Toxicological Profiling of Potential Shikimate Kinase Inhibitors Against Mycobacterium tuberculosis.

Over the last decade, Mycobacterium tuberculosis has mutated into a putative 'superbug', as treatments against it have failed due to increasing antimicrobial resistance. As a result, the rising incidence of multidrug-resistant tuberculosis (MDR-TB) is posing a significant public health threat, thus, the need to develop effective drugs for MDR-TB has become an urgent priority. To identify new drug candidates for the treatment of MDR-TB, the present study was based on mycobacterial shikimate kinase (MtSK) as the pharmacological target. One hundred potential MtSK inhibitors were identified from literature and database searches to identify compounds that were designed to specifically function as MtSK antagonists. The ADME properties of these compounds were evaluated by using the SwissADME web tool. ProTox-II software was also used to investigate any potential endocrine disrupting effects, mediated through their interaction with oestrogenic and/or androgenic receptors. This study also aimed to predict LD50 values of potential drug candidates that would be active against the standard H37Rv strain of M. tuberculosis, by using the ProTox-II in silico tool. The molecules for which no structural hazard alerts were identified with these software tools were further subjected to molecular docking analyses and molecular dynamic simulations to estimate their ability to interact with the MtSK enzyme. Preliminary results from SwissADME indicated that 30 molecules were drug-like, due to their physicochemical and pharmacokinetic properties. However, subsequent analysis with ToxTree and ProTox-II indicated that only three of these 30 drug-like molecules were suitable for taking forward into further in vitro experiments. This study, which is based on the use of commonly used open-source in silico tools, identified new MtSK ligands for potential use in the development of new drugs for the therapeutic management of tuberculosis. An initial prediction of their safety profile was also generated.

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

pH-Responsive Upconversion Mesoporous Silica Nanospheres for Combined Multimodal Diagnostic Imaging and Targeted Photodynamic and Photothermal Cancer Therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF4:Yb/Er/Gd,Bi2Se3) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF4:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while Bi2Se3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects in vitro and in vivo via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

pH-responsive upconversion mesoporous silica nanospheres for combined multimodal diagnostic imaging and targeted photodynamic and photothermal cancer therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have garnered considerable interest as non-invasive cancer treatment modalities. However, these approaches remain limited by low solubility, poor stability and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome these limitations, we have designed biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium and gadolinium) and bismuth selenide (NaYF 4 :Yb/Er/Gd,Bi 2 Se 3 ) within a mesoporous silica shell that encapsulates a PS, Chlorin e6 (Ce6), in its pores. NaYF 4 :Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites the Ce6 to generate cytotoxic reactive oxygen species (ROS), while the PTA Bi 2 Se 3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging (MRI) of the nanospheres. The mesoporous silica shell is coated with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG) to ensure retention of the encapsulated Ce6 and minimize interactions with serum proteins and macrophages that impede tumor targeting. Finally, the coat is functionalized with the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into cancer cells within the mildly acidic tumor microenvironment. Following uptake by cancer cells in vitro , NIR laser irradiation of the nanospheres caused substantial cytotoxicity due to ROS production and hyperthermia. The nanospheres facilitated tumor MRI and thermal imaging, and exhibited potent NIR laser light-induced antitumor effects in vivo via combined PDT and PTT, with no observable toxicity to healthy tissue, thereby substantially prolonging survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

Enumerating Stable Nanopores in Graphene and Their Geometrical Properties Using the Combinatorics of Hexagonal Lattices.

