Management of Anticoagulation and Antifibrinolytics in Catastrophic Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder that presents with hypercoagulability and results in a lab artifact of prolonged PTT. The most severe form is catastrophic antiphospholipid antibody syndrome (CAPS), which manifests as rapidly progressing thromboses in multiple organ systems leading to multi-organ ischemia. The mainstay management CAPS is anticoagulation and systemic corticosteroids. Antifibrinolytic agents have previously been thought to be relatively contraindicated in CAPS due to the pro-thrombotic nature of the disease; the complex coagulation profile of CAPS can make it difficult to assess the risks and benefits of antifibrinolytic therapy. Also, should a patient with CAPS require cardiopulmonary bypass (CPB) for surgery, it poses a unique challenge in providing appropriate anticoagulation in the setting of prolonged ACT. We present a case of a 32-year-old postpartum female with CAPS requiring heart transplant who safely received intraoperative antifibrinolytic therapy and was successfully anticoagulated during CPB after perioperative plasmapheresis.

Exploring role of natural compounds in molecular alterations associated with brain ageing: A perspective towards nutrition for ageing brain.

Aging refers to complete deterioration of physiological integrity and function. By midcentury, adults over 60 years of age and children under 15 years will begin to outnumber people in working age. This shift will bring multiple global challenges for economy, health, and society. Eventually, aging is a natural process playing a vital function in growth and development during pediatric stage, maturation during adult stage, and functional depletion. Tissues experience negative consequences with enhanced genomic instability, deregulated nutrient sensing, mitochondrial dysfunction, and decline in performance on cognitive tasks. As brain ages, its volume decreases, neurons & glia get inflamed, vasculature becomes less developed, blood pressure increases with a risk of stroke, ischemia, and cognitive deficits. Diminished cellular functions leads to progressive reduction in functional and emotional capacity with higher possibility of disease and finally death. This review overviews cellular as well as molecular aspects of aging, biological pathway related to accelerated brain aging, and strategies minimizing cognitive aging. Age-related changes include altered bioenergetics, decreased neuroplasticity and flexibility, aberrant neural activity, deregulated Ca2+ homeostasis in neurons, buildup of reactive oxygen species, and neuro-inflammation. Unprecedented progress has been achieved in recent studies, particularly in terms of how herbal or natural substances affect genetic pathways and biological functions that have been preserved through evolution. Herein, the present work provides an overview of ageing and age-related disorders and explore the molecular mechanisms that underlie therapeutic effects of herbal and natural chemicals on neuropathological signs of brain aging.

Unveiling the Latest Breakthroughs: A Comprehensive Review of the Therapeutic Activity and Safety Profile of Aloe vera.

The use of herbal drugs as alternative and complementary medicine has increased in popularity, raising concerns about their safety profile. Aloe vera, a plant with diverse therapeutic properties, has been extensively used for centuries. This review aims to assess the therapeutic activity and safety profile of Aloe vera. A comprehensive literature search was conducted to gather relevant information from various biomedical databases. The chemical composition, mechanism of action, and therapeutic activities of Aloe vera were analyzed. Aloe vera contains numerous active components such as vitamins, enzymes, minerals, sugars, lignin, saponins, and anthraquinones. Its mechanisms of action involve collagen synthesis, anti-inflammatory effects, immune modulation, laxative properties, and antiviral activity. Aloe vera has demonstrated potential therapeutic benefits in wound healing, diabetes management, liver and kidney protection, and glycemic control. However, it is essential to consider potential side effects, such as skin irritation and allergic reactions. This review provides evidence-based information to improve patient safety and promote informed decisions regarding the use of Aloe vera as a therapeutic agent.

Multifaceted Neuroprotective Role of Punicalagin: A Review.

