Fenestration: Integrating Wings Into the Atrial Septal Occluder for Navigating a Challenging Terrain.

Background Atrial septal defect (ASD) closure with significant left-to-right shunt and concurrent comorbidities poses challenges for intervention. A fenestrated atrial septal defect (FASD) device is a viable option for patients who cannot undergo complete occlusion due to hemodynamic and medical reasons. This study explores the use of FASD occluders in patients with secundum ASD and associated comorbidities where complete occlusion is difficult. Methodology This retrospective study collected the details of patients recommended for FASD closure diagnosed with significant secundum ASD and who had additional comorbidities between July 2015 and July 2023 in a tertiary cardiac center in eastern India. Among this cohort, patients who underwent FASD device placement were subjected to a comprehensive analysis. Results In total, 16 patients diagnosed with secundum ASD, characterized by significant left-to-right shunt and concurrent comorbidities, were considered for FASD closure during the study period. Ultimately, 13 patients (first group) underwent fenestrated atrial septal occluder implantation. The average age was 45.07 years, with the majority being females (n = 9). Comorbidities among this cohort included substantial left ventricular diastolic dysfunction (n = 7), left ventricular diastolic dysfunction coupled with moderate pulmonary hypertension (n = 1), severe pulmonary hypertension (n = 1), severe pulmonary valvular stenosis with right ventricular diastolic dysfunction (n = 2), and systemic lupus erythematosus (SLE) (n = 2). From this cohort, three patients did not undergo the intervention. The second group consisted of an elderly patient with severe left ventricular diastolic dysfunction, a young adult with a history of left atrial arrhythmia, and a child with Duchenne muscular dystrophy (DMD). The average ASD size among patients who underwent the intervention was 26.38 mm, with a thick-to-thick dimension measuring 31.15 mm. The procedure was successful in all 13 patients, with the most frequently used device being a 34 mm occluder (range = 28-40 mm). All devices, excluding the initial one, were custom-made atrial septal occluders (Lifetech Scientific). Among the patients, 12 exhibited left-to-right fenestration flow, while one patient experienced fenestration constriction, likely due to occluder overcrowding. The first patient had a handmade 5 mm fenestration in a 40 mm Amplatzer septal occluder, which got closed off at the one-year follow-up. The procedure was well-tolerated hemodynamically in all patients, with no major complications during the peri-procedural period. Short-term follow-up indicated favorable patient progress. Conclusions FASD closure emerges as a pivotal alternative for intricate scenarios involving secundum ASD coupled with concurrent comorbidities, offering individualized tailored solutions. Alongside the conventional associated comorbidities, such as left ventricular diastolic dysfunction and pulmonary hypertension, FASD devices hold the potential to extend their benefits to patients grappling with other complexities, including severe pulmonary valvular stenosis, SLE, predisposition to left atrial arrhythmia, and conditions like DMD. Ensuring meticulous evaluation of patient suitability and providing ongoing vigilant care becomes paramount for achieving optimal outcomes. The validation of these findings and the broadening of the comprehension of this approach necessitate further comprehensive investigations.

Metal-Free C-H Sulfamidation of 1,4-Naphthoquinone in Water.

Direct sulfamidation of 1,4-naphthoquinones using N-methoxy sulfonamides under metal-free conditions in water was developed. Base-mediated nucleophilic addition of N-methoxy sulfonamides, followed by N-O bond cleavage allowed the formation of enesulfonamides. Further, the synthesis of pyrrolonaphthoquinones proved the practicability of the current approach.

Unexpected stormy course after uneventful device closure of atrial septal defect - Possibly due to post-COVID-19 inflammatory state.

COVID-19 infection has myriad manifestations from self-limiting illness to stormy multi-organ failure. A 28-year-old woman negative for COVID reverse transcription-polymerase chain reaction underwent an uneventful elective device closure of atrial septal defect on intubation anesthesia. While a brief postprocedural endotracheal bleed was noted, significant hypoxia and respiratory distress ensued after extubation with biventricular dysfunction, pleural effusion, and radiographic evidence of acute respiratory distress syndrome. COVID antibodies were positive, and inflammatory markers were elevated. After a conservative multipronged medical management including anticoagulation, antibiotics, aspirin, beta-blocker, diuretics, and sildenafil, she improved in 1 week. The clinical course during this pandemic era gives a possibility of a post-COVID inflammatory syndrome as a potential etiology.

