Apixaban for Prevention of Thromboembolism in Pediatric Heart Disease.

BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).

Retrieval of Large Balloon Fragments During Transcatheter Pulmonary Valve Implantation Using a Novel Retrieval System.

The removal of balloon fragments from the pulmonary artery without damaging the pulmonary and tricuspid valves can be difficult. Four cases during transcatheter pulmonary valve replacement are described in which a novel retrieval system was used to facilitate safe removal. (Level of Difficulty: Advanced.).

Single tertiary center experience using Gore Cardioform Atrial Septal Defect Occluder for secundum atrial septal defect closure with a focus on deficient rims.

BACKGROUND: The data on the use of Gore Cardioform Septal Occluder (GCA; W. L. Gore and Associates, Inc.) for atrial septal defect (ASD) with deficient rims is limited. METHODS: All patients evaluated by transesophageal echocardiogram (TEE) for ASD occlusion were included. TEE planes at 35°, 0°, and 90° were assessed for anterior-superior (AS) and posterior (P), anterior-inferior (AI) and posterior-superior (PS), as well as superior (S) and inferior (I) rims. ASD size >20 mm, and rims less than 5 mm were defined as large and deficient, respectively. We included patients who had a procedural failure along with the patients in whom the procedure was not attempted after echocardiogram in the unsuccessful group. RESULTS: In 148 patients, the median weight, age, and ASD size were 36 kg (range, 8-60 kg), 11.8 years (range, 1-60 years), and 14.2 ± 8.28 mm, respectively. One or more deficient rims were noted in 112 of 148 (75.7%): 99 (67%) AS, 36 (24%) P, 17 (11%) AI, 30 (20%) PS, 26 (18%) S, and 33 (22%) I. ASD closure was performed in 115 (78%) patients. The procedure was successful in 111 (96.5%) patients with procedural failure in 4 (3.4%) patients. Multiple deficient rims were associated with reduced procedural success (OR 0.36, 95% CI, 0.25-0.56). On multivariate analysis deficient P, PS, and I rims were associated with an unsuccessful group (P = .001, .046, and .005, respectively). Complications included 1 device embolization, 1 vascular injury, and 5 arrhythmias. CONCLUSIONS: Transcatheter closure of ASDs with deficient rims is feasible using GCA. Large ASDs with deficient P, PS, and I rims were associated with unsuccessful closure. Risk stratification and comprehensive evaluation of ASD rims is vital for the use of GCA.

Co-administration of saffron and chamomile: to determine the efficacy as an adjuvant therapy for mild to moderate depression in human subjects. A pilot randomized clinical trial.

OBJECTIVE: To determine the combined effects of chamomile and saffron herbs as an adjuvant therapy in patients with metabolic alterations associated with mild to moderate depression. METHODS: The prospective, randomised, blinded, end-point pilot study was conducted at the Aga Khan University, Karachi, from August to October 2020, and comprised patients with mild to moderate depression with or without diabetes, hypertension and dyslipidaemia. The subjects were randomised into intervention group A, which was given herbal tea sachets containing saffron 1mg and chamomile 20mg for twice a day oral use for a month along with medications, and control group B, which was advised to continue their routine medications. Data was collected at baseline and post-intervention using Patient Health Questionnaire-9 for assessing depression severity, and blood samples for cholesterol estimations. Data was analysed using SPSS 20. RESULTS: Of the 50 subjects, 25(50%) were in each of the two groups. Cholesterol, high-density lipoprotein, low-density lipoprotein and depression values were significantly better in group A than in group B (p<0.05). CONCLUSIONS: Potential benefits of combined doses of chamomile and saffron were found in depressive patients by improving metabolic alterations.

Mechanistic and biophysical insight into the inhibitory and disaggregase role of antibiotic moxifloxacin on human lysozyme amyloid formation.