Millions of people worldwide are currently afflicted with neurologic conditions like a seizure, depression, stress, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, the precise etiopathology of these diseases is still unknown. Substantial studies are being conducted to discover more treatments against these disorders because many patients do not experience the therapeutic benefits that would be expected from using existing pharmaceutical strategies. Herbal medicines which have been used in traditional medicine for millennia to treat various neurological problems are also being investigated and scientifically assessed. Punicalagin is a known polyphenol that has significant antioxidant, anti-inflammatory, anti-viral, anti-proliferative, and anti-cancer properties. Around the world, traditional use of herbal drugs is gaining wider acceptance as a part of complementary and alternative medicine. The scientific community should pay attention to these many neuroprotective pharmacodynamic activities of Punicalagin to create effective pharmacotherapeutic plans, as evidenced by mounting data in pre-clinical research investigations. The current review describes the recent studies on the pharmacological effects of Punicalagin in a variety of neurological illnesses and paves the way for further study in this field.

Exploring quantum computational, molecular docking, and molecular dynamics simulation with MMGBSA studies of ethyl-2-amino-4-methyl thiophene-3-carboxylate.

2-aminothiophenes derivative, Ethyl-2-amino-4-methyl thiophene-3-carboxylate (EAMC) has been synthesized, characterized, and investigated quantum chemically. It was experimentally investigated by different spectroscopic methods like- NMR (1H-NMR and 13C-NMR), FT-IR, and UV-Visible. B3LYP method and 6-311++G(d,p) basis set were employed for optimization of molecular structure and calculation of wave numbers of normal modes of vibrations and various other important parameters. Calculated bond lengths and angles were compared with the experimental bond lengths and Bond Angle Parameters. Optimized bond parameters and experimental bond parameters were found in good agreement. Complete potential energy distribution assignments were done successfully by VEDA. The HOMO/LUMO energy gap emphasizes adequate charge transfer happening within the molecule. A study of donor-acceptor interconnections was done via NBO analysis. MEP surface analysis was done to demonstrate charge distribution and reactive areas qualitatively in the molecule. The degree of relative localization of electrons was analyzed via ELF Diagram. The Fukui function analysis showed possible sites for attacks by different substituents. By using the TD-DFT method and PCM solvent model, the UV-Vis spectrum (gas, methanol, DMSO) and the maximum absorption wavelength was computed and compared with experimental data. 3D and 2D intermolecular interactions in the crystal were analyzed via Hirshfeld surface analysis and fingerprint plots reveal that the EAMC crystal was stabilized by H--H/H--H/C--H bond formation. The molecular docking was done with 7 different protein receptors on the molecule to find the best ligand-protein interactions. Molecular dynamic simulations and MMGBSA calculations were also carried out to find out the best binding of the ligand with the protein.Communicated by Ramaswamy H. Sarma.

Surgical Aortic Valve Replacement to Treat Prosthetic Valve Endocarditis After Valve-in-Valve Transcatheter Aortic Valve Replacement.

Prosthetic valve endocarditis (PVE) is an uncommon complication after heart valve replacement surgery that can result in increased morbidity and mortality. Current guidelines for management of PVE recommend antibiotic therapy followed by surgical valve replacement. The number of aortic valve replacements is expected to rise in the coming years with the expanded indications for use of transcatheter aortic valve replacement (TAVR) in patients with low, intermediate, and high surgical risk, as well as in patients with a failed aortic bioprosthetic valve. Current guidelines do not address the use of valve-in-valve (ViV) TAVR for management of PVE in patients who are at high risk for surgical intervention. The authors present a case of a patient with aortic valve PVE after surgical aortic valve replacement (SAVR); he was treated with valve-in-valve (ViV) TAVR due to the high surgical risk. The patient was discharged, but he returned to the hospital with PVE and valve dehiscence 14 months after ViV TAVR, after which he successfully underwent re-operative SAVR.

Uncovering the cytotoxic effects of air pollution with multi-modal imaging of in vitro respiratory models.