A comprehensive overview on Micro RNA signature in type 2 diabetes Mellitus and its complications.

MicroRNAs (miRNAs) are small endogenous, non-coding RNA molecules that can modulate the expression of their target genes. Since its discovery, an enormous breakthrough has been established regarding its biogenesis and pathophysiological action, which has revolutionized the field of molecular biology. In addition, recent studies have identified the existence of stable extracellular/circulating miRNAs tissues and in biological fluids like blood where they are safeguarded from endogenous ribonuclease activity. Type 2 diabetes mellitus (T2DM) has emerged as a prime health issue worldwide. Incidence has increased considerably over the past decade. There are various tests that have been employed to diagnose T2DM. But for early detection and development, the establishment of biomarkers are of paramount importance. Contemporary evidence also validates the signature of a set of this epigenetic factor miRNA in the development of various diseases, including T2DM. This article reviews the contemporary corroboration associating miRNAs and T2DM and emphasizes the potential role of miRNA as a circulatory biomarker that could alert the growing prevalence of T2DM. Also, it acknowledges the valuable compendium of information regarding biogenesis and functional role of circulating miRNA in insulin resistance which is intimately linked to T2DM. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01069-1.

PULMOEAST: A Comprehensive Analysis of Pulmonary Hypertension in Eastern India.

Background Pulmonary hypertension (PH) is a debilitating cardiovascular disorder characterized by abnormally elevated blood pressure within the lungs. The diverse range of causes and varied clinical presentations contribute to the complexity of its diagnosis and management. In eastern India and surrounding areas, awareness of PH remains limited, and resources for its management are scarce. This study aims to address this knowledge gap by investigating clinical characteristics and treatment approaches adopted for PH patients in eastern India. Methods This retrospective-prospective cohort study included patients diagnosed with PH, defined by a pulmonary artery systolic pressure (PASP) > 50 mmHg or a mean pulmonary artery pressure (mPAP) >20 mmHg, between July 2015 and October 2023. Data retrieved from hospital records formed the retrospective cohort, while the prospective cohort comprised patients directly recruited for the study. Results The PULMOEAST study enrolled 93 patients with confirmed PH, divided into prospective (59 patients) and retrospective (34 patients) cohorts. The most prevalent cause of PH was congenital heart disease (CHD), with shunt lesions (59.13%), followed by complex CHD (13.97%) and idiopathic PH (20.43%). Six additional patients presented with rare causes of PH, and three experienced transient PH following atrial septal defect device closure. Geographic distribution revealed that 72.04% of patients originated from eastern India, while 18.27% hail from other eastern states and 8.6% from neighboring countries. Patients exhibited varying functional classes (FC), with 57 classified as FC-II and 31 classified as FC-III. Treatment strategies primarily involve supportive medications and pulmonary vasodilators. Monotherapy was administered to 26 patients (27.95%), dual therapy to 50 patients (53.76%), and triple therapy to one patient. Notably, 16 patients did not receive any vasodilator therapy as they were waiting for further evaluation. Among the vasodilator regimen, two patients received Selexipag. Three patients underwent intervention for shunt lesion closure, including one patient who received a fenestrated atrial septal occluder implant. Additionally, one patient underwent clot removal for pulmonary thromboembolism. Despite the overall positive response to treatment, the study recorded eight fatalities (8.6%) during the observation period. However, most patients exhibited significant improvement, including a decrease in functional class, during a mean follow-up duration of 14.31 months. Conclusion The PULMOEAST study undertook a comprehensive exploration of PH in eastern India and surrounding regions, revealing a stark dominance of CHD as the primary culprit. The study confirmed the pivotal role of echocardiography as a readily available and effective tool for both initial and follow-up evaluations in resource-scarce settings. It painted a hopeful picture by showcasing significant clinical improvement in most treated patients, with supportive medications and pulmonary vasodilators playing a crucial role. However, the diverse etiologies, limited access to PH-specific resources, and lack of widespread awareness within the region continue to pose substantial challenges for patients. The study underscores the need for refined diagnostic approaches, cost-effective management strategies, collaborative care initiatives, and enhanced patient education to optimize PH care and improve outcomes in eastern India.