Nanopores in two-dimensional (2D) materials, including graphene, can be used for a variety of applications, such as gas separations, water desalination, and DNA sequencing. So far, however, all plausible isomeric shapes of graphene nanopores have not been enumerated. Instead, a probabilistic approach has been followed to predict nanopore shapes in 2D materials, due to the exponential increase in the number of nanopores as the size of the vacancy increases. For example, there are 12 possible isomers when N = 6 atoms are removed, a number that theoretically increases to 11.7 million when N = 20 atoms are removed from the graphene lattice. In this regard, the development of a smaller, exhaustive data set of stable nanopore shapes can help future experimental and theoretical studies focused on using nanoporous 2D materials in various applications. In this work, we use the theory of 2D triangular "lattice animals" to create a library of all stable graphene nanopore shapes based on a modification of a well-known algorithm in the mathematical combinatorics of polyforms known as Redelmeier's algorithm. We show that there exists a correspondence between graphene nanopores and triangular polyforms (called polyiamonds) as well as hexagonal polyforms (called polyhexes). We develop the concept of a polyiamond ID to identify unique nanopore isomers. We also use concepts from polyiamond and polyhex geometries to eliminate unstable nanopores containing dangling atoms, bonds, and moieties. We verify using density functional theory calculations that such pores are indeed unstable. The exclusion of these unstable nanopores leads to a remarkable reduction in the possible nanopores from 11.7 million for N = 20 to only 0.184 million nanopores, thereby indicating that the number of stable nanopores is almost 2 orders of magnitude lower and is much more tractable. Not only that, by extracting the polyhex outline, our algorithm allows searching for nanopores with dimensions and shape factors in a specified range, thus aiding the design of the geometrical properties of nanopores for specific applications. We also provide the coordinate files of the stable nanopores as a library to facilitate future theoretical studies of these nanopores.

Hyperglycemic conditions induce rapid cell dysfunction-promoting transcriptional alterations in human aortic endothelial cells.

Hyperglycemia is a major risk factor in the development of diabetic complications and promotes vascular complications through dysregulation of endothelial cell function. Various mechanisms have been proposed for endothelial cell dysregulation but the early transcriptomic alterations of endothelial cells under hyperglycemic conditions are not well documented. Here we use deep time-series RNA-seq profiling of human aortic endothelial cells (HAECs) following exposure to normal (NG) and high glucose (HG) conditions over a time course from baseline to 24 h to identify the early and transient transcriptomic changes, alteration of molecular networks, and their temporal dynamics. The analysis revealed that the most significant pathway activation/inhibition events take place in the 1- to 4-h transition and identified distinct clusters of genes that underlie a cascade of coordinated transcriptional events unique to HG conditions. Temporal co-expression and causal network analysis implicate the activation of type 2 diabetes (T2D) and growth factor signalling pathways including STAT3 and NF-κB. These results document HAEC transcriptional changes induced by hyperglycemic conditions and provide basic insight into the rapid molecular alterations that promote endothelial cell dysfunction.

Antiplatelets and Vascular Dementia: A Systematic Review.

Vascular dementia (VD) is a neurocognitive disorder whose precise definition is still up for debate. VD generally refers to dementia that is primarily caused by cerebrovascular disease or impaired cerebral blood flow. It is a subset of vascular cognitive impairment, a class of diseases that relate any cerebrovascular injury as a causal or correlating factor for cognitive decline, most commonly seen in the elderly. Patients who present with both cognitive impairment and clinical or radiologic indications of cerebrovascular pathology should have vascular risk factors, particularly hypertension, examined and treated. While these strategies may be more effective at avoiding dementia than at ameliorating it, there is a compelling case for intensive secondary stroke prevention in these patients. Repeated stroke is related to an increased chance of cognitive decline, and poststroke dementia is connected with an increased risk of death. In general, most physicians follow recommendations for secondary stroke prevention in patients with VD, which can be accomplished by the use of antithrombotic medicines such as antiplatelets (aspirin, clopidogrel, ticlopidine, cilostazol, etc.). In individuals with a high risk of atherosclerosis and those with documented symptomatic cerebrovascular illness, antiplatelets treatment lowers the risk of stroke. While this therapy strategy of prevention and rigorous risk management has a compelling justification, there is only limited and indirect data to support it. The following systematic review examines the role of antiplatelets in the management of vascular dementia in published clinical trials and studies and comments on the current evidence available to support their use and highlights the need for further study.

Anti-tuberculosis drugs used in a directly observed treatment short course (DOTS) schedule alter endocrine patterns and reduce the ovarian reserve and oocyte quality in the mouse.

