CSI clinical practice guidelines for dyslipidemia management: Executive summary.

Dyslipidemias are the most important coronary artery disease (CAD) risk factor. Proper management of dyslipidemia is crucial to control the epidemic of premature CAD in India. Cardiological Society of India strived to develop consensus-based guidelines for better lipid management for CAD prevention and treatment. The executive summary provides a bird's eye-view of the 'CSI: Clinical Practice Guidelines for Dyslipidemia Management' published in this issue of the Indian Heart Journal. The summary is focused on the busy clinician and encourages evidence-based management of patients and high-risk individuals. The summary has serialized various aspects of lipid management including epidemiology and categorization of CAD risk. The focus is on management of specific dyslipidemias relevant to India-raised low density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol (non-HDL-C), apolipoproteins, triglycerides and lipoprotein(a). Drug therapies for lipid lowering (statins, non-statin drugs and other pharmaceutical agents) and lifestyle management (dietary interventions, physical activity and yoga) are summarized. Management of dyslipidemias in oft-neglected patient phenotypes-the elderly, young and children, and patients with comorbidities-stroke, peripheral arterial disease, kidney failure, posttransplant, HIV (Human immunodeficiency virus), Covid-19 and familial hypercholesterolemia is also presented. This consensus statement is based on major international guidelines (mainly European) and expert opinion of lipid management leaders from India with focus on the dictum: earlier the better, lower the better, longer the better and together the better. These consensus guidelines cannot replace the individual clinician judgement who remains the sole arbiter in management of the patient.

COVID-19 infected ST-Elevation myocardial infarction in India (COSTA INDIA).

OBJECTIVE: To find out differences in the presentation, management and outcomes of COVID-19 infected STEMI patients compared to age and sex-matched non-infected STEMI patients treated during the same period. METHODS: This was a retrospective multicentre observational registry in which we collected data of COVID-19 positive STEMI patients from selected tertiary care hospitals across India. For every COVID-19 positive STEMI patient, two age and sex-matched COVID-19 negative STEMI patients were enrolled as control. The primary endpoint was a composite of in-hospital mortality, re-infarction, heart failure, and stroke. RESULTS: 410 COVID-19 positive STEMI cases were compared with 799 COVID-19 negative STEMI cases. The composite of death/reinfarction/stroke/heart failure was significantly higher among the COVID-19 positive STEMI patients compared with COVID-19 negative STEMI cases (27.1% vs 20.7% p value = 0.01); though mortality rate did not differ significantly (8.0% vs 5.8% p value = 0.13). Significantly lower proportion of COVID-19 positive STEMI patients received reperfusion treatment and primary PCI (60.7% vs 71.1% p value=< 0.001 and 15.4% vs 23.4% p value = 0.001 respectively). Rate of systematic early PCI (pharmaco-invasive treatment) was significantly lower in the COVID-19 positive group compared with COVID-19 negative group. There was no difference in the prevalence of high thrombus burden (14.5% and 12.0% p value = 0.55 among COVID-19 positive and negative patients respectively) CONCLUSIONS: In this large registry of STEMI patients, we did not find significant excess in in-hospital mortality among COVID-19 co-infected patients compared with non-infected patients despite lower rate of primary PCI and reperfusion treatment, though composite of in-hospital mortality, re-infarction, stroke and heart failure was higher.

Concertina Effect.

Accordion effect or concertina effect - also known as "crumpled coronary" - is an uncommon occurrence during coronary angioplasty. It usually has no major clinical sequelae and should be differentiated from spasm, dissection, and thrombosis, which require special management.

An agent-based model to investigate microbial initiation of Alzheimer's via the olfactory system.

BACKGROUND: Alzheimer's disease (AD) is a degenerative brain disease. A novel agent-based modelling framework was developed in NetLogo 3D to provide fundamental insights into the potential mechanisms by which a microbe (eg. Chlamydia pneumoniae) may play a role in late-onset AD. The objective of our initial model is to simulate one possible spatial and temporal pathway of bacterial propagation via the olfactory system, which may then lead to AD symptoms. The model maps the bacteria infecting cells from the nasal cavity and the olfactory epithelium, through the olfactory bulb and into the olfactory cortex and hippocampus regions of the brain. RESULTS: Based on the set of biological rules, simulated randomized infection by the microbe led to the formation of beta-amyloid (Aß) plaque and neurofibrillary (NF) tangles as well as caused immune responses. Our initial simulations demonstrated that breathing in C. pneumoniae can result in infection propagation and significant buildup of Aß plaque and NF tangles in the olfactory cortex and hippocampus. Our model also indicated how mucosal and neural immunity can play a significant role in the pathway considered. Lower immunities, correlated with elderly individuals, had quicker and more Aß plaque and NF tangle formation counts. In contrast, higher immunities, correlated with younger individuals, demonstrated little to no such formation. CONCLUSION: The modelling framework provides an organized visual representation of how AD progression may occur via the olfactory system to better understand disease pathogenesis. The model confirms current conclusions in available research but can be easily adjusted to match future evidence and be used by researchers for their own individual purposes. The goal of our initial model is to ultimately guide further hypothesis refinement and experimental testing to better understand the dynamic system interactions present in the etiology and pathogenesis of AD.