Envelope Glycoprotein based multi-epitope vaccine against a co-infection of Human Herpesvirus 5 and Human Herpesvirus 6 using in silico strategies.

The Human Betaherpesviruses HHV-5 and HHV-6 are quite inimical in immunocompromised hosts individually. A co-infection of both has been surmised to be far more disastrous. This can be attributed to a synergetic effect of their combined pathologies. While there have been attempts to develop a vaccine against each virus, no efforts were made to contrive an effective prophylaxis for the highly detrimental co-infection. In this study, an ensemble of viral envelope glycoproteins from both the viruses was utilized to design a multi-epitope vaccine using immunoinformatics tools. A collection of bacterial protein toll-like receptor agonists (BPTAs) was screened to identify a highly immunogenic adjuvant for the vaccine construct. The constructed vaccine was analysed using an array of methodologies ranging from World population coverage analysis to Immune simulation, whose results indicate high vaccine efficacy and stability. Furthermore, codon optimization and in silico cloning analysis were performed to check for efficient expression in a bacterial system. Collectively, these findings demonstrate the potential of the constructed vaccine to elicit an immune response against HHV-5 and HHV-6, thus supporting the viability of in vitro and in vivo studies.

Metabolomics of Multimorbidity: Could It Be the Quo Vadis?

Multimorbidity, the simultaneous presence of two or more chronic diseases, affects the health care to a great extent. Its association with health care cost, more disability, and poor quality of life makes it a major public health risk. The matter of worry is that management of a multimorbid condition is complicated by the fact that multiple types of treatment may be required to treat different diseases at a time, and the interaction between some of the therapies can be detrimental. Understanding the causal factors of simultaneously occurring disease conditions and investigating the connected pathways involved in the whole process may resolve the complication. When different disease conditions present in an individual share common responsible factors, treatment strategies targeting at those common causes will certainly reduce the chance of development of multimorbidity occurring because of those factors. Metabolomics that can dig out the underlying metabolites/molecules of a medical condition is believed to be an effective technique for identification of biomarkers and intervention of effective treatment strategies for multiple diseases. We hypothesize that understanding the metabolic profile may shed light on targeting the common culprit for different/similar chronic diseases ultimately making the treatment strategy more effective with a combinatorial effect.

Urinary MMP-7: A Predictive, Noninvasive Early Marker for Chronic Kidney Disease Development in Patients with Hypertension.

OBJECTIVE: Upregulation of matrix metalloproteinase-7 (MMP-7) is associated with hypertension and kidney fibrosis, which can progress to chronic kidney disease (CKD). Currently, kidney fibrosis is only detectable by an invasive procedure. Therefore, we set out to determine whether MMP-7 can act as a noninvasive biomarker in patients with hypertension to enable early detection of kidney fibrosis. MATERIALS AND METHODS: Diagnosed patients with hypertension and control patients were sampled. We diagnosed CKD using clinical and laboratory parameters. Serum urea, creatinine, urinary microalbumin, the albumin-to-creatinine ratio, and urinary MMP-7 were analyzed. RESULTS: The 195 patients with hypertension had significantly elevated MMP-7. Of these patients, 166 had MMP-7 >25.8 µg/L, whereas only 29 had MMP-7 <25.8 µg/L. Thirty-two patients with hypertension showed features of CKD, all of whom had urinary MMP-7 >25.8 µg/L. However, the urinary MMP-7 level did not differ with the severity of CKD or with the duration of hypertension. CONCLUSION: Elevated urinary MMP-7 can be a potential noninvasive, early indicator in patients with hypertension progressing to CKD, thus enabling early therapeutic intervention.

A Review on Low-Dimensional Nanomaterials: Nanofabrication, Characterization and Applications.