CONTEXT: Tuberculosis is one of the major infectious diseases, with people of reproductive age group having a high risk of infection. AIMS: The present study was designed to understand the consequences of anti-tuberculosis drugs (ATDs) used in DOTS (directly observed treatment short course) schedule on ovarian function. METHODS: Adult female Swiss albino mice were orally administered with combinations of ATDs used in the DOTS schedule every day for 4weeks. At 2weeks after the cessation of ATDs administration, the endocrine changes and ovarian function were assessed in mice. KEY RESULTS: Administration of ATDs to mice resulted in a prolonged estrous cycle, reduced ovarian follicle reserve, alteration in FSH, LH, and progesterone level, and decreased the number of ovulated oocytes. Further, the degree of fragmentation, degeneration, abnormal distribution of cytoplasmic organelles, abnormal spindle organisation, and chromosomal misalignment were higher in oocytes that were ovulated following superovulation. Blastocysts derived from ATDs treated mice had significantly lower total cell numbers and greater DNA damage. A marginal increase in the number of resorbed fetuses was observed in all the ATDs treated groups except in the multidrug resistance treatment group. Male progeny of ATDs treated mice had decreased sperm count and lower progressive motility, while female progeny exhibited a non-significant reduction in the number of oocytes ovulated. CONCLUSIONS: Theresults of this study suggest that ATDs can have significant adverse effects on the ovarian reserve, cytoplasmic organisation of oocytes, and can potentially cause transgenerational changes. IMPLICATIONS: The findings of the present study indicate ovarian toxicity of ATDs and warrant further research in the direction of identifying alternate drugs with minimal toxicity, and strategies to mitigate the ovarian toxicity induced by these drugs.

Obstructive Sleep Apnea as a Risk Factor for Venous Thromboembolism: A Systematic Review.

Obstructive sleep apnea (OSA), is a prevalent condition characterized by repeated episodes of pharyngeal airway obstruction resulting in hypopnea and apnea episodes during sleep leading to nightly awakenings. OSA is a major contributor to the healthcare burden worldwide due to its high cardiovascular morbidity and mortality. There is growing evidence to support a pathophysiological link between OSA and venous thromboembolism (VTE). The pro-inflammatory state along with intermittent hypoxia that is invoked in OSA is associated with blood hypercoagulability, venous stasis, and endothelial dysfunction leading to deep vein thrombosis (DVT) and pulmonary embolism (PE). In this systematic review, we aim to analyze and assess the available literature on OSA and VTE (or DVT/PE) to determine whether OSA is an independent risk factor for VTE.

Linking Alzheimer's Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aß and IAPP Hetero-Aggregates.

The cytotoxic self-aggregation of ß-amyloid (Aß) peptide and islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of Alzheimer's disease (AD) and Type 2 diabetes (T2D), respectively. Increasing evidence, particularly the co-deposition of Aß and IAPP in both brain and pancreatic tissues, suggests that Aß and IAPP cross-interaction may be responsible for a pathological link between AD and T2D. Here, we examined the nature of IAPP-Aß40 co-aggregation and its inhibition by small molecules. In specific, we characterized the kinetic profiles, morphologies, secondary structures and toxicities of IAPP-Aß40 hetero-assemblies and compared them to those formed by their homo-assemblies. We demonstrated that monomeric IAPP and Aß40 form stable hetero-dimers and hetero-assemblies that further aggregate into ß-sheet-rich hetero-aggregates that are toxic (cell viability <50%) to both PC-12 cells, a neuronal cell model, and RIN-m5F cells, a pancreatic cell model for ß-cells. We then selected polyphenolic candidates to inhibit IAPP or Aß40 self-aggregation and examined the inhibitory effect of the most potent candidate on IAPP-Aß40 co-aggregation. We demonstrated that epigallocatechin gallate (EGCG) form inter-molecular hydrogen bonds with each of IAPP and Aß40. We also showed that EGCG reduced hetero-aggregate formation and resulted in lower ß-sheets content and higher unordered structures in IAPP-Aß40-EGCG samples. Importantly, we showed that EGCG is highly effective in reducing the toxicity of IAPP-Aß40 hetero-aggregates on both cell models, specifically at concentrations that are equivalent to or are 2.5-fold higher than the mixed peptide concentrations. To the best of our knowledge, this is the first study to report the inhibition of IAPP-Aß40 co-aggregation by small molecules. We conclude that EGCG is a promising candidate to prevent co-aggregation and cytotoxicity of IAPP-Aß40, which in turn, contribute to the pathological link between AD and T2D.

