Clarifying the Anatomy of Tetralogy of Fallot with S-shaped Ascending Aorta.

We recently encountered several cases of tetralogy of Fallot with an abnormally oriented S-shaped ascending aorta. In this retrospective study, we sought to clarify morphology of this unusual under-recognized variant. Databases were reviewed to identify all patients with tetralogy of Fallot having an S-shaped ascending aorta. Computed tomographic angiography was used for the assessment of cardiac morphology. Out of the 21 patients, 18 (86%) had a right aortic arch, 2 (9%) had a left aortic arch, and the remaining patient (5%) had a double aortic arch. Patients with a right aortic arch, compared to age and sex-matched patients with a right aortic arch but normally oriented ascending aorta, had lesser aortic override (29.3 ± 14% vs 54.8 ± 13.2%; p = 0.0001) and a wider ascending aorta (25.2 ± 6.9 vs 18.0 ± 3.2 mm; p = 0.0003). The S-shaped ascending aorta was located posteriorly, with a higher sterno-aortic distance (25.5 ± 7.7 vs 9.9 ± 4.5 mm; p = 0.0001). The ascending aorta among patients with tortuosity was longer (4.12 ± 1.7 vs 3.07 ± 0.82, p = 0.03) but with similar tortuosity index (1.22 ± 0.19 vs 1.15 ± 0.17, p = 0.23). Of the cases with right aortic arch and S-shaped ascending aorta, 16 (89%) had extrinsic compression of the right pulmonary artery (p = 0.0001), while 7 (39%) had crossed pulmonary arteries (p = 0.008), with no such findings among those with normally oriented ascending aorta. Tetralogy of Fallot with an S-shaped ascending aorta is a variant with lesser aortic override and a more posteriorly located ascending aorta. Compression of the right pulmonary artery and crossed pulmonary arteries is frequent in the presence of a right-sided aortic arch. These findings have important implications for optimal diagnosis and surgical repair.

Immunomodulation by juglone alleviates acute graft-versus-host disease without compromising the graft-versus-leukaemia activity in mice.

BACKGROUND AND PURPOSE: Acute graft-versus-host disease (GVHD) remains a major barrier to successful transplantation outcomes. Recent studies have shown that pharmacotherapy for GVHD should target both the innate and adaptive inflammatory immune responses. Juglone, a redox-active phytochemical found in walnuts, has shown potent anti-inflammatory effects in models of colitis and inflammatory bowel disease. However, its effects on T-cell-mediated immune responses remain largely unknown. Considering the overlapping mediators of inflammation in GVHD and the aforementioned conditions, we investigated the use of juglone as a prophylactic agent for GVHD. EXPERIMENTAL APPROACH: Immunomodulatory activity and mechanism of action of juglone were studied using murine splenic leukocytes in vitro. The GVHD prophylactic efficacy of orally administered juglone was evaluated using a murine model of allogeneic haematopoietic stem cell transplantation based on an MHC mismatch. KEY RESULTS: Juglone exhibited immunomodulatory activity by (i) inhibiting the activation of dendritic cells and CD4+ T-cells, (ii) inhibiting cytokine secretion and lymphocyte proliferation, and (iii) inducing exhaustion of CD4+ T-cells, as shown by increased expression of CTLA-4 (CD152) and Fas (CD95). Oral administration of juglone significantly reduced mortality and morbidity associated with GVHD while maintaining graft-versus-leukaemia activity. This was accompanied by a decrease in the number of naïve CD4+ cells, and an increase in the number of CD4+ and CD8+ central memory T-cells. CONCLUSION AND IMPLICATIONS: Juglone is a potent immunomodulator for GVHD prophylaxis. Our study is the first to provide a dosage framework for the oral administration of juglone that can be used for clinical development.

Understanding the diabetes self-care behaviour in rural areas: Perspective of patients with type 2 diabetes mellitus and healthcare professionals.

