Publications by authors named "Swati Arya"

19 Publications

  • Page 1 of 1

Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma.

Biochim Biophys Acta Rev Cancer 2021 Jul 29;1876(2):188598. Epub 2021 Jul 29.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, St James's Hospital, Dublin 8, Ireland. Electronic address:

Oesophageal adenocarcinoma (OAC) is a disease with an incredibly poor survival rate and a complex makeup. The growth and spread of OAC tumours are profoundly influenced by their surrounding microenvironment and the properties of the tumour itself. Constant crosstalk between the tumour and its microenvironment is key to the survival of the tumour and ultimately the death of the patient. The tumour microenvironment (TME) is composed of a complex milieu of cell types including cancer associated fibroblasts (CAFs) which make up the tumour stroma, endothelial cells which line blood and lymphatic vessels and infiltrating immune cell populations. These various cell types and the tumour constantly communicate through environmental cues including fluctuations in pH, hypoxia and the release of mitogens such as cytokines, chemokines and growth factors, many of which help promote malignant progression. Eventually clusters of tumour cells such as tumour buds break away and spread through the lymphatic system to nearby lymph nodes or enter the circulation forming secondary metastasis. Collectively, these factors need to be considered when assessing and treating patients clinically. This review aims to summarise the ways in which these various factors are currently assessed and how they relate to patient treatment and outcome at an individual level.
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http://dx.doi.org/10.1016/j.bbcan.2021.188598DOI Listing
July 2021

Leptin and Obesity: Role and Clinical Implication.

Front Endocrinol (Lausanne) 2021 18;12:585887. Epub 2021 May 18.

Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese () gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.
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http://dx.doi.org/10.3389/fendo.2021.585887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167040PMC
May 2021

Pulse Dipolar EPR Reveals Double-Histidine Motif Cu-NTA Spin-Labeling Robustness against Competitor Ions.

J Phys Chem Lett 2021 Mar 13;12(11):2815-2819. Epub 2021 Mar 13.

School of Medicine, University of St. Andrews, North Haugh, St. Andrews, KY16 9TF, U.K.

Pulse-dipolar EPR is an appealing strategy for structural characterization of complex systems in solution that complements other biophysical techniques. Significantly, the emergence of genetically encoded self-assembling spin labels exploiting exogenously introduced double-histidine motifs in conjunction with Cu-chelates offers high precision distance determination in systems nonpermissive to thiol-directed spin labeling. However, the noncovalency of this interaction exposes potential vulnerabilities to competition from adventitious divalent metal ions, and pH sensitivity. Herein, a combination of room-temperature isothermal titration calorimetry (ITC) and cryogenic relaxation-induced dipolar modulation enhancement (RIDME) measurements are applied to the model protein group G. protein G, B1 domain (GB1). Results demonstrate double-histidine motif spin labeling using Cu-nitrilotriacetic acid (Cu-NTA) is robust against the competitor ligand Zn-NTA at >1000-fold molar excess, and high nM binding affinity is surprisingly retained under acidic and basic conditions even though room temperature affinity shows a stronger pH dependence. This indicates the strategy is well-suited for diverse biological applications, with the requirement of other metal ion cofactors or slightly acidic pH not necessarily being prohibitive.
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http://dx.doi.org/10.1021/acs.jpclett.1c00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006131PMC
March 2021

Achilles Tendon Rupture: Can the Tendon Gap on Ultrasound Scan Predict the Outcome of Functional Rehabilitation Program?

Cureus 2020 Sep 7;12(9):e10298. Epub 2020 Sep 7.

Trauma and Orthopaedics, University Hospital of Derby and Burton NHS Foundation Trust, Burton, GBR.

