Successful hybrid management of hypertensive patent ductus arteriosus with unilateral absence of the right pulmonary artery - A case report.

Unilateral absence of pulmonary artery (UAPA) can be either isolated or associated with other congenital cardiac defects. It is a rare congenital lesion with a diverse clinical presentation. We present a case of absent right pulmonary artery and large patent ductus arteriosus (PDA) with severe unilateral pulmonary hypertension. We describe our strategy of staged ductus arteriosus closure in this patient and successful outcome on long term follow up.

Transcatheter management of combined patent ductus arteriosus and left pulmonary artery stenosis in congenital rubella syndrome: A series of three patients and an insight into case selection for intervention.

Transcatheter closure of patent ductus arteriosus (PDA) is now the standard of care with some exceptions. Best treatment for peripheral pulmonary artery (PA) stenosis in small children is still debatable. Surgical augmentation, balloon dilatation, and stenting are the available options with each having its own risks and limitations. Here, we are reporting complete transcatheter management of three cases of congenital rubella syndrome who had PDA and left branch PA stenosis by device closure and stent placement, with successful outcome in two cases and complication, leading to surgery in one. We also share our understanding of case selection for a better outcome.

New-onset headache after percutaneous atrial septal defect closure.

Background: Percutaneous closure of atrial septal defect (ASD) is a well-established procedure both in children and adults with very good long-term outcomes. Migraine headache (MHA) can be precipitated after ASD device closure and the mechanism is not fully understood. Methods: We reviewed medical records of all patients undergoing ASD device closure from January 2015 to January 2021 for new onset headache after the procedure. Diagnosis of migraine was established by guidelines of the International Headache Society. Results: Out of 325 patients undergoing ASD device closure, five patients (1.5%) of various age groups (range 3.5-35 years) complained of severe migraine-like headaches within 2 weeks of the procedure. MHA was reported exclusively by females. All the patients were treated with oral paracetamol for the management of headaches. Three of 5 (60%) patients had a positive family history of migraine. Three patients reported complete disappearance of symptoms within 4-6 months. While two others (40%) had ongoing symptoms at 6 months follow-up. Conclusions: MHA can be precipitated after ASD device closure. The risk is specifically high in females with a family history of migraine. Dual antiplatelet drugs for the first 3 months after device closure may prevent such episodes. Prospective studies are needed to establish the universal role of dual antiplatelet drugs after ASD device closure.

Transcatheter closure of ventricular septal defects in children less than 10 kg: experience from a tertiary care referral hospital in Eastern India.

OBJECTIVE: To assess the feasibility of percutaneous transcatheter device closure of ventricular septal defects in children weighing less than 10 kg. BACKGROUND: Although percutaneous transcatheter device closure of ventricular septal defect is a well-established method of treatment in older children and adolescents, there is limited data on device closure in small children weighing less than 10 kg. We present our institutional experience of transcatheter VSD closure in children weighing less than 10 kg. METHOD: Medical records were reviewed for 16 children, who were selected for device closure of ventricular septal defects based on the inclusion criteria. RESULTS: Out of 65 patients with a diagnosis of ventricular septal defect, 16 children less than 10 kg were attempted for percutaneous device closure. In 13 patients, the device was successfully released, and 3 patients needed surgical closure of the defect. Mean age and weight of the patients were 17.3 ± 12.7 months and 6.8 ± 3.2 kg, respectively. Mean defect size was 6 mm (range 3-10). There was no incidence of device embolisation or heart block or death. Five patients had residual left-to-right shunt immediately after the device release, which got closed by the first month's follow-up. We had one accidental perforation of right ventricular free wall at the time of crossing of the defect, which was successfully repaired surgically. CONCLUSION: Percutaneous device closure of ventricular septal defect in small children with weight below 10 kg is feasible with good short-term outcome. Careful patient selection is essential for procedural success and to avoid complications.

Hyperviscosity syndrome revisited.

Secondary erythrocytosis occurs in cyanotic heart disease as a physiological response to chronic hypoxia, and this leads to hyperviscosity and various complications of the same. Microvascular stasis due to hyperviscosity results in symptoms including headache, fatigue, paraesthesia, and loss of vision. An important and dreadful feature of hyperviscosity is overt thrombosis in organ systems, resulting in cerebrovascular accident and myocardial infarction. Limited body iron store in a state of secondary erythrocytosis brings forth iron-deficient microcytic red cells; these being more rigid and less deformable than normocytic cells, further aggravate vascular occlusion. The management of hyperviscosity syndrome starts with intravenous hydration and correction of latent iron deficiency. However, therapeutic phlebotomy may be employed as a rescue measure if symptoms persist despite correction of dehydration and anemia. We present a series of four patients with uncorrected cyanotic congenital heart disease who presented with a spectrum of features of hyperviscosity and discuss pathophysiology, clinical features, and management of hyperviscosity in detail.

Intervention Challenges in Patients with Congenital Heart Disease with Coexisting Interruption of the Inferior Vena Cava - A Case Series.