BACKGROUND: Diabetes self-care behaviour plays a crucial role in managing the diabetes effectively and preventing complications. Patients with type 2 diabetes mellitus (T2DM) and health care professionals (HCPs) of rural areas often face unique challenges when it comes to diabetes self-care practices (SCPs). Therefore, this study aim to explore the perspectives of patients with T2DM and HCPs on diabetes SCPs. METHODS: Eight focus group discussions (FGDs) among individuals with T2DM and In-depth interviews (IDIs) with 15 HCPs were conducted in rural areas of Punjab, North India. Capability, Opportunity, Motivation, and Behaviour model (COM-B) was employed for thematic framework analyses. RESULTS: The study participants perceived that a limited understanding of diabetes mellitus (DM), beliefs in alternative therapies, drug side effects, attitudes towards DM (psychological capability), comorbidities (physical capability), family support (social opportunity), financial and time constraints, and weather conditions (physical opportunity) contributed to lack of DM SCPs. Physicians' guidance and support were motivating them to adhere to SCPs, especially when aligned with their sense of self-efficacy (reflective motivation). HCPs constraints in providing patient-centred care are due to training limitations (psychological capability) and a lack of essential resources (physical opportunities). Participants expressed need for comprehensive diabetes care (automatic motivation) through structured diabetes education intervention to improve diabetes SCPs. CONCLUSIONS: The study findings indicate that various factors influence diabetes SCPs from the perspectives of both patients with T2DM and HCPs and emphasizes the need for a multi-faceted approach to improve diabetes SCPs in rural areas. Implementing a structured diabetes self-care intervention strategy in rural areas may help for preventing and mitigating the impact of diabetes-related complications in rural areas.

Preclinical evaluation of engineered L-asparaginase variants to improve the treatment of Acute Lymphoblastic Leukemia.

INTRODUCTION: Escherichia coli l-asparaginase (EcA), an integral part of multi-agent chemotherapy protocols of acute lymphoblastic leukemia (ALL), is constrained by safety concerns and the development of anti-asparaginase antibodies. Novel variants with better pharmacological properties are desirable. METHODS: Thousands of novel EcA variants were constructed using protein engineering approach. After preliminary screening, two mutants, KHY-17 and KHYW-17 were selected for further development. The variants were characterized for asparaginase activity, glutaminase activity, cytotoxicity and antigenicity in vitro. Immunogenicity, pharmacokinetics, safety and efficacy were tested in vivo. Binding of the variants to pre-existing antibodies in primary and relapsed ALL patients' samples was evaluated. RESULTS: Both variants showed similar asparaginase activity but approximately 24-fold reduced glutaminase activity compared to wild-type EcA (WT). Cytotoxicity against Reh cells was significantly higher with the mutants, although not toxic to human PBMCs than WT. The mutants showed approximately 3-fold lower IgG and IgM production compared to WT. Pharmacokinetic study in BALB/c mice showed longer half-life of the mutants (KHY-17- 267.28±9.74; KHYW-17- 167.41±14.4) compared to WT (103.24±18). Single and repeat-doses showed no toxicity up to 2000 IU/kg and 1600 IU/kg respectively. Efficacy in ALL xenograft mouse model showed 80-90 % reduction of leukemic cells with mutants compared to 40 % with WT. Consequently, survival was 90 % in each mutant group compared to 10 % with WT. KHYW-17 showed over 2-fold lower binding to pre-existing anti-asparaginase antibodies from ALL patients treated with l-asparaginase. CONCLUSION: EcA variants demonstrated better pharmacological properties compared to WT that makes them good candidates for further development.

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect.

Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.

Comparative evaluation of divergent concoction of NGF, BDNF, EGF, and FGF growth factor's role in enhancing neuronal differentiation of adipose-derived mesenchymal stem cells.

MSCs (Mesenchymal Stem Cells) can differentiate into various lineages, including neurons and glial cells. In the past few decades, MSCs have been well explored in the context of neuronal differentiation and have been reported to have the immense potential to form distinct kinds of neurons. The distinguishing features of MSCs make them among the most desired cell sources for stem cell therapy. This study involved the trans-differentiation of Adipose-derived human Mesenchymal Stem Cells (ADMSCs) into neurons. The protocol employs a cocktail of chemical inducers in different combinations, including Brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and Nerve growth factor (NGF) Fibroblastic growth factor (FGF), in induction media. Both types have been successfully differentiated into neurons, confirmed by morphological aspects and the presence of neural-specific markers through RT-PCR (Reverse transcription polymerase chain reaction) studies and immunocytochemistry assay. They have shown excellent morphology with long neurites, synaptic connections, and essential neural markers to validate their identity. The results may significantly contribute to cell replacement therapy for neurological disorders.

Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a type of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. The goal of AML treatment is to eliminate the leukemic blasts, which is accomplished through intensive chemotherapy. Cytarabine is a key component of the standard induction chemotherapy regimen for AML. However, despite a high remission rate, 70-80% of AML patients relapse and develop resistance to Cytarabine, leading to poor clinical outcomes. Mitocurcumin (MitoC), a derivative of curcumin that enters mitochondria, leading to a drop in mitochondrial membrane potential and mitophagy induction. Further, it activates oxidative stress-mediated JNK/p38 signaling to induce apoptosis. MitoC demonstrated a preferential ability to kill leukemic cells from AML cell lines and patient-derived leukemic blasts. RNA sequencing data suggests perturbation of DNA damage response and cell proliferation pathways in MitoC-treated AML. Elevated reactive oxygen species (ROS) in MitoC-treated AML cells resulted in significant DNA damage and cell cycle arrest. Further, MitoC treatment resulted in ROS-mediated enhanced levels of p21, which leads to suppression of CHK1, RAD51, Cyclin-D and c-Myc oncoproteins, potentially contributing to Cytarabine resistance. Combinatorial treatment of MitoC and Cytarabine has shown synergism, increased apoptosis, and enhanced DNA damage. Using AML xenografts, a significant reduction of hCD45+ cells was observed in AML mice bone marrow treated with MitoC (mean 0.6%; range0.04%-3.56%) compared to control (mean 38.2%; range10.1%-78%), p = 0.03. The data suggest that MitoC exploits stress-induced leukemic oxidative environment to up-regulate JNK/p38 signaling to lead to apoptosis and can potentially overcome Cytarabine resistance via ROS/p21/CHK1 axis.

Congenital Heart Disease Illustrated: Use of Cross-sectional Imaging in Pediatric Cardiology.

In the modern era of cardiac imaging, there is increasing use of cardiac computed tomography and cardiac magnetic resonance for visualization of congenital heart disease (CHD). Advanced visualization techniques such as virtual dissection, 3-dimensional modeling, and 4-dimensional flow are also commonly used in clinical practice. This review highlights such methods in five common forms of CHD, including double outlet right ventricle, common arterial trunk, sinus venosus defects, Tetralogy of Fallot variants, and heterotaxy, providing visualizations of pathology in both conventional and novel formats.

Reciprocal impulses of junctional origin causing trigeminy.

Reciprocal impulses of junctional origin were seen in a patient with left isomerism who had undergone Kawashima repair in infancy. Heterotaxy syndromes are associated with disturbances in sinus node function. Junctional rhythm is hence common in this group. Junctional rhythm can conduct both anterogradely, to the ventricles, and retrogradely, back to the atrium. When it conducts retrogradely, it is termed as atrial echo, which can further conduct back to the ventricle. Our patient had a junctional rhythm with atrial echo beats that conduct to the ventricle, along with an ectopic atrial focus that does not conduct to the ventricle. This is due to variation in the RP interval [between R wave and subsequent P wave] of the echo beat and the atrial ectopic beat with respect to the preceding QRS complex. The timing of the P wave after the QRS complex determines the refractoriness of the atrioventricular node. This exhibits a trigeminal rhythm in our patient.

Recanalized vein of marshall following bidirectional glenn surgery.

A 6-year-old boy with a case of double outlet right ventricle with large non-routable ventricle septal defect and severe pulmonary stenosis was deemed unsuitable for biventricular repair on a prior evaluation. Hence, a bidirectional Glenn (BDG) shunt was performed at 3 years of age following cardiac catheterization.

COVID-19 associated renal artery stenosis in infancy - A report of two cases.