Lysozyme amyloidosis is a systemic non-neuropathic disease caused by the accumulation of amyloids of mutant lysozyme. Presently, therapeutic interventions targeting lysozyme amyloidosis, remain elusive with only therapy available for lysozyme amyloidosis being supportive management. In this work, we examined the effects of moxifloxacin, a synthetic fluoroquinolone antibiotic on the amyloid formation of human lysozyme. The ability of moxifloxacin to interfere with lysozyme amyloid aggregation was examined using various biophysical methods like Rayleigh light scattering, Thioflavin T fluorescence assay, transmission electron microscopy and docking method. The reduction in scattering and ThT fluorescence along with extended lag phase in presence of moxifloxacin, suggest that the antibiotic inhibits and impedes the lysozyme fibrillation in concentration dependent manner. From ANS experiment, we deduce that moxifloxacin is able to decrease the hydrophobicity of the protein molecule thereby preventing aggregation. Our CD and DLS results show that moxifloxacin stabilizes the protein in its native monomeric structure, thus also showing retention of lytic activity upto 69% and inhibition of cytotoxicity at highest concentration of moxifloxacin. The molecular docking showed that moxifloxacin forms a stable complex of -7.6 kcal/mol binding energy and binds to the aggregation prone region of lysozyme thereby stabilising it and preventing aggregation. Moxifloxacin also showed disaggregase potential by disrupting fibrils and decreasing the ß-sheet content of the fibrils. Our current study, thus highlight the anti-amyloid and disaggregase property of an antibiotic moxifloxacin and hence sheds light on the future of antibiotics against protein aggregation, a hallmark event in many neurodegenerative diseases.

Pre-Fontan Assessment Utilizing Combined Cardiac Catheterization and Cardiac MRI: Comparison to the Pre-Fontan Catheterization.

Single ventricle patients eligible for Fontan completion undergo pre-Fontan catheterization for hemodynamic and anatomic assessment prior to surgery. Cardiac magnetic resonance imaging may be used to evaluate pre-Fontan anatomy, physiology, and collateral burden. We describe our center's outcomes in patients undergoing pre-Fontan catheterization combined with cardiac magnetic resonance imaging. A retrospective review of patients undergoing pre-Fontan catheterization from 10/2018 to 04/2022 at Texas Children's Hospital was performed. Patients were divided into 2 groups: combined cardiac magnetic resonance imaging and catheterization (combined group) and those who underwent catheterization only (catheterization only group). There were 37 patients in the combined group and 40 in the catheterization only group. Both groups were similar in age and weight. Patients undergoing combined procedures received less contrast, and experienced less in-lab time, fluoroscopy time and catheterization procedure time. Median radiation exposure was lower in the combined procedure group but was not statistically significant. Intubation and total anesthesia times were higher in the combined procedure group. Patients undergoing a combined procedure were less likely to have collateral occlusion performed than in the catheterization only group. Bypass time, intensive care unit length of stay, and chest tube duration were similar in both groups at the time of Fontan completion. Combined pre-Fontan assessment decreases catheterization procedure and fluoroscopy time associated with cardiac catheterization at the expense of longer anesthetic times, and results in similar Fontan outcomes compared to when cardiac catheterization alone is utilized.

Extra-cardiac and complex Fontan baffle fenestration using radio frequency current via surgical electrocautery.

BACKGROUND: Fontan baffle punctures and creation of Fontan fenestration for cardiac catheterisation procedures remain challenging especially due to the heavy calcification of prosthetic material and complex anatomy. OBJECTIVES: We sought to evaluate our experience using radiofrequency current via surgical electrocautery needle for Fontan baffle puncture to facilitate diagnostic, electrophysiology, and interventional procedures. METHODS: A retrospective chart review of all Fontan patients (pts) who underwent Fontan baffle puncture using radiofrequency energy via surgical electrocautery from three centres were performed from January 2011 to July 2021. RESULTS: A total of 19 pts underwent 22 successful Fontan baffle puncture. The median age and weight were 17 (3-36 years) and 55 (14-88) kg, respectively. The procedural indications for Fontan fenestration creation included: diagnostic study (n = 1), atrial septostomy and stenting (n = 1), electrophysiology study and ablation procedures (n = 8), Fontan baffle stenting for Fontan failure including protein-losing enteropathy (n = 7), and occlusion of veno-venous collaterals (n = 2) for cyanosis. The type of Fontan baffles included: extra-cardiac conduits (n = 12), lateral tunnel (n = 5), classic atrio-pulmonary connection (n = 1), and intra-cardiac baffle (n = 1). A Fontan baffle puncture was initially attempted using traditional method in 6 pts and Baylis radiofrequency trans-septal system in 2 pts unsuccessfully. In all pts, Fontan baffle puncture using radiofrequency energy via electrocautery needle was successful. The radiofrequency energy utilised was (10-50 W) and required 1-5 attempts for 2-5 seconds. There were no vascular or neurological complications. CONCLUSIONS: Radiofrequency current delivery using surgical electrocautery facilitates Fontan baffle puncture in patients with complex and calcified Fontan baffles for diagnostic, interventional, and electrophysiology procedures.