Annually, an estimated seven million deaths are linked to exposure to airborne pollutants. Despite extensive epidemiological evidence supporting clear associations between poor air quality and a range of short- and long-term health effects, there are considerable gaps in our understanding of the specific mechanisms by which pollutant exposure induces adverse biological responses at the cellular and tissue levels. The development of more complex, predictive, in vitro respiratory models, including two- and three-dimensional cell cultures, spheroids, organoids and tissue cultures, along with more realistic aerosol exposure systems, offers new opportunities to investigate the cytotoxic effects of airborne particulates under controlled laboratory conditions. Parallel advances in high-resolution microscopy have resulted in a range of in vitro imaging tools capable of visualizing and analysing biological systems across unprecedented scales of length, time and complexity. This article considers state-of-the-art in vitro respiratory models and aerosol exposure systems and how they can be interrogated using high-resolution microscopy techniques to investigate cell-pollutant interactions, from the uptake and trafficking of particles to structural and functional modification of subcellular organelles and cells. These data can provide a mechanistic basis from which to advance our understanding of the health effects of airborne particulate pollution and develop improved mitigation measures.

Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aß (1-42), IRS-1 (s307), GSK-3ß, TNF-α, IL-1ß, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Quantum Computational, Spectroscopic (FT-IR, FT-Raman, NMR, and UV-Vis) Hirshfeld Surface and Molecular Docking-Dynamics Studies on 5-Hydroxymethyluracil (Monomer and Trimer).

For many decades, uracil has been an antineoplastic agent used in combination with tegafur to treat various human cancers, including breast, prostate, and liver cancer. Therefore, it is necessary to explore the molecular features of uracil and its derivatives. Herein, the molecule's 5-hydroxymethyluracil has been thoroughly characterized by NMR, UV-Vis, and FT-IR spectroscopy by means of experimental and theoretical analysis. Density functional theory (DFT) using the B3LYP method at 6-311++G(d,p) was computed to achieve the optimized geometric parameters of the molecule in the ground state. For further investigation and computation of the NLO, NBO, NHO analysis, and FMO, the improved geometrical parameters were utilized. The potential energy distribution was used to allocate the vibrational frequencies using the VEDA 4 program. The NBO study determined the relationship between the donor and acceptor. The molecule's charge distribution and reactive regions were highlighted using the MEP and Fukui functions. Maps of the hole and electron density distribution in the excited state were generated using the TD-DFT method and PCM solvent model in order to reveal electronic characteristics. The energies and diagrams for the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) were also provided. The HOMO-LUMO band gap estimated the charge transport within the molecule. When examining the intermolecular interactions in 5-HMU, Hirshfeld surface analysis was used, and fingerprint plots were also produced. The molecular docking investigation involved docking 5-HMU with six different protein receptors. Molecular dynamic simulation has given a better idea of the binding of the ligand with protein.

Evaluation of experimental, computational, molecular docking and dynamic simulation of flucytosine.

Flucytosine (5-fluorocytosine), a fluorine derivative of pyrimidine, has been studied both experimentally and quantum chemically. To obtain the optimized structure, vibrational frequencies and other various parameters, the B3LYP method with a 6-311++G(d,p) basis set was used. Atom-in-molecule theory was used to calculate the binding energies, ellipticity and isosurface projection by electron localization of the molecule (AIM). In addition, the computational results from IR and Raman were compared with the experimental spectra. NBO analysis was used to analyze the donor and acceptor interactions. To know the reactive region of the molecule, the molecular electrostatic potential (MEP) and Fukui functions were determined. The UV-Vis spectrum calculated by the TD-DFT/PCM method was also compared with the experimentally determined spectrum. The HOMO-LUMO energy outcomes proved that there was a good charge exchange occurring within the molecule. With DMSO and MeOH as the solvents, maps of the hole and electron density distribution (EDD and HDD) were produced in an excited state. An electrophilicity index parameter was looked at to theoretically test the bioactivity of the compound. To find the best ligand-protein interactions, molecular docking was also carried out with various receptor proteins. In order to verify the inhibitory potency for the receptor protein complex predicted by docking and molecular dynamic simulation studies, the binding free energy of the receptor protein complex was calculated. Using the MM/GBSA technique, we determined the docked complex's binding free energy. To confirm the molecule's drug similarity, a biological drug similarity investigation was also executed.Communicated by Ramaswamy H. Sarma.