Organ-specific vasculitis is an uncommon, delayed complication of COVID-19 infection. It is usually seen in mildly symptomatic or asymptomatic patients. Underlying endothelitis is the most likely pathophysiological mechanism for such a manifestation. We report two infants with renal artery stenosis, most likely consequent to COVID-19 infection.

Kawasaki disease or polyarteritis nodosa: coronary involvement, a diagnostic conundrum.

Polyarteritis nodosa (PAN) is a medium-vessel vasculitis presenting with cutaneous and multisystem involvement with considerable morbidity. The necrotizing vasculitis in PAN typically involves renal, celiac, and mesenteric vascular beds. Coronary artery involvement is a characteristic feature of Kawasaki disease, another medium-vessel vasculitis; however, it has been rarely reported with PAN. Here, we present 2 cases with PAN involving coronaries mimicking Kawasaki disease. A 3.5-year-old boy with classical features of Kawasaki disease with giant coronary aneurysm refractory to IVIg, methylprednisolone, infliximab presented with persistent rise in inflammatory markers and gastrointestinal bleeding. Digital subtraction angiography (DSA) revealed celiac artery branches stenosis and beading suggestive of PAN. Another 2-year-old girl presented with persistent fever, abdominal pain, and distension. She had hypertension, hepatomegaly, and splenomegaly on examination. Echocardiography revealed multiple coronary aneurysms and DSA revealed numerous renal artery aneurysms. Coronary aneurysm although is a rare presentation of childhood PAN, and can mimic Kawasaki disease. Although both are medium-vessel vasculitis differentiation between these two entities is pivotal, as there are differences in treatment modalities, duration of immunomodulatory therapy, and the outcome. This manuscript describes the salient differences which can help differentiate PAN masquerading as Kawasaki disease at initial presentation.

Potential Use of Nucleic Acids as a Preceramic Polymer to Synthesize Nanodiamond-Embedded Phosphate Glass for Hard Tissue Engineering.

In recent years, nucleic acid has emerged as a versatile molecule that has been strategically used in material synthesis and biomedical applications. Keeping in mind the presence of the phosphate group, a glass former in the nucleic acids, we synthesized a transparent glass-like material by the thermal treatment of nucleic acids (DNA and RNA) at 900 °C at atmospheric pressure. Characterization of this material by transmission electron microscopy, X-ray photoelectron spectroscopy, and confocal fluorescence microscopy suggested the presence of in situ-formed nanodiamonds within the phosphate glass matrix. The molecular structure of glass investigated by X-ray photoelectron and infrared spectroscopy indicated a nearly equal proportion of metaphosphates and smaller phosphate units (pyro- and ortho-phosphate) that form the phosphate glass matrix. Thereafter, in vitro biological experiments showed that the nucleic acid-derived glass was non-toxic and cytocompatible, enhanced extracellular matrix secretion, and increased intracellular alkaline phosphatase activity, with potential application in hard tissue engineering. Our work offers insights into nanodiamond synthesis at atmospheric pressure and proves that nucleic acids could be used as a precursor to making an innovative glass-ceramic biomaterial.

Multimodality hemodynamic evaluation for optimizing management of anomalous origin of the right pulmonary artery from the aorta in an adolescent.

The hemodynamics of anomalous origin of the pulmonary artery (PA) from the aorta is challenging. Different sources of blood supply to the lungs lead to a unique state of differential flow, pressure, and pulmonary vascular resistance in each lung. The decision for surgical reimplantation of the anomalous PA during infancy is easy. The assessment of operability beyond infancy, however, is perplexing. In this report, we describe stepwise multimodal hemodynamic evaluation and successful surgical management in a 15-year-old boy with an isolated anomalous origin of the right PA from the aorta. We also report 5-year hemodynamic data confirming sustained benefit over the long term, thus providing much-needed clinical validation of often cited Poiseuille's and Ohm's laws.

Successful balloon dilatation of an infolded polytetrafluoroethylene graft: An unusual cause of early Fontan failure.

Despite optimal medical management, an 8-year-old boy had persistent pleural drainage following total cavopulmonary connection. Detailed evaluation, including computed tomography angiography, confirmed obstruction at the lower end of the circuit due to infolding of the polytetrafluoroethylene graft. Balloon dilation of the obstruction resulted in prompt resolution of pleural effusion with sustained relief at 1-year follow-up. The case demonstrates the importance of careful assessment in the diagnosis and successful nonsurgical management of an unusual cause of obstruction in the Fontan circuit.