Pulmonary Vein Atresia: Feasibility of Initial Recanalization Attempts with Subsequent Follow-up.

Pulmonary vein atresia (PVA) may lead to pulmonary hypertension, cardiac failure, and death. Transcatheter or surgical treatments have rarely been offered to this population because of perceived poor outcomes. We describe single center outcomes of transcatheter management of PVA. Retrospective chart review of PVA patients who underwent cardiac catheterization at a single tertiary center. Sixty patients underwent catheterization for evaluation of PVA from 1995 to 2019. The age at the initial catheterization was 1.6 (0.7, 5.97) years. Two thirds of PVA patients had associated congenital heart disease (n=40). PVA recanalization was attempted in 34 patients, successful in 23/34 (68%) of the initial attempts. 3/23 (13%) underwent balloon angioplasty alone, and 20/23 (87%) received drug-eluting stents, with no procedural mortalities. 22/23 patients had transcatheter reinterventions during an interval of 2.1 (0.3, 5.1) years. Right ventricular systolic to aortic systolic pressure ratio (in biventricular patients) at the index catheterization was 0.45 (0.34, 0.68) in survivors versus 0.69 (0.54, 0.83) in those who died; P = 0.012 (n=45). The baseline right ventricular or pulmonary artery systolic to aortic systolic pressure ratio of ≥0.54 at the initial catheterization was predictive of mortality. We hereby demonstrate that transcatheter recanalization of PVA with placement of drug-eluting stents can be performed safely with acceptable success rate. With appropriate use of re-interventions for restenosis as indicated, PVA can be successfully palliated with good long-term patency and distal growth of the affected veins. Pulmonary hypertension is a risk factor for mortality in patients with PVA and biventricular circulation. Percutaneous recanalization of PVA is safe and feasible, and with placement of drug-eluting stents, carries a high acute success rate and results in growth of the distal pulmonary veins. However, close vigilance and reinterventions are required due to restenosis.

Natural remedies for Alzheimer's disease: A systematic review of randomized controlled trials.

Alzheimer's disease (AD) is the common type of dementia and is currently incurable. Existing FDA-approved AD drugs may not be effective for everyone, they cannot cure the disease nor stop its progression and their effects diminish over time. Therefore, the present review aimed to explore the role of natural alternatives in the treatment of AD. A systematic search was conducted using Ovid MEDLINE, CINAHL, Cochrane and PubMed databases and reference lists up to November 30, 2021. Only randomized control trials were included and appraised using the National Institute of Health framework. Data analysis showed that herbs like Gingko Biloba, Melissa Officinalis, Salvia officinalis, Ginseng and saffron alone or in combination with curcumin, low-fat diet, NuAD-Trail, and soy lecithin showed significant positive effects on AD. Moreover, combination of natural and pharmaceuticals has far better effects than only allopathic treatment. Thus, different herbal remedies in combination with FDA approved drugs are effective and more promising in treatment of AD.

Interactions of Apigenin and Safranal with the 5HT1A and 5HT2A Receptors and Behavioral Effects in Depression and Anxiety: A Molecular Docking, Lipid-Mediated Molecular Dynamics, and In Vivo Analysis.

BACKGROUND: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. METHODS: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. RESULTS: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. CONCLUSIONS: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety.