Assessment of Prognostic Factors and Natural History of Idiopathic Pulmonary Arterial Hypertension in Eastern India.

BACKGROUND AND OBJECTIVES: Idiopathic pulmonary arterial hypertension (IPAH) is rare disorder of unknown aetiology associated with poor survival. Disease severity assessment by various prognostic factors play important role in management of these patients. The aim of our study was to assess various factors and their natural history and course of disease in Indian population. MATERIAL AND METHODS: We followed 27 patients of IPAH after complete work up of exclusion of other causes of pulmonary hypertension and analysed various demographic, echocardiographic and haemodynamic parameters and their correlation with mortality. RESULTS: A total of 27 patients (14 new and 13 previously diagnosed) were followed for mean duration of 18 months. At time of data analysis, 11 patients were alive and 16 patients died with overall mortality rate of 59.25%. Among various factors, presence of pericardial effusion (p=0.005), pulmonary artery acceleration time (PAAT) (p = 0.005), tricuspid Annular Plane Systolic Excursion (TAPSE) (p = 0.0004), heart rate (p=0.031), mean blood pressure (p =0.017), right atrial pressure (p=0.045), mean pulmonary artery pressure (PAP) (p=0.039) and six minute walk distance (p= 0.0002) were significantly associated with mortality. On multivariate cox proportional hazard analysis, PAAT (p =0.034), TAPSE (p=0.003) and six minute walk distance (p=0.002) remained significant predictors of mortality. CONCLUSION: Idiopathic pulmonary arterial hypertension is associated with poor prognosis and survival despite advancements of disease specific therapies. Higher mortality in our study is due to delayed presentation and diagnosis. Also lack of availability of prostacyclins and lung transplantation in advanced stages of disease contribute to higher mortality in Indian setup. Non-invasive echocardiographic factors and six minute walk distance are important prognostic factors that help in disease severity stratification to identify patients in need of intensive medical management.

A Physiologically-Based Pharmacokinetic Model for Targeting Calcitriol-Conjugated Quantum Dots to Inflammatory Breast Cancer Cells.

Quantum dots (QDs) conjugated with 1,25 dihydroxyvitamin D3 (calcitriol) and Mucin-1 (MUC-1) antibodies (SM3) have been found to target inflammatory breast cancer (IBC) tumors and reduce proliferation, migration, and differentiation of these tumors in mice. A physiologically-based pharmacokinetic model has been constructed and optimized to match experimental data for multiple QDs: control QDs, QDs conjugated with calcitriol, and QDs conjugated with both calcitriol and SM3 MUC1 antibodies. The model predicts continuous QD concentration for key tissues in mice distinguished by IBC stage (healthy, early-stage, and late-stage). Experimental and clinical efforts in QD treatment of IBC can be augmented by in silico simulations that predict the short-term and long-term behavior of QD treatment regimens.

GutLogo: Agent-based modeling framework to investigate spatial and temporal dynamics in the gut microbiome.

Knowledge of the spatial and temporal dynamics of the gut microbiome is essential to understanding the state of human health, as over a hundred diseases have been correlated with changes in microbial populations. Unfortunately, due to the complexity of the microbiome and the limitations of in vivo and in vitro experiments, studying spatial and temporal dynamics of gut bacteria in a biological setting is extremely challenging. Thus, in silico experiments present an excellent alternative for studying such systems. In consideration of these issues, we have developed a user-friendly agent-based model, GutLogo, that captures the spatial and temporal development of four representative bacterial genera populations in the ileum. We demonstrate the utility of this model by simulating population responses to perturbations in flow rate, nutrition, and probiotics. While our model predicts distinct changes in population levels due to these perturbations, most of the simulations suggest that the gut populations will return to their original steady states once the disturbance is removed. We hope that, in the future, the GutLogo model is utilized and customized by interested parties, as GutLogo can serve as a basic modeling framework for simulating a variety of physiological scenarios and can be extended to capture additional complexities of interest.