Interruption of the inferior vena cava with azygos continuation is a rare congenital anomaly. This anomaly becomes clinically important during cardiac interventions.

A Mechanistic Site-Of-Action Model: A Tool for Informing Right Target, Right Compound, And Right Dose for Therapeutic Antagonistic Antibody Programs.

Quantitative modeling is increasingly utilized in the drug discovery and development process, from the initial stages of target selection, through clinical studies. The modeling can provide guidance on three major questions-is this the right target, what are the right compound properties, and what is the right dose for moving the best possible candidate forward. In this manuscript, we present a site-of-action modeling framework which we apply to monoclonal antibodies against soluble targets. We give a comprehensive overview of how we construct the model and how we parametrize it and include several examples of how to apply this framework for answering the questions postulated above. The utilities and limitations of this approach are discussed.

d-Transposition of Great Arteries and Total Anomalous Pulmonary Venous Connection With Left Ventricular Regression-A Rarity.

Transposition of great arteries (TGA) in association with total anomalous pulmonary venous connection (TAPVC) has been rarely reported. With increasing age, left ventricular (LV) regression further complicates the clinical scenario. Management strategy is not clearly defined. We describe a rare combination of TGA, TAPVC, and LV regression and outline a successful management strategy.

Metabolic reprogramming dynamics in tumor spheroids: Insights from a multicellular, multiscale model.

Mathematical modeling provides the predictive ability to understand the metabolic reprogramming and complex pathways that mediate cancer cells' proliferation. We present a mathematical model using a multiscale, multicellular approach to simulate avascular tumor growth, applied to pancreatic cancer. The model spans three distinct spatial and temporal scales. At the extracellular level, reaction diffusion equations describe nutrient concentrations over a span of seconds. At the cellular level, a lattice-based energy driven stochastic approach describes cellular phenomena including adhesion, proliferation, viability and cell state transitions, occurring on the timescale of hours. At the sub-cellular level, we incorporate a detailed kinetic model of intracellular metabolite dynamics on the timescale of minutes, which enables the cells to uptake and excrete metabolites and use the metabolites to generate energy and building blocks for cell growth. This is a particularly novel aspect of the model. Certain defined criteria for the concentrations of intracellular metabolites lead to cancer cell growth, proliferation or death. Overall, we model the evolution of the tumor in both time and space. Starting with a cluster of tumor cells, the model produces an avascular tumor that quantitatively and qualitatively mimics experimental measurements of multicellular tumor spheroids. Through our model simulations, we can investigate the response of individual intracellular species under a metabolic perturbation and investigate how that response contributes to the response of the tumor as a whole. The predicted response of intracellular metabolites under various targeted strategies are difficult to resolve with experimental techniques. Thus, the model can give novel predictions as to the response of the tumor as a whole, identifies potential therapies to impede tumor growth, and predicts the effects of those therapeutic strategies. In particular, the model provides quantitative insight into the dynamic reprogramming of tumor cells at the intracellular level in response to specific metabolic perturbations. Overall, the model is a useful framework to study targeted metabolic strategies for inhibiting tumor growth.

Left subclavian artery stenosis treated with transcatheter stent placement in pediatric patients.

Left subclavian artery (LSA) stenosis causing limb length shortening or vascular compromise or significant pulse volume and blood pressure differences between two upper limbs are rarely described in pediatric patients. Here, we are presenting three such cases, two of them were congenital and another one acquired in origin. All of them were successfully treated with transcatheter implantation of stent in LSA. Normalization of limb length was detected on follow-up.

Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer.

Reprogramming of energy metabolism is a hallmark of cancer that enables the cancer cells to meet the increased energetic requirements due to uncontrolled proliferation. One prominent example is pancreatic ductal adenocarcinoma, an aggressive form of cancer with an overall 5-year survival rate of 5%. The reprogramming mechanism in pancreatic cancer involves deregulated uptake of glucose and glutamine and other opportunistic modes of satisfying energetic demands in a hypoxic and nutrient-poor environment. In the current study, we apply systems biology approaches to enable a better understanding of the dynamics of the distinct metabolic alterations in KRAS-mediated pancreatic cancer, with the goal of impeding early cell proliferation by identifying the optimal metabolic enzymes to target. We have constructed a kinetic model of metabolism represented as a set of ordinary differential equations that describe time evolution of the metabolite concentrations in glycolysis, glutaminolysis, tricarboxylic acid cycle and the pentose phosphate pathway. The model is comprised of 46 metabolites and 53 reactions. The mathematical model is fit to published enzyme knockdown experimental data. We then applied the model to perform in silico enzyme modulations and evaluate the effects on cell proliferation. Our work identifies potential combinations of enzyme knockdown, metabolite inhibition, and extracellular conditions that impede cell proliferation. Excitingly, the model predicts novel targets that can be tested experimentally. Therefore, the model is a tool to predict the effects of inhibiting specific metabolic reactions within pancreatic cancer cells, which is difficult to measure experimentally, as well as test further hypotheses toward targeted therapies.

DNA-Binding Kinetics Determines the Mechanism of Noise-Induced Switching in Gene Networks.