Protein misfolding and related human diseases: A comprehensive review of toxicity, proteins involved, and current therapeutic strategies.

Most of the cell's chemical reactions and structural components are facilitated by proteins. But proteins are highly dynamic molecules, where numerous modifications or changes in the cellular environment can affect their native conformational fold leading to protein aggregation. Various stress conditions, such as oxidative stress, mutations and metal toxicity may cause protein misfolding and aggregation by shifting the conformational equilibrium towards more aggregation-prone states. Most of the protein misfolding diseases (PMDs) involve aggregation of protein. We have discussed such proteins like Aß peptide, α-synuclein, amylin and lysozyme involved in Alzheimer's, Parkinson's, type II diabetes and non-neuropathic systemic amyloidosis respectively. Till date, all advances in PMDs therapeutics help symptomatically but do not prevent the root cause of the disease, i.e., the aggregation of protein involved in the diseases. Current efforts focused on developing therapies for PMDs have employed diverse strategies; repositioning pre-existing drugs as it saves time and money; natural compounds that are touted as potential drug candidates have an advantage of being taken in diet normally and will induce lesser side effects. This review also covers recently developed therapeutic strategies like antisense drugs and disaggregases which has yielded therapeutic agents that have transitioned from preclinical studies into human clinical trials.

A randomized clinical trial to test efficacy of chamomile and saffron for neuroprotective and anti-inflammatory responses in depressive patients.

Depression is one of the common psychiatric problems in growing world population caused by long-term stressful events that may trigger the down regulation of neurogenesis. The pathogenesis of depression initially relies on serotonin deficiency which is associated with depressive feelings. Tryptophan (TRP) depletion participate crucial role in inducing depressive symptoms. Long-term reduction of 5-HT may disseminate to high sensitivity of MDD and alters the level of BDNF. Some studies have also revealed the strong association between excessive neuroinflammation and BDNF levels, due the release of pro-inflammatory cytokines. The treatment approach through FDA approved medicine has their own merits and drawbacks. Therefore, herbal alternatives have recently garnered attention for their effectiveness against depression. However, evidence-based synergic effects of antidepressant with different herbal agents are limited. The purpose of this study was to assess the synergistic effects of two well-known herbs, chamomile and saffron, as an adjuvant therapy in patients with mild to moderate depression. The present study was study randomized, open, blinded trial and comprised of 120 participants randomly allocated to control (n = 60) and test (n = 60). After consent, the patient health questionnaire- 9 (PHQ-9) was filled to obtain depression scores. The test participants were received herbal tea sachets twice a day for one month (20 mg Chamomile and 1 mg Saffron/sachet) along with routine medicines, while control participants were received only allopathic medications. Blood samples were taken before and after the treatment. The depressive symptoms improved significantly with both treatments. The effect of herbs enhanced the efficacy of medications and significantly improved PHQ-9 scale and BDNF while reduced the inflammatory markers (CRP) and TRP level in plasma thereby increased the availability of TRP in brain. It has been concluded that the herbal adjuvant therapy produced long term improvement against depression and enhanced the efficacy of allopathic treatment.

Ameliorative effects of half-dose saffron and chamomile combination on Psycho-endocrinological changes in a diabetic murine model.