The development of modern cutting-edge technology relies heavily on the huge success and advancement of nanotechnology, in which nanomaterials and nanostructures provide the indispensable material cornerstone. Owing to their nanoscale dimensions with possible quantum limit, nanomaterials and nanostructures possess a high surface-to-volume ratio, rich surface/interface effects, and distinct physical and chemical properties compared with their bulk counterparts, leading to the remarkably expanded horizons of their applications. Depending on their degree of spatial quantization, low-dimensional nanomaterials are generally categorized into nanoparticles (0D); nanorods, nanowires, and nanobelts (1D); and atomically thin layered materials (2D). This review article provides a comprehensive guide to low-dimensional nanomaterials and nanostructures. It begins with the classification of nanomaterials, followed by an inclusive account of nanofabrication and characterization. Both top-down and bottom-up fabrication approaches are discussed in detail. Next, various significant applications of low-dimensional nanomaterials are discussed, such as photonics, sensors, catalysis, energy storage, diverse coatings, and various bioapplications. This article would serve as a quick and facile guide for scientists and engineers working in the field of nanotechnology and nanomaterials.

The combined chemical and mechanical modifications of cigarette: a novel methodology to reduce harmful effects.

Without hindering the taste, making a cigarette less harmful by reducing the percentage of toxic and carcinogenic compounds in the smoke of the cigarette is a challenging task for the current generation of researchers. In the current work, by implementing mechanical, chemical and combined modification techniques, the above stated is tried to mitigate. In addition to the above, the optimum suction pressure, burning time and the number of puffing are also determined. Mechanical modification technique considers filter to cigarette ratio and filter design as the controlling parameters. The mathematical calculation reveals that puffing should stop when the cigarette length reaches 0.15 times of its original length. Furthermore, it is also identified that the concentrations of suspended solids and droplets in the smoke decrease significantly (separation efficiency = 56.81%) if the cigarette to filter ratio is maintained at 2.32. In case of chemical modification, by using various types of adsorbents such as charcoal and Zeolite 13X, the harmful effects are further reduced. These processes depict significant reduction in harmful effect (separation efficiency up to 62.1%) by showing the decrement in the suspended solids and droplets in the smoke due to the adsorption on the active sites of adsorbents. In case of combined modification, the achieved separation efficiency is 66.51%. For the experimentation, an experimental setup fitted with artificial lungs was used.

Radiofrequency ablation for fascicular ventricular tachycardia causing tachycardiomyopathy and brief literature review.

A 10-years-old boy presented with a history of effort intolerance and palpitations for 4 months. His electrocardiogram showed wide complex tachycardia suggestive of fascicular ventricular tachycardia (VT). The echocardiogram showed moderate-to-severe left ventricular systolic dysfunction without any structural lesion. The tachycardia was unresponsive to adenosine and direct current cardioversion. It responded to oral verapamil. The electrophysiology study confirmed the tachycardia as left posterior fascicular VT. The tachycardia was successfully ablated guided by Purkinje potential on three-dimensional mappings. He showed improvement in ventricular functions before discharge. He is doing well on short-term follow-up.

Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production.

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

Novel use of Konar-multifunctional occluder.

INTRODUCTION: Lifetech Konar-multifunctional occluder is a novel device which is primarily used for the closure of ventricular septal defects. Being "multifunctional", the occluder has the potential to be useful in various structural cardiac defects. MATERIALS AND METHODS: We share our retrospective review from two centres regarding non-conventional usage of multifunctional occluders in CHD. Eight patients who underwent interventions using multifunctional occluders for lesions other than ventricular septal defects between March 2019 to September 2019 were included in the study. The patients were analysed based on demography, the size and type of lesion, procedural success, and development of complications. All patients were followed up in the outpatient department for a minimum period of 6 months. RESULTS: The median age and weight of the cohort were 3.2 years and 9 kg, respectively. Six patients had patent ductus arteriosus, while one patient had aorto-pulmonary window and one had a coronary arterio-venous fistula. The sizing of the occluders and the procedural approach were based on the underlying pathology. The most commonly used occluder was 6 × 4 mm variant. One patient had successful implantation but had significant intra-device residual flow and was thus replaced by a different occluder. There were no major complications, nor any incidences of device embolisation or malposition. On follow-up, all patients had uneventful course. CONCLUSION: Konar-multifunctional occluder can be safely used in lesions other than ventricular septal defects, when needed under specific circumstances. Its unique characteristics make it a versatile choice in a variety of cardiac lesions.