Recurrent Bacterial Infections in Cutaneous T-cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a dermatologically manifesting immune cell disorder. We present a case of a 76-year-old female with a past medical history of CTCL, presenting with cellulitis of the left foot. After diagnosis of CTCL, the patient was admitted multiple times for treatment of cutaneous and soft-tissue infections with methicillin-resistant Staphylococcus aureus. Her recurrent infection with S. aureus had led to treatment for sepsis and a below-knee amputation on the right during prior hospitalizations. On this admission, the patient was treated with intravenous vancomycin and cefepime as in-patient and oral linezolid as out-patient. Recent articles show that patients with CTCL have an increased tendency to harbor S. aureus, which leads to recurrent infections. Additionally, evidence suggests that S. aureus toxins aid the progression of CTCL by helping the cancer to escape immune regulation. Our patient demonstrates this unique relationship between CTCL and S. aureus, and moreover, we make a case that S. aureus infection in CTCL, as compared to that in other dermatitis, should be better managed to not exacerbate the disease.

Venous thromboembolic events in the setting of extracorporeal membrane oxygenation support in adults: A systematic review.

Extracorporeal membrane oxygenation (ECMO) is a form of prolonged mechanical cardiopulmonary supportive therapy implemented for the survival of patients with refractory cardiac and respiratory dysfunction. Venovenous (VV) and venoarterial (VA) ECMO are both used to buy time in severe respiratory failure while VA ECMO also provides hemodynamic support. Unfortunately, the risk of developing circuit or cannula associated and systemic thrombosis in patients supported by ECMO and post circuit decannulation is a devastating complication, although the relationship between venous thromboembolism (VTE) and ECMO use has not been fully established. Due to the lack of knowledge and literature centered on this topic area, currently there are no official guidelines for prompt diagnosis by screening or to optimize prevention and treatment of VTE in this specific population. This review analyzes the relationship between ECMO and subsequent VTE. We also discuss pertinent prophylactic and therapeutic anticoagulation treatments in patients diagnosed with VTE while on ECMO along with the obstacles associated with them.

Accelerated atherosclerosis in rheumatoid arthritis: a systematic review.

Background: Rheumatoid arthritis (RA) is a highly prevalent, chronic inflammatory condition of the synovial joints that affects approximately 1% of the global population. The pathogenesis of RA is predominantly inflammatory in nature, thereby accelerating the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. Apart from traditional cardiovascular risk factors, RA patients possess a multitude of other factors that predispose them to early atherosclerotic disease. The aim of this systematic review is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis. We also discussed novel biomarkers that can be used to predict early atherosclerosis in RA and current guidelines used to treat RA. Methods: This review followed the PRISMA guidelines to select and analyze relevant articles. A literature search for articles was performed on February 25, 2022, through three research databases including PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was "Rheumatoid arthritis and atherosclerosis" and the search duration was set from 2012-2022. Relevant articles were selected based on the inclusion and exclusion criteria. Results: Our initial search generated 21,235 articles. We narrowed our search according to the inclusion and exclusion criteria. After assessing eligibility based on the full content of the articles, 73 articles were ultimately chosen for this review. Conclusion: There is an increased prevalence of accelerated atherosclerosis among RA patients. We found evidence to explain the role of proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology RA-mediated atherosclerosis. Therapies targeting either the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Novel markers of atherosclerosis in RA may be useful in predicting premature atherosclerosis and serve as new targets for therapeutic intervention.

A Review of Risk Factors and Predictors for Hemorrhagic Transformation in Patients with Acute Ischemic Stroke.