Linagliptin, a DPP-4 inhibitor, ameliorates Aß (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aß) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aß (1-42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aß (1-42), IRS-1 (s307), GSK-3ß, TNF-α, IL-1ß, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aß (1-42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD.

Breaking Bad: a case of Lactobacillus bacteremia and liver abscess.

We present a case of a 46-year-old Hispanic male with a past medical history significant for uncontrolled diabetes presenting with abdominal pain, nausea and vomiting and found to have Lactobacillus bacteremia and liver abscess. A PubMed and Clinical Key literature review of the other known cases of Lactobacillus liver abscess was performed. Through examination of previous case reports, the patient presented in this paper, and the associated risk factors of Lactobacillus liver abscess it is likely that the incidence of this rare condition will increase and would therefore be prudent to further study Lactobacillus as a pathogenic bacteria so that its complications may be better treated and prevented.

Peptide generated anisotropic gold nanoparticles as efficient siRNA vectors.

Based on the cell penetrating ability of tryptophan-containing peptides, eight linear hexapeptides have been designed, synthesized and explored their efficiency toward the synthesis of gold nanoparticles under sunlight. The peptide generated gold nanoparticles (LP-GNPs) have been characterized by UV-visible spectroscopy, Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) techniques. The binding ability of LP-GNPs toward siRNA, evaluated by gel electrophoresis indicates that sequence-selective-GNPs without any surface modifications exhibit strong affinity toward negatively charged biomolecules. Cellular uptake studies suggest that LP-GNPs exhibit significant uptake of fluorescence-labeled siRNA inside the cells as evidenced from Fluorescence Microscopy. In vitro gene silencing efficiency using newly generated GNPs revealed that above mentioned LP-GNPs efficiently down-regulate the level of GAPGH gene in colon cancer cells. Comparative gene silencing efficiency results indicate that anisotropic LP7-GNPs exhibit comparable efficacy to other existing carrier systems, such as Lipofectamine 2000 in presence of serum, mimicking in-vivo system. In conclusion, our results demonstrate that peptide-GNPs based delivery system for siRNA emerges to be effective to deliver RNAi therapeutics, uncovering new avenue in oncotherapy.

Input matters: Speed of word recognition in 2-year-olds exposed to multiple accents.

Although studies investigating language abilities in young children exposed to more than one language have become common, there is still surprisingly little research examining language development in children exposed to more than one accent. Here, we report two looking-while-listening experiments examining the impact of routine home exposure to multiple accents on 2-year-olds' word recognition abilities. In Experiment 1, we found that monolingual English-learning 24-month-olds who routinely receive exposure to both Canadian English and a non-native variant of English are less efficient in their recognition of familiar words spoken in Canadian English than monolingual English-learning 24-month-olds who hear only Canadian English at home. In Experiment 2, we found that by 34months of age all children recognize words equally quickly regardless of their accent exposure at home. We conclude that monolingual toddlers in some locations may form a less homogeneous population than past work has assumed, a factor that should be considered when drawing generalizations about language development across different populations.

Ticks and salt: an atypical case of neuroborreliosis.