INTRODUCTION: Diabetes mellitus is a chronic metabolic disorder with an increasing prevalence worldwide. Reduction in blood insulin level alters brain function by inducing oxidative stress with changes in dopamine and norepinephrine neurotransmission, ultimately leading to neuropsychological symptoms. The efficacy of currently available psychotropic drugs is not satisfactory. Therefore, this study was conducted to explore the beneficial effects of a combination of the natural herbs, saffron and chamomile, in treating diabetes and its resultant neuropsychological effects using a rodent model of diabetes mellitus. METHOD: The rats were randomly divided in to eight groups (n = 10), healthy control (HC), diabetic control (DC) and six groups of diabetic rats treated with various concentrations and combinations of saffron and chamomile. Diabetic treatment groups individually received methanolic extract and water decoction of chamomile (30 mg/kg) and saffron (10mg/kg) and their combined half doses (saffron 5mg/kg and chamomile 15mg/kg) for two weeks. Open field test (OFT) and forced swim test (FST) were used to measure the anxiolytic and antidepressant effects of herbs, respectively. Finally, biochemical, and neurochemical estimations were made. RESULTS: The present study suggests the therapeutic effects of herbs especially in co-administrated decoction, against diabetes with improved antioxidant profile and enhanced levels of dopamine and norepinephrine. Anxiolytic and antidepressant effects were evident with improvements in the OFT and FST. Examination of the cortex of the diabetic group revealed cellular damage and tangle formation, which indicates advanced stages of dementia. CONCLUSION: This study shows that the use of a combination of saffron and chamomile improves diabetes control and reduces its related psychiatric effects.

Moxifloxacin Disrupts and Attenuates Aß42 Fibril and Oligomer Formation: Plausibly Repositioning an Antibiotic as Therapeutic against Alzheimer's Disease.

The aggregation of Aß42 is established as a key factor in the development of Alzheimer's disease (AD). Consequently, molecules that inhibit aggregation of peptide may lead to therapies to prevent or control AD. Several studies suggest that oligomeric intermediates present during aggregation may be more cytotoxic than fibrils themselves. In this work, we examine the inhibitory activity of an antibiotic MXF on aggregation (fibrils and oligomers) and disaggregation of Aß42 using various biophysical and microscopic studies. Computational analysis was done to offer mechanistic insight. The amyloid formation of Aß42 is suppressed by MXF, as demonstrated by the decrease in both the corresponding ThT fluorescence intensity and other biophysical techniques. The lag phase of amyloid formation doubled from 4.53 to 9.66 h in the presence of MXF. The addition of MXF at the completion of the fibrillation reaction, as monitored by ThT, led to a rapid, concentration dependent, exponential decrease in fluorescence signal that was consistent with loss of fibrils. We used TEM to directly demonstrate that MXF caused fibrils to disassemble. Our docking results show that MXF binds to both monomeric and fibrillar forms of Aß42 with significant affinities. We also observed breaking of fibrils in the presence of MXF through molecular dynamics simulation. These findings suggest that antibiotic MXF could be a promising lead compound with dual role as fibril/oligomer inhibitor and disaggregase for further development as potential repurposed therapeutic against AD.

The amyloid state of proteins: A boon or bane?

Proteins and their aggregation is significant field of research due to their association with various conformational maladies including well-known neurodegenerative diseases like Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases. Amyloids despite being given negative role for decades are also believed to play a functional role in bacteria to humans. In this review, we discuss both facets of amyloid. We have shed light on AD, which is one of the most common age-related neurodegenerative disease caused by accumulation of Aß fibrils as extracellular senile plagues. We also discuss PD caused by the aggregation and deposition of α-synuclein in form of Lewy bodies and neurites. Other amyloid-associated diseases such as HD and amyotrophic lateral sclerosis (ALS) are also discussed. We have also reviewed functional amyloids that have various biological roles in both prokaryotes and eukaryotes that includes formation of biofilm and cell attachment in bacteria to hormone storage in humans, We discuss in detail the role of Curli fibrils' in biofilm formation, chaplins in cell attachment to peptide hormones, and Pre-Melansomal Protein (PMEL) roles. The disease-related and functional amyloids are compared with regard to their structural integrity, variation in regulation, and speed of forming aggregates and elucidate how amyloids have turned from foe to friend.

Workplace-Based Entrustment Scales for the Core EPAs: A Multisite Comparison of Validity Evidence for Two Proposed Instruments Using Structured Vignettes and Trained Raters.