Acute ischemic strokes (AIS) and hemorrhagic strokes lead to disabling neuropsychiatric and cognitive deficits. A serious and fatal complication of AIS is the occurrence of hemorrhagic transformation (HT). HT is cerebral bleeding that occurs after an ischemic event in the infarcted areas. This review summarises how specific risk factors such as demographic factors like age, gender, and race/ethnicity, comorbidities including essential hypertension, atrial fibrillation, diabetes mellitus, congestive heart failure, and ischemic heart disease along with predictors like higher NIHSS score, larger infarction size, cardioembolic strokes, systolic blood pressure/pulse pressure variability, higher plasma glucose levels, and higher body temperature during ischemic event, lower low-density lipoprotein and total cholesterol, early ischemic changes on imaging modalities, and some rare causes make an individual more susceptible to developing HT. We also discuss few other risk factors such as the role of blood-brain barrier, increased arterial stiffness, and globulin levels in patients postreperfusion using thrombolysis and mechanical thrombectomy. In addition, we discuss the implications of dual antiplatelet therapy and the length of treatment in reference to the incidence of developing HT. Current research into inflammatory mediators and biomarkers such as Cyclooxygenase-2, matrix metalloproteinases, and soluble ST2 and their potential role as treatment options for HT is also briefly discussed. Finally, this review calls for more research into use of dual antiplatelet and the timing of antiplatelet and anticoagulant use in reference to hemorrhagic transformation.

Current Trends in the Duration of Anticoagulant Therapy for Venous Thromboembolism: A Systematic Review.

Anticoagulation therapy is the first line and drug of choice for both the treatment and prophylaxis of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism). Anticoagulation drugs, ranging from different preparations of heparin, warfarin, and newer direct oral drugs such as rivaroxaban and dabigatran, work mainly by inhibiting important factors and enzymes in the coagulation cascade by preventing fibrin formation, platelet aggregation, and clot assembly. With recurrent thrombosis and embolisms being a feared complication for many physicians treating such cases, anticoagulation is often extended beyond the initial three- to six-month acute phase after an incident of venous thromboembolism. For some groups of patients, anticoagulation needs to be offered indefinitely to decrease the risk of a recurrent thrombosis. However, this concomitantly increases obvious and dangerous adverse effects such as increased risk of hemorrhage, as the ability to clot is hindered. This tradeoff between recurrent venous thromboembolism and bleeding is what underscores the controversy of the clinical question: for how long should anticoagulation be administered for venous thromboembolism? This review analyzes the use of anticoagulants in different types of venous thromboembolism and remarks on current consensus and trends on the length of anticoagulation treatment. We are doing so while acknowledging that venous thromboembolism management is an active area of research that is rapidly evolving. A literature search was performed looking at recent studies on anticoagulant administration for the treatment of venous thromboembolism with a focus on varying durations and patient populations. Factors that affect clinical decisions of duration are also elucidated. The most clinically relevant anticoagulants were discussed and their effects on the risk of recurrent thrombosis and embolism, and the risk of bleeding in relation to other drugs were analyzed. Ultimately, this article discussed patterns of anticoagulant treatments duration and which patient groups are likely to benefit the most from certain durations, shedding light on the ambiguity in how physicians should approach administering anticoagulation therapy over time for a broad range of presentations of venous thromboembolism.

Carotid Artery Calcification: What We Know So Far.

Carotid artery calcification (CAC) is a well-known marker of atherosclerosis and is linked to a high rate of morbidity and mortality. CAC is divided into two types: intimal and medial calcifications, each with its own set of risk factors. Vascular calcification is now understood to be an active, enzymatically regulated process involving dystrophic calcification and endothelial dysfunction at an early stage. This causes a pathogenic inflammatory response, resulting in calcium phosphate deposition in the form of microcalcifications, which causes plaque formation, ultimately becoming unstable with sequelae of complications. If the inflammation goes away, hydroxyapatite crystal formation takes over, resulting in macro-calcifications that help to keep the plaque stable. As CAC can be asymptomatic, it is critical to identify it early using diagnostic imaging. The carotid artery calcification score is calculated using computed tomography angiography (CTA), which is a confirmatory test that enables the examination of plaque composition and computation of the carotid artery calcification score. Magnetic resonance angiography (MRA), which is sensitive as CTA, duplex ultrasound (DUS), positron emission tomography, and computed tomography (PET-CT) imaging with (18) F-Sodium Fluoride, and Optical Coherence Tomography (OCT) are some of the other diagnostic imaging modalities used. The current therapeutic method starts with the best medical care and is advised for all CAC patients. Carotid endarterectomy and carotid stenting are two treatment options that have mixed results in terms of effectiveness and safety. When patient age and anatomy, operator expertise, and surgical risk are all considered, the agreement is that both techniques are equally beneficial.