It is well documented that central nervous system (CNS) infections may lead to syndrome of inappropriate anti-diuretic hormone secretion (SIADH), but diagnosing these can prove difficult in patients with atypical presentations. We present a case of SIADH and muscle weakness in a patient without typical signs of CNS infection who was tested and diagnosed with neuroborreliosis based largely on her likelihood of exposure. This case indicates the need for Lyme testing in patients with unexplained SIADH who live in endemic areas. The patient was an 83-year-old female with a history of type 2 diabetes and hypertension, who presented from her primary care physician's office when her sodium was found to be 123 mEq/L. Her sole symptom was proximal muscle weakness. The diagnosis of SIADH was reached based on laboratory data. A trial of fluid restriction was initiated, but neither her sodium nor her muscle weakness improved. Lyme testing was performed as the patient lived in an endemic area and was positive. Lumbar puncture showed evidence of neurologic involvement. After realizing the appropriate treatment for hyponatremia in this case, intravenous ceftriaxone was started, and patient's sodium levels improved and muscle weakness resolved. Studies show that SIADH is associated with CNS infections, likely related to the inflammatory cascade. However, the atypical presentation of neuroborreliosis for our patient delayed the appropriate diagnosis and treatment. Our case demonstrates the need to screen for Lyme disease in endemic areas in patients presenting with neurologic symptoms and SIADH.

Structures, stability and hydrogen bonding in inositol conformers.

Various ab initio calculations using the density-functional (DFT), the second order Möller-Plesset perturbation (MP2) and self-consistent reaction field (SCRF) theories were performed on thirteen theoretically possible inositol stereoisomers. Gas phase calculations reveal that the myo- and neo-isomers of inositol (bearing one and two axial hydroxyl groups, respectively) are marginally more stable (by 0.5 kcal mol(-1)) than the all equatorially substituted scyllo-inositol. The calculations when done in different polar solvents show that the scyllo-inositol becomes the most stable inositol isomer, a fact attributed to weaker intramolecular hydrogen bonds. The individual hydrogen bond energy in all the isomers of inositol was also estimated using the molecular tailoring approach (MTA). The calculated hydrogen bond energies in these isomers are in excellent agreement with reported O-H···O hydrogen bond distances and ν(O-H) stretching frequencies. The estimated H-bond energy values suggest that the order of the intramolecular hydrogen bond strength follows: axial-axial > equatorial-axial > axial-equatorial > equatorial-equatorial hydrogen bonds. The intramolecular hydrogen bonds in the scyllo isomer are much weaker than those in other conformers, thus making this isomer more stable in polar solvents.

Crystal structure of N (1),N (1)-diethyl-N (4)-[(quinolin-2-yl)methyl-idene]benzene-1,4-di-amine.

The title compound, C20H21N3, is non-planar with a dihedral angle between the planes of the quinoline and phenyl-enedi-amine rings of 9.40 (4)°. In the crystal, mol-ecules are connected by C-H⋯π inter-actions, generating a chain extending along the a-axis direction. Weak C-H⋯π inter-actions also occur.

A rare case of generalized pyogenic granuloma: a case report.

Gingival enlargement is defined as an overgrowth or increase in size of the gingiva. Enlargement can be of many types depending on etiologic factors like inflammation, drug-induced effects, neoplasm, hormonal imbalance, and systemic involvement (leukemia, etc). Drugs and hormonal imbalance are the most common causes of gingival enlargement. Nonspecific conditioned enlargement, or pyogenic granuloma, is considered an exaggerated conditioned response to minor trauma or chronic irritation. Pyogenic granuloma occurring in the oral cavity is a common phenomenon. However, simultaneously occurring generalized pyogenic granuloma in the oral cavity is a rare entity. Generalized pyogenic granuloma on the back and skin have been reported. This is the first case report of generalized pyogenic granuloma in the oral cavity. A 19-year-old male patient reported with a complaint of difficulty in mastication and generalized swelling of the gingiva that developed within a span of 15 days. Family and systemic history were noncontributory. Based on the clinical findings, histopathology report, and immunohistochemistry result, the patient was diagnosed with generalized pyogenic granuloma. Scaling and root planing were performed as the first phase of therapy followed by external bevel gingivectomy. The patient was followed for 3 months. The patient was advised to visit the clinic for regular maintenance visits for 1 year, as pyogenic granuloma has a tendency to recur.