PURPOSE: In undergraduate medical education (UME), competency-based medical education has been operationalized through the 13 Core Entrustable Professional Activities for Entering Residency (Core EPAs). Direct observation in the workplace using rigorous, valid, reliable measures is required to inform summative decisions about graduates' readiness for residency. The purpose of this study is to investigate the validity evidence of 2 proposed workplace-based entrustment scales. METHOD: The authors of this multisite, randomized, experimental study used structured vignettes and experienced raters to examine validity evidence of the Ottawa scale and the UME supervisory tool (Chen scale) in 2019. The authors used a series of 8 cases (6 developed de novo) depicting learners at preentrustable (less-developed) and entrustable (more-developed) skill levels across 5 Core EPAs. Participants from Core EPA pilot institutions rated learner performance using either the Ottawa or Chen scale. The authors used descriptive statistics and analysis of variance to examine data trends and compare ratings, conducted interrater reliability and generalizability studies to evaluate consistency among participants, and performed a content analysis of narrative comments. RESULTS: Fifty clinician-educators from 10 institutions participated, yielding 579 discrete EPA assessments. Both Ottawa and Chen scales differentiated between less- and more-developed skill levels (P < .001). The interclass correlation was good to excellent for all EPAs using Ottawa (range, 0.68-0.91) and fair to excellent using Chen (range, 0.54-0.83). Generalizability analysis revealed substantial variance in ratings attributable to the learner-EPA interaction (59.6% for Ottawa; 48.9% for Chen) suggesting variability for ratings was appropriately associated with performance on individual EPAs. CONCLUSIONS: In a structured setting, both the Ottawa and Chen scales distinguished between preentrustable and entrustable learners; however, the Ottawa scale demonstrated more desirable characteristics. These findings represent a critical step forward in developing valid, reliable instruments to measure learner progression toward entrustment for the Core EPAs.

A narrative review on manifestations of gluten free casein free diet in autism and autism spectrum disorders.

Autism and Autism Spectrum Disorder (ASD) are specific neurological disorders that affect the brain, frequently characterised by challenging paediatric behaviour. The current narrative review using PubMed and Google Scholar was conducted in line with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and comprised randomised controlled trials and clinical control trials with gluten-free, casein-free (GFCF) diets published till 2020. Of the 80 studies selected, 7(8.75%) were included in the review. It was observed that the gluten-free, casein-free diet was safe with therapeutic benefits in autistic children. Therefore, a tailored dietary approach can be a beneficial management regimen. The trials related to utility of gluten-free, casein-free diet among autistic children are sparse, with limited sampling size, and indication of bias in the findings. Therefore, larger cohort studies on gluten-free, casein-free trials are required to provide further insight into the therapeutic benefits of the diet.

Inhibition and disruption of amyloid formation by the antibiotic levofloxacin: A new direction for antibiotics in an era of multi-drug resistance.

Neurodegenerative diseases are a group of debilitating maladies involving protein aggregation. To this day, all advances in neurodegenerative disease therapeutics have helped symptomatically but have not prevented the root cause of the disease, i.e., the aggregation of involved proteins. Antibiotics are becoming increasingly obsolete due to the rising multidrug resistance strains of bacteria. Thus, antibiotics, if put to different use as therapeutics against other diseases, could pave a new direction to the world of antibiotics. Hence, we studied the antibiotic levofloxacin for its potential anti-amyloidogenic behavior using human lysozyme, a protein involved in non-systemic amyloidosis, as a model system. At the sub-stoichiometric level, levofloxacin was able to inhibit amyloid formation in human lysozyme as observed by various spectroscopic and microscopic methods, with IC50 values as low as 8.8 ± 0.1 µM. Levofloxacin also displayed a retarding effect on seeding phenomena by elongating the lag-phase (from 0 to 88 h) at lower concentration, and arresting lysozyme fibrillation at the lag stage in sub-stoichiometric concentrations. Structural and computational analyses provided mechanistic insight showing that levofloxacin stabilizes the lysozyme in the native state by binding to the aggregation-prone residues, and thereby inhibiting amyloid fibrillation. Levofloxacin also showed the property of disrupting amyloid fibrils into a smaller polymeric form of proteins which were less cytotoxic as confirmed by hemolytic assay. Therefore, we throw new light on levofloxacin as an amyloid inhibitor and disruptor which could pave way to utilization of levofloxacin as a potential therapeutic against non-systemic amyloidosis and neurodegenerative diseases.