ER-α dominant T47D BC cell lines, PBMCs and ER-α competitor assay kit. From this study, two representative compounds 6e and 6f showing most promising activity were advanced for gene expression studies for targeting ER-α. Cell imaging experiment undoubtedly indicate that both the compounds were able to cross cellular bio membrane and accumulate thus instigating cytotoxicity. RT-PCR and Western blotting experiments further strengthened that both compounds altered the expression of mRNA and receptor protein of ER-α, thereby forestalling downstream transactivation and signalling pathway in T47D cells line. Structural investigation from induced fit simulation study suggest that indole moiety of the compounds 6e and 6f helps in the anchoring of the xanthendione moiety in the hydrophobic region of the cavity thus enabling the compound to bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these finding collectively imply that compound 6e and 6f represents a novel potent ER-α antagonist and in the development of SERMs for the management of BC.

Multitargeted Molecular Docking Study of Natural-Derived Alkaloids on Breast Cancer Pathway Components.

BACKGROUND: Targeting of multiple sites is a pharmacologically, pharmacokinetic and dynamically more acceptable approach for complex diseases such as BC. It is recommended that the women who are at high risk of developing BC might be given foods enhanced by indole alkaloids from vegetables like cabbage and broccoli. Administration of indole-3-carbinol is associated with decreased incidence of hormone-responsive BC (HRBC) which is implicated due to the induction of cytochrome P450 and glutathione-S-transferase which metabolizes chemical mutagens and by altering estrogen metabolism. OBJECTIVE: To determine the molecular mechanism behind the anticancer activity of natural indole alkaloids present in various food and nutraceuticals products by utilizing Induced-fit docking (IFD) approach. METHODS: Indole alkaloids were obtained from the database maintained by ChEBI (The database and ontology of Chemical Entities of Biological Interest) with ChEBI id 38958. The 3-dimentional and X-ray structure coordinates of Estrogen receptor- α (ER-α), Estrogen receptor- ß (ER-ß), and aromatase were obtained from protein data bank with PDB id codes 3ERT, 3OLS, and 3S7S (www.rcsb.org). The Induced fit molecular docking and ADME properties were calculated using Maestro 9.6. RESULTS: IFD analysis showed that bromocriptine exhibits maximum binding affinity towards ER-α and fellutanine B towards ER-ß and aromatase. CONCLUSION: Present research provided in-depth analysis of molecular mechanism and helped in the future design of new pharmacophores based on natural indole alkaloids targeting BC.

Recent developments of C-4 substituted coumarin derivatives as anticancer agents.

Cancer is a prominent cause of death in global. Currently, the numbers of drugs that are in clinical practice are having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. Coumarin scaffold became an attractive subject due to their broad spectrum of pharmacological activities. Coumarin derivatives extensively explored for anticancer activities as it possesses minimum side effect along with multi-drug reversal activity. Coumarin derivatives can act by various mechanisms on different tumor cell lines depending on substitution pattern of the core structure of coumarin. Substitution on coumarin nucleus leads to the search for more potent compounds. In this review, we have made an effort to give a synthetic strategy for the preparation of C-4 substituted coumarin derivatives as anticancer agents based on their mechanism of action and also discuss the SAR of the most active compound.

Synthesis of rebaudioside A from stevioside and their interaction model with hTAS2R4 bitter taste receptor.

Steviol glycosides (SG's) from Stevia rebaudiana (Bertoni) have been used as a natural low-calorie sweeteners. Its aftertaste bitterness restricts its use for human consumption and limits its application in food and pharmaceutical products. In present study, we have performed computational analysis in order to investigate the interaction of two major constituents of SG's against homology model of the hTAS2R4 receptor. Molecular simulation study was performed using stevioside and rebaudioside A revealed that, sugar moiety at the C-3'' position in rebaudioside A causes restriction of its entry into the receptor site thereby unable to trigger the bitter reception signaling cascade. Encouraged by the current finding, we have also developed a greener route using ß-1,3-glucanase from Irpex lacteus for the synthesis of de-bittered rebaudioside A from stevioside. The rebaudioside A obtained was of high quality with percent conversion of 62.5%. The results here reported could be used for the synthesis of rebaudioside A which have large application in food and pharmaceutical industry.

Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies.

Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. It possesses immeasurable anticancer potential with minimum side effects depending on the substitutions on the basic nucleus. Coumarins have a tremendous ability to regulate diverse range of cellular pathways that can be explored for selective anticancer activity. This is the first standalone review that emphasis on the assorted retrosynthetic approaches, important targets for molecularly targeted cancer therapy and structure activity relationship studies that highlight the chemical groups responsible for evoking the anticancer potential of coumarin derivatives reported from 2011 to 2014.

Indole Derivatives as Anticancer Agents for Breast Cancer Therapy: A Review.

Breast cancer (BC) is the second most common cause of cancer-related deaths in women throughout the world. Multiple drugs have been approved by US-FDA for breast related malignancies. Frequent emergence of resistances creates the severe need of newer moieties that are free from such problems. Drugs targeting breast cancer have been observed to be based on the multiple mechanisms of action, and various indole based anticancer agents have also been explored. Moreover, indoles have promising anti-cancer potential; there has been the emphasis on the synthesis of indole derivatives to overcome problems faced by existing therapeutic agents. Taking into consideration the above-mentioned facts we have analyzed in detail the possible role of indole based anticancer agents typically for breast related malignancies. This is the first exhaustive review that jointly covers various synthetic anticancer indole derivatives and related signaling pathways by which these derivatives have shown promising anti-breast cancer potential.