Gene regulatory networks are multistable dynamical systems in which attractor states represent cell phenotypes. Spontaneous, noise-induced transitions between these states are thought to underlie critical cellular processes, including cell developmental fate decisions, phenotypic plasticity in fluctuating environments, and carcinogenesis. As such, there is increasing interest in the development of theoretical and computational approaches that can shed light on the dynamics of these stochastic state transitions in multistable gene networks. We applied a numerical rare-event sampling algorithm to study transition paths of spontaneous noise-induced switching for a ubiquitous gene regulatory network motif, the bistable toggle switch, in which two mutually repressive genes compete for dominant expression. We find that the method can efficiently uncover detailed switching mechanisms that involve fluctuations both in occupancies of DNA regulatory sites and copy numbers of protein products. In addition, we show that the rate parameters governing binding and unbinding of regulatory proteins to DNA strongly influence the switching mechanism. In a regime of slow DNA-binding/unbinding kinetics, spontaneous switching occurs relatively frequently and is driven primarily by fluctuations in DNA-site occupancies. In contrast, in a regime of fast DNA-binding/unbinding kinetics, switching occurs rarely and is driven by fluctuations in levels of expressed protein. Our results demonstrate how spontaneous cell phenotype transitions involve collective behavior of both regulatory proteins and DNA. Computational approaches capable of simulating dynamics over many system variables are thus well suited to exploring dynamic mechanisms in gene networks.

Rate turnover in mechano-catalytic coupling: A model and its microscopic origin.

A novel aspect in the area of mechano-chemistry concerns the effect of external forces on enzyme activity, i.e., the existence of mechano-catalytic coupling. Recent experiments on enzyme-catalyzed disulphide bond reduction in proteins under the effect of a force applied on the termini of the protein substrate reveal an unexpected biphasic force dependence for the bond cleavage rate. Here, using atomistic molecular dynamics simulations combined with Smoluchowski theory, we propose a model for this behavior. For a broad range of forces and systems, the model reproduces the experimentally observed rates by solving a reaction-diffusion equation for a "protein coordinate" diffusing in a force-dependent effective potential. The atomistic simulations are used to compute, from first principles, the parameters of the model via a quasiharmonic analysis. Additionally, the simulations are also used to provide details about the microscopic degrees of freedom that are important for the underlying mechano-catalysis.

Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.

Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

Slowing down single-molecule trafficking through a protein nanopore reveals intermediates for peptide translocation.

The microscopic details of how peptides translocate one at a time through nanopores are crucial determinants for transport through membrane pores and important in developing nano-technologies. To date, the translocation process has been too fast relative to the resolution of the single molecule techniques that sought to detect its milestones. Using pH-tuned single-molecule electrophysiology and molecular dynamics simulations, we demonstrate how peptide passage through the α-hemolysin protein can be sufficiently slowed down to observe intermediate single-peptide sub-states associated to distinct structural milestones along the pore, and how to control residence time, direction and the sequence of spatio-temporal state-to-state dynamics of a single peptide. Molecular dynamics simulations of peptide translocation reveal the time- dependent ordering of intermediate structures of the translocating peptide inside the pore at atomic resolution. Calculations of the expected current ratios of the different pore-blocking microstates and their time sequencing are in accord with the recorded current traces.

Rowell's syndrome: presenting features of systemic lupus erythematosus.

A subset of patients with lupus erythematosus develops erythema multiforme-like skin lesions with speckled pattern of antinuclear antibodies, positive rheumatoid factor, anti-Ro (SS-A), and anti-La antibodies (SS-B), which known as Rowell's syndrome. We report an adolescent boy presented with erythema multiforme-like skin lesions and pericardial effusion; he fulfilled criteria of both Rowell's syndrome and systemic lupus erythematosus (SLE). Such initial presentation of SLE is rarely reported in literature.

Growth hormone deficiency in fanconis anemia.

Two cases of Fanconis anemia (FA) are reported here. Case 1 presented with hypoplastic anemia and skeletal abnormality. Case 2, his older brother had stunted growth, investigations detected growth hormone deficiency and mild hematological derangement without other endocrine abnormality. FA was confirmed by positive chromosomal breakages studies in both cases.

Childhood steroid-responsive ophthalmoplegic migraine.

Ophthalmoplegic migraine (OM) is characterized by recurrent attacks of headache with paresis of ocular cranial nerves. Previously, it was classified as a variant of migraine, but recently, International Headache Classification (IHCD-II) has reclassified OM to the category of neuralgia. Presently, OM is considered a type of recurrent demyelinating cranial neuropathy. We report an adolescent girl with OM, who had been treated with steroid and showed dramatic improvement.

Morgagni hernia presenting as obstructive jaundice.

Morgagnis hernia is rare in pediatrics, representing 1%-6% of all congenital diaphragmatic hernias (CDH). We report a young boy presented with obstructive jaundice caused by compression of common bile duct (CBD) due to stretching and rotation of second part of duodenum in right-sided Morgagni hernia. Such presentation is rarely reported in literature.