Long-Term Surgical Outcomes of Patients With Isomeric Right and Left Atrial Appendages.

Objectives: To compare the long-term outcomes of biventricular, univentricular, and so-called one-and-one-half ventricular repairs in patients with left and right isomerism. Methods: Surgical correction was undertaken, between 2000 and 2021, in 198 patients with right, and 233 with left isomerism. Results: The median age at operation was 24 days (interquartile range [IQR]: 18-45) and 60 days (IQR: 29-360) for those with right and left isomerism, respectively. Multidetector computed-tomographic angiocardiography demonstrated more than half of those with right isomerism had superior caval venous abnormalities, and one-third had a functionally univentricular heart. Almost four-fifths of those with left isomerism had an interrupted inferior caval vein, and one-third had complete atrioventricular septal defect. Biventricular repair was achieved in two-thirds of those with left isomerism, but under one-quarter with right isomerism (P < .001). Hazard regression for mortality revealed odds for prematurity at 5.5, pulmonary atresia at 2.81, atrioventricular septal defect with a common valvar orifice at 2.28, parachute mitral valve at 3.73, interrupted inferior caval vein at 0.53, and functionally univentricular heart with a totally anomalous pulmonary venous connection at 3.77. At a median follow-up of 124 months, the probability of survival was 87% for those with left, and 77% for those with right isomerism (P = .006). Conclusions: Multimodality imaging characterizes and delineates the relevant anatomical details, facilitating surgical management of individuals with isomeric atrial appendages. Continuing higher mortality despite surgical intervention in those with right isomerism points to the need for the reassessment of strategies for management.

CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications.

The lack of currently available drugs for treating diabetes complications has stimulated our interest in finding new Aldose Reductase inhibitors (ARIs) with more beneficial biological properties. One metabolic method uses aldose reductase inhibitors in the first step of the polyol pathway to control excess glucose flux in diabetic tissues. Computer-aided drug discovery (CADD) is key in finding and optimizing potential lead substances. AR inhibitors (ARI) have been widely discussed in the literature. For example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China. Inhibiting R in patients with severe to moderate diabetic autonomic neuropathy benefits heart rate variability. AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it reduces inflammation and cardiac damage. In summary, these results from animal and human studies strongly indicate that AR can cause cardiovascular complications in diabetes. The current multi-center, large-scale randomized human study of the newly developed powerful ARI may prove its role in diabetic cardiovascular disease to establish therapeutic potential. During the recent coronavirus disease (COVID-19) outbreak in 2019, diabetes and cardiovascular disease were risk factors for severely negative clinical outcomes in patients with COVID19. New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19.

Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice.

Withaferin-A (WA) is the principle component of Withania somnifera (Ashwagandha). It has several biological activities including anti-cancer, anti-diabetic, neuroprotective, hepatoprotective and immune-modulatory properties. The acute and sub-acute toxicity of oral WA was investigated in mice. In the acute toxicity study, up to 2000 mg/kg of WA was well tolerated without any signs of toxicity or death. In the sub-acute toxicity study, mice were orally administered 10, 70 and 500 mg/kg of WA respectively, daily for 28 days. Upon physiological, serum chemistry, hematology and histopathogical examination, no features suggestive of drug-induced toxicity were observed at any dose levels, thereby confirming the No-Observed Adverse Effect Level (NOAEL) to be at least 500 mg/kg. Furthermore, the oral bioavailability of WA was evaluated using single intravenous and oral doses of 10 mg/kg and 70 mg/kg respectively using sparse sampling strategy. Bioanalysis was carried out using a validated LC-MS/MS method. The AUC of WA was found to be 3996.9 ± 557.6 ng/mL*h and 141.7 ± 16.8 ng/mL*h for the intravenous and oral routes of administration respectively. The oral bioavailability was determined to be 1.8%. To conclude, WA was found to be extremely safe even at high doses, with a low oral bioavailability.