Stimulant Usage by Medical Students for Cognitive Enhancement: A Systematic Review.

Stimulants have been used throughout human history for a variety of reasons. High levels of stress and the demanding nature of medical school make their usage among medical students particularly common. The most prevalent stimulant used by students is coffee, followed by tea and other forms of caffeine like sugary energy drinks. In addition, amphetamine-based medications for treating attention deficit hyperactivity disorder (ADHD) have been increasing in popularity, which many students take illicitly. Students report taking various forms of stimulants to promote cognitive enhancement, prolong wakefulness and retain focus for long periods of time. Moderate doses of caffeine and amphetamines would lead to enhanced alertness and concentration. However, large increases in dosage or frequency would lead to an increased risk of toxicity and adverse effects. The positive outcomes from stimulant consumption are often overshadowed by the negative side effects and incorrect dosage. Thus, it appears that usage of stimulants should be limited, in favor of a more sustainable approach to cognitive enhancement. This review analyzes the use of stimulants among the medical student community, consequences of misuse and discussed the healthy and organic approaches to lessen the stress and improve academic performance. This article also discusses the mechanisms of action, acceptable doses, additives, ingredients of stimulants commonly used by medical students for cognitive enhancement and the implications of long-term use as the stress of practicing medicine extends well beyond the medical school years.

In vivo oral insulin delivery via covalent organic frameworks.

With diabetes being the 7th leading cause of death worldwide, overcoming issues limiting the oral administration of insulin is of global significance. The development of imine-linked-covalent organic framework (nCOF) nanoparticles for oral insulin delivery to overcome these delivery barriers is herein reported. A gastro-resistant nCOF was prepared from layered nanosheets with insulin loaded between the nanosheet layers. The insulin-loaded nCOF exhibited insulin protection in digestive fluids in vitro as well as glucose-responsive release, and this hyperglycemia-induced release was confirmed in vivo in diabetic rats without noticeable toxic effects. This is strong evidence that nCOF-based oral insulin delivery systems could replace traditional subcutaneous injections easing insulin therapy.

Environmental Enrichment and Brain Neuroplasticity in the Kainate Rat Model of Temporal Lobe Epilepsy.

BACKGROUND AND PURPOSE: Environmental enrichment (EE) improves brain function and ameliorates cognitive impairments; however, whether EE can reverse the learning and memory deficits seen following seizures remains unknown. METHODS: We tested the hypothesis that EE augments neurogenesis and attenuates the learning and memory deficits in rats subjected to kainate-induced seizures in hippocampus, amygdala and motor cortex. EE consisted of daily exposures immediately after KA lesioning (early EE) and after a 60-day period (late EE). Morphometric counting of neuron numbers (NN), dendritic branch-points and intersections (DDBPI) were performed. Spatial learning in a T-maze test was described as percent correct responses and memory in a passive-avoidance test was calculated as time spent in the small compartment where they were previously exposed to an aversive stimulus. RESULTS: EE increased NN and DDBPI in the normal control and in the KA-lesioned rats in all brain areas studied, after both early and late exposure to EE. Late EE resulted in significantly fewer surviving neurons than early EE in all brain areas (p < 0.0001). EE increased the percent correct responses and decreased time spent in the small compartment, after both early and late EE. The timing of EE (early vs. late) had no effect on the behavioral measurements. CONCLUSIONS: These findings demonstrate that, after temporal lobe and motor cortex epileptic seizures in rats, EE improves neural plasticity in areas of the brain involved with emotional regulation and motor coordination, even if the EE treatment is delayed for 60 days. Future studies should determine whether EE is a useful therapeutic strategy for patients affected by seizures.