A simple and accurate rule-based modeling framework for simulation of autocrine/paracrine stimulation of glioblastoma cell motility and proliferation by L1CAM in 2-D culture.

BACKGROUND: Glioblastoma multiforme (GBM) is a devastating brain cancer for which there is no known cure. Its malignancy is due to rapid cell division along with high motility and invasiveness of cells into the brain tissue. Simple 2-dimensional laboratory assays (e.g., a scratch assay) commonly are used to measure the effects of various experimental perturbations, such as treatment with chemical inhibitors. Several mathematical models have been developed to aid the understanding of the motile behavior and proliferation of GBM cells. However, many are mathematically complicated, look at multiple interdependent phenomena, and/or use modeling software not freely available to the research community. These attributes make the adoption of models and simulations of even simple 2-dimensional cell behavior an uncommon practice by cancer cell biologists. RESULTS: Herein, we developed an accurate, yet simple, rule-based modeling framework to describe the in vitro behavior of GBM cells that are stimulated by the L1CAM protein using freely available NetLogo software. In our model L1CAM is released by cells to act through two cell surface receptors and a point of signaling convergence to increase cell motility and proliferation. A simple graphical interface is provided so that changes can be made easily to several parameters controlling cell behavior, and behavior of the cells is viewed both pictorially and with dedicated graphs. We fully describe the hierarchical rule-based modeling framework, show simulation results under several settings, describe the accuracy compared to experimental data, and discuss the potential usefulness for predicting future experimental outcomes and for use as a teaching tool for cell biology students. CONCLUSIONS: It is concluded that this simple modeling framework and its simulations accurately reflect much of the GBM cell motility behavior observed experimentally in vitro in the laboratory. Our framework can be modified easily to suit the needs of investigators interested in other similar intrinsic or extrinsic stimuli that influence cancer or other cell behavior. This modeling framework of a commonly used experimental motility assay (scratch assay) should be useful to both researchers of cell motility and students in a cell biology teaching laboratory.

Assessment of Right Ventricular Function by Newer Imaging in Echocardiography in Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: The aims of the study were to assess the right ventricular (RV) functions in patients with idiopathic pulmonary arterial hypertension (IPAH) with RV longitudinal strain (RVLS) in addition to conventional parameters, as well as its correlation with severity and prognosis in IPAH. METHODS: Twenty-two IPAH patients were followed up for 1 year. ANOVA and Gabriel's pairwise comparison tests were used for comparison of RVLS with respect to WHO functional class status. Patients were divided into non-survival (group 1) and survival (group 2), and clinical and echocardiographic parameters of RV function were compared at baseline and at 6 months with t-test & Mann-Whitney test. RESULTS: At baseline, with respect to WHO functional class, mean RVLS showed no significant interclass difference (P = 0.0781). Among the other conventional echocardiographic parameters, RV E/A showed significant difference at baseline (P = 0.004), but not at 6 months (P = 0.366); whereas tricuspid annular plane systolic excursion (TAPSE) which had no significant difference initially (P = 0.174) revealed a significance level at 6 months (P = 0.029) between the two groups. Fractional area change (FAC), RV index of myocardial performance (RIMP), and right atrial (RA) area displayed significant difference neither at baseline nor at 6 months. RVLS exhibited significant difference neither at baseline (P = 0.912) nor at 6 months (P = 0.181). None of the echocardiographic parameters including RVLS showed a significant average change with change in severity of PAH both at 6 and 12 months. CONCLUSION: RVLS was not proved to be a useful parameter for early detection of RV dysfunction and prognosis in patients with IPAH in comparison with the conventional echocardiographic parameters.

Novel systems modeling methodology in comparative microbial metabolomics: identifying key enzymes and metabolites implicated in autism spectrum disorders.

Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial "fingerprints" in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. This paper proposes a computational approach whereby metagenomes characteristic of "healthy" and autistic individuals are artificially constructed via genomic information, analyzed for the enzymes coded within, and then these enzymes are compared in detail. This is a text mining application. A custom-designed online application was built and used for the comparative metabolomics study and made publically available. Several of the enzyme-catalyzing reactions involved with the amino acid glutamate were curiously missing from the "autism" microbiome and were coded within almost every organism included in the "control" microbiome. Interestingly, there exists a leading hypothesis regarding autism and glutamate involving a neurological excitation/inhibition imbalance; but the association with this study is unclear. The results included data on the transsulfuration and transmethylation pathways, involved with oxidative stress, also of importance to autism. The results from this study are in alignment with leading hypotheses in the field, which is impressive, considering the purely in silico nature of this study. The present study provides new insight into the complex metabolic interactions underlying autism, and this novel methodology has potential to be useful for developing new hypotheses. However, limitations include sparse genome data availability and conflicting literature experimental data. We believe our software tool and methodology has potential for having great utility as data become more available, comprehensive and reliable.