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

Constitutive Expression of the Immunosuppressive Tryptophan Dioxygenase TDO2 in Glioblastoma Is Driven by the Transcription Factor C/EBPß.

Catabolism of the essential amino acid tryptophan is a key metabolic pathway contributing to the immunosuppressive tumor microenvironment and therefore a viable drug target for cancer immunotherapy. In addition to the rate-limiting enzyme indoleamine-2,3-dioxygenase-1 (IDO1), tryptophan catabolism via tryptophan-2,3-dioxygenase (TDO2) is a feature of many tumors, particularly malignant gliomas. The pathways regulating TDO2 in tumors are poorly understood; using unbiased promoter and gene expression analyses, we identify a distinct CCAAT/enhancer-binding protein ß (C/EBPß) binding site in the promoter of TDO2 essential for driving constitutive TDO2 expression in glioblastoma cells. Using The Cancer Genome Atlas (TCGA) data, we find that C/EBPß expression is correlated with TDO2, and both are enriched in malignant glioma of the mesenchymal subtype and associated with poor patient outcome. We determine that TDO2 expression is sustained mainly by the LAP isoform of CEBPB and interleukin-1ß, which activates TDO2 via C/EBPß in a mitogen-activated protein kinase (MAPK) kinase-dependent fashion. In summary, we provide evidence for a novel regulatory and therapeutically targetable pathway of immunosuppressive tryptophan degradation in a subtype of glioblastoma with a particularly poor prognosis.

The therapeutic potential of targeting tryptophan catabolism in cancer.

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Hypoxia decreases the T helper cell-suppressive capacity of synovial fibroblasts by downregulating IDO1-mediated tryptophan metabolism.

OBJECTIVE: The development of RA is linked to local infiltration of immune cells and to changes in the phenotype of synovial fibroblasts. Synovial fibroblasts possess the capacity to suppress T cell responses through indoleamine 2, 3-dioxygenase 1 (IDO1)-mediated tryptophan metabolism. However, synovial fibroblasts from RA patients are restricted in this immune-modulatory function. Moreover, hypoxic conditions are detected within synovial tissues of RA patients, with oxygen tensions of only 3.2% O2. This study aims at investigating the effects of hypoxia on the interaction between T cells and synovial fibroblasts, particularly on the T cell-suppressive capacities of synovial fibroblasts. METHODS: Synovial fibroblasts were cultured with Th cells under normoxic and hypoxic conditions (3% O2). Th cell proliferation was detected by flow cytometry. Tryptophan and kynurenine amounts were measured by HPLC. IDO1 expression and signal transducer and activator of transcription 1 (STAT1) phosphorylation were quantified by real-time PCR or western blot, and cytokine secretion by ELISA. RESULTS: Hypoxic conditions strongly diminished the Th cell-suppressive capacities of both OA synovial fibroblasts and RA synovial fibroblasts. Accordingly, IDO1 mRNA and protein expression, STAT1 phosphorylation and tryptophan metabolism were greatly reduced in OA synovial fibroblasts by hypoxia. MMP-3, IL-6, IL-10 and IFNγ secretion were significantly decreased under hypoxia in synovial fibroblast-Th cell co-cultures, while IL-17A levels were elevated. Supplementation with IFNγ, a well-known inducer of IDO1 expression, could rescue neither IDO1 expression nor Th cell suppression under hypoxic conditions. CONCLUSION: Hypoxia strongly affected the crosstalk between synovial fibroblasts and Th cells. By reducing the efficiency of synovial fibroblasts to restrict Th cell proliferation and by increasing the expression of IL-17A, hypoxia might have implications on the pathophysiology of RA.