Background and objectives  There is a growing use of functional rehabilitation programs for the treatment of Achilles tendon rupture. Factors such as patient age and level of activity have been used to guide the decision. One of the debated indications is the gap size between the ruptured ends of the tendon. This study aims to define any correlation between the amount of the initial gap between tendon ends and patients outcome treated with the functional rehabilitation program. Method  A prospective case series study of all patients with acute Achilles tendon rupture treated non-surgically with the functional rehabilitation program between 2016 and 2018. The tendon gap was measured with an ultrasound scan on the initial presentation. Patients were followed for a minimum of 12 months and assessed for Achilles Tendon Rupture Score (ATRS), plantarflexion strength, and re-rupture rate.  Results  A total of 56 patients completed one-year follow-up, and 2 patients had re-ruptures. The mean plantar flexion gap was 13.7 mm. The mean ATRS at 12 months was 85.12. There was no statistically significant correlation between the final ATRS and the mean rupture gap. Conclusion  The outcome following non-operative functional rehabilitation treatment of rupture Achilles tendon did not correlate with the size of the tendon gap, and authors recommend that decision on functional rehabilitation should not be based on these criteria.
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http://dx.doi.org/10.7759/cureus.10298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540077PMC
September 2020

Accidental extubation during parotid surgery: An unusual but dreaded complication.

Indian J Anaesth 2019 Dec 11;63(12):1043-1044. Epub 2019 Dec 11.

Department of Anaesthesiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.

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http://dx.doi.org/10.4103/ija.IJA_532_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921312PMC
December 2019

Quantitative proteomic changes in LPS-activated monocyte-derived dendritic cells: A SWATH-MS study.

Sci Rep 2019 03 13;9(1):4343. Epub 2019 Mar 13.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK.

Dendritic cells are key immune cells that respond to pathogens and co-ordinate many innate and adaptive immune responses. Quantitative mass spectrometry using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) was performed here to determine the global alterations in monocyte-derived dendritic cells (moDCs) in response to stimulation with lipopolysaccharide (LPS). A moDC library of 4,666 proteins was generated and proteins were quantified at 0, 6 and 24 h post-LPS stimulation using SWATH-MS. At 6 h and 24 h post-LPS exposure, the relative abundance of 227 and 282 proteins was statistically significantly altered (p-value ≤ 0.05), respectively. Functional annotation of proteins exhibiting significant changes in expression between the various time points led to the identification of clusters of proteins implicated in distinct cellular processes including interferon and interleukin signalling, endocytosis, the ER-phagosome pathway and antigen-presentation. In SWATH-MS major histocompatibility complex (MHC) class I proteins were highly upregulated at 24 h, whilst MHC class II proteins exhibited comparatively fewer changes over this period. This study provides new detailed insight into the global proteomic changes that occur in moDCs during antigen processing and presentation and further demonstrates the potential of SWATH-MS for the quantitative study of proteins involved in cellular processes.
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http://dx.doi.org/10.1038/s41598-019-40773-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416353PMC
March 2019

Epistaxis as the initial presentation in a case of rheumatic heart disease.

J Family Med Prim Care 2018 Sep-Oct;7(5):1136-1138

Department of Medicine, AIIMS, Rishikesh, Uttarakhand, India.

Rheumatic heart disease (RHD) remains prevalent in developing nations and shows varied presentations, causing diagnostic challenge. Here, we report a case of RHD in a 13-year-old boy who presented with recurrent epistaxis as the initial symptom. On detailed work-up, echocardiography revealed the incidental finding of involvement of mitral and aortic valves but the patient never had any symptom as per the diagnostic criteria for RHD. This report highlights the clinical and epidemiological significance of atypical presentations as such cases might go undiagnosed and untreated, seeking medical attention in advanced stages, which would have otherwise contributed to the actual prevalence of the disease in the population.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_211_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259542PMC
January 2019

On the origin of proteins in human drusen: The meet, greet and stick hypothesis.

Prog Retin Eye Res 2019 05 17;70:55-84. Epub 2018 Dec 17.

UCL Institute of Ophthalmology, University College London, London, UK; Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, Northern Ireland, UK.

Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly understood. Attention has focused on lipids and minerals, but relatively little is known about the origin of drusen-associated proteins and how they are retained in the space between the basal lamina of the retinal pigment epithelium and the inner collagenous layer space (sub-RPE-BL space). While some authors suggested that drusen proteins are mainly derived from cellular debris from processed photoreceptor outer segments and the RPE, others suggest a choroidal cell or blood origin. Here, we reviewed and supplemented the existing literature on the molecular composition of the retina/choroid complex, to gain a more complete understanding of the sources of proteins in drusen. These "drusenomics" studies showed that a considerable proportion of currently identified drusen proteins is uniquely originating from the blood. A smaller, but still large fraction of drusen proteins comes from both blood and/or RPE. Only a small proportion of drusen proteins is uniquely derived from the photoreceptors or choroid. We next evaluated how drusen components may "meet, greet and stick" to each other and/or to structures like hydroxyapatite spherules to form macroscopic deposits in the sub-RPE-BL space. Finally, we discuss implications of our findings with respect to the previously proposed homology between drusenogenesis in AMD and plaque formation in atherosclerosis.
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http://dx.doi.org/10.1016/j.preteyeres.2018.12.003DOI Listing
May 2019

Crosstalk between zinc and free fatty acids in plasma.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 04 25;1864(4):532-542. Epub 2018 Sep 25.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. Electronic address:

In mammalian blood plasma, serum albumin acts as a transport protein for free fatty acids, other lipids and hydrophobic molecules including neurodegenerative peptides, and essential metal ions such as zinc to allow their systemic distribution. Importantly, binding of these chemically extremely diverse entities is not independent, but linked allosterically. One particularly intriguing allosteric link exists between free fatty acid and zinc binding. Albumin thus mediates crosstalk between energy status/metabolism and organismal zinc handling. In recognition of the fact that even small changes in extracellular zinc concentration and speciation modulate the function of many cell types, the albumin-mediated impact of free fatty acid concentration on zinc distribution may be significant for both normal physiological processes including energy metabolism, insulin activity, heparin neutralisation, blood coagulation, and zinc signalling, and a range of disease states, including metabolic syndrome, cardiovascular disease, myocardial ischemia, diabetes, and thrombosis.
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http://dx.doi.org/10.1016/j.bbalip.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372834PMC
April 2019

Ischemia-modified albumin: Crosstalk between fatty acid and cobalt binding.

Prostaglandins Leukot Essent Fatty Acids 2018 08 20;135:147-157. Epub 2018 Jul 20.

School of Medicine, University of St Andrews, St Andrews, United Kingdom. Electronic address:

Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis. "Ischemia-modified albumin" (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. More recent work suggested that Co ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co to sites A and/or B. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels.
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http://dx.doi.org/10.1016/j.plefa.2018.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109191PMC
August 2018

Quantitative analysis of hydroxyapatite-binding plasma proteins in genotyped individuals with late-stage age-related macular degeneration.

Exp Eye Res 2018 07 24;172:21-29. Epub 2018 Mar 24.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK. Electronic address:

Age-related macular degeneration (AMD) is associated with the formation of sub-retinal pigment epithelial (RPE) deposits that block circulatory exchange with the retina. The factors that contribute to deposit formation are not well understood. Recently, we identified the presence of spherular hydroxyapatite (HAP) structures within sub-RPE deposits to which several AMD-associated proteins were bound. This suggested that protein binding to HAP represents a potential mechanism for the retention of proteins in the sub-RPE space. Here we performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on plasma samples from 23 patients with late-stage neovascular AMD following HAP-binding. Individuals were genotyped for the high risk CFH variant (T1277C) and binding to HAP was compared between wild type and risk variants. From a library of 242 HAP binding plasma proteins (1% false discovery rate), SWATH-MS revealed significant quantitative differences in the abundance of 32 HAP-binding proteins (p < 0.05) between the two homozygous groups. The concentrations of six proteins (FHR1, FHR3, APOC4, C4A, C4B and PZP) in the HAP eluted fractions