An agent-based modeling framework for evaluating hypotheses on risks for developing autism: effects of the gut microbial environment.

The number of cases diagnosed with Autism Spectrum Disorders is rising at an alarming rate with the Centers for Disease Control estimating the 2014 incidence rate as 1 in 68. Recently, it has been hypothesized that gut bacteria may contribute to the development of autism. Specifically, the relative balances between the inflammatory microbes clostridia and desulfovibrio and the anti-inflammatory microbe bifidobacteria may become destabilized prior to autism development. The imbalance leads to a leaky gut, characterized by a more porous epithelial membrane resulting in microbial toxin release into the blood, which may contribute to brain inflammation and autism development. To test how changes in population dynamics of the gut microbiome may lead to the imbalanced microbial populations associated with autism patients, we constructed a novel agent-based model of clostridia, desulfovibrio, and bifidobacteria population interactions in the gut. The model demonstrates how changing physiological conditions in the gut can affect the population dynamics of the microbiome. Simulations using our agent-based model indicate that despite large perturbations to initial levels of bacteria, the populations robustly achieve a single steady-state given similar gut conditions. These simulation results suggests that disturbance such as a prebiotic or antibiotic treatment may only transiently affect the gut microbiome. However, sustained prebiotic treatments may correct low population counts of bifidobacteria. Furthermore, our simulations suggest that clostridia growth rate is a key determinant of risk of autism development. Treatment of high-risk infants with supra-physiological levels of lysozymes may suppress clostridia growth rate, resulting in a steep decrease in the clostridia population and therefore reduced risk of autism development.

Adult-Onset Blue Rubber Bleb Nevus Syndrome.

A 64-year-old, nondiabetic, nonhypertensive Indian woman was admitted to our hospital for evaluation of lethargy that had been present for the past 10 months. In addition, she had developed multiple, gradually progressive, bluish nodules scattered over the skin and mucous membranes for the preceding 15 years. There was no history of recent weight loss, vomiting of blood, passing of bloody stool, or any other external bleeding. There was no significant family history and medical and surgical history was noncontributory. She had received iron preparations repeatedly in the past.

Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.

Model-based hypothesis of gut microbe populations and gut/brain barrier permeabilities in the development of regressive autism.

Regressive autism is a devastating disorder affecting children between the ages of 15-30 months. The disorder is characterized by the loss of social interaction and communication ability following otherwise healthy development. In spite of rising autism prevalence, current detection methods and treatment options for this disease are lacking. Therefore, this study introduces a systems-level model, which suggests that gut microbes and intestinal inflammation influence the onset of regressive autism through increasing gut permeability. This computational model provides a framework for quantitative understanding of how imbalances in populations of gut microbes alters the whole-body and brain distributions of neurotoxins produced by GI tract bacteria. Our results indicate that increased levels of the bacteria Bacteroides vulgatus lead to increased brain levels of propionic acid, a neurotoxin which has been known to cause symptoms characteristic of autism when injected into the brain of rats. Our results further indicate that immune response to virulence factors produced by bacteria in the gut leads to increased systemic levels of inflammatory cytokines, such as IL-1ß, which significantly alter the permeability of the gut epithelial layer and the blood-brain barrier. Due to the large size of cytokines, however, we predict the time required for concentrations in the brain to stabilize to be on the order of years. This suggests that treatments preventing autism development could be administered after identifying microbial biomarkers of disease but before debilitating brain inflammation leads to regressive autism progression. Future research extending this work could provide new treatment options and diagnostic techniques to help combat regressive autism.

Synthesis and Characterization of L-Lysine Conjugated Silver Nanoparticles Smaller Than 10 nM.

A rapid and convenient batch method for synthesizing lysine-conjugated silver nanoparticles of approximately 5 nm of size was developed. Nanoparticles of size less than 100 nm exhibit significant medical potential. L-Lysine demonstrates potential for therapeutic applications and silver nanoparticles are an optimal choice for drug delivery because of its intrinsic anti-platelet, anti-bacterial and anti-inflammatory capabilities. Current synthesis protocols for Lysine-capped particles under 10 nm are time consuming and tedious and allow only for the sythesis of small quantities of particles. The synthesis of Lysin-capped silver nanoparticles was based on the reaction in which AgNO3 was reduced by excess NaBH4. L-Lysine, a known essential amino acid, served as the capping agent to minimize initial aggregation. The particles were then separated by size chromatography. Capping occurred through the amide bond on L-Lysine as determined by FT-IR. The conjugation of the particle to the amide bond is important, since this leaves the amino group of Lysine open to further modifications. The particles were further characterized in regards to their shape, size and stability. Finally we demonstrated that the synthesized particles exhibit limited to no toxicity in cells, using HEK 293 cell line as a model system. Our sythesis protocol can be successfully used for scale-up and synthesis of high quantities of nanoparticles.

Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability.

Autism Spectrum Disorders are neurodevelopmental disorders with symptoms that include cognitive impairments, stereotyped behaviors, and impairments in social skills. The dramatic increase in incidence of autism in recent years has created an increased need to find effective treatments. This paper proposes a hypothesis for a systems model of the connections between Autism Spectrum Disorder pathogenesis routes observed in recent studies. A combination treatment option is proposed to combat multiple pathogenesis mechanisms at once. Autism has been cited as being linked to gastrointestinal symptoms and is thought to be caused by a combination of genetic predisposition and environmental factors. Neuroinflammation as a result of increased gastrointestinal permeability has been noted as being a likely cause of Autism Spectrum Disorders, with possible primary causes stemming from abnormal intestinal bacteria and/or sulfur metabolic deficiencies. Our pathogenesis model proposes a circular relationship: oxidative stress and sulfur metabolic deficiencies could cause changes in colonic bacterial composition; and environmental bacterial contaminants could lead to elevated oxidative stress in individuals. It would thus be a self-perpetuating process where treatment options with single targets would have short-lived effects. It is believed that bacterial toxins, oxidative stress and dietary allergens such as gluten could all lead to increased epithelial permeability. Therefore, we propose a combination treatment to combat intestinal permeability, abnormal bacteria and/or bacterial overgrowth, and sulfur metabolic deficiencies. It is our hope that the proposed model will inspire new studies in finding effective treatments for individuals with Autism Spectrum Disorders. We suggest possible future studies that may lend more credibility to the proposed model.

Development of Physiologically Based Pharmacokinetic Model (PBPK) of BMP2 in Mice.

Bone Morphogenetic protein 2 holds great promise for potential applications in the clinic. It is a potent growth factor for the use in the cervical spine surgery (FDA approved 2002) and has been marketed as "Infuse" for treating open tibial shaft fractures (FDA approved 2004). However, its use is limited by several significant side effects that maybe due to its potency and effect on different stem cell populations in the spine. BMP2 is expressed throughout the human body in several tissues and at a very high concentration in the blood. BMP receptors, especially BMP receptor type Ia, is ubiquitously expressed in most tissues. Currently, it is difficult to determine how BMP2 is physiologically distributed in mice or humans and no quantitative models are available. A Physiologically-Based Pharmaco-Kinetic (PBPK) model has been developed to determine steady-state distribution of BMP2 in mice. The multi-compartmental PBPK model represents relevant organ/tissues with physiological accuracy. The organs/tissue compartments chosen were brain, lung, heart, liver, pancreas, kidney, uterus, bone and fat. A blood compartment maintained connectivity among the various organs. Four processes characterized the change in the concentration of the protein in every compartment: blood flow in, blood flow out, protein turnover and receptor binding in the organ. The unique aspects of the model are the determination of elimination using receptor kinetics and generation using protein turnover. The model also predicts steady state concentrations of BMP2 in tissues in mice and may be used for possible scale-up of dosage regimens in humans.

Caveolae regulate Smad signaling as verified by novel imaging and system biology approaches.

The contribution of caveolae in Bone Morphogenetic Protein 2 (BMP2) activated Smad signaling was quantified using a system biology approach. BMP2 plays crucial roles during processes such as hematopoiesis, embryogenesis, and skeletal development. BMP2 signaling is tightly regulated on the plasma membrane by its receptors. The localization of BMP receptors in caveolae and endocytosis through clathrin-coated pits are thought to regulate the signaling; however the conclusions in the current literature are inconsistent. Therefore published literature was used to establish a mathematical model that was validated using confocal AFM (atomic force microscopy), confocal microscopy, and sucrose density centrifugation followed by Western blots, and reporter gene assays. The model and experiments confirmed that both caveolae and CCPs regulate the Smad-dependent signaling pathway, however caveolae are centers at the plasma membrane where receptor-ligand interaction is crucial, Smad phosphorylation occurs, and a high degree of Smad signaling is regulated. This demonstrates a role for caveolae that needs to be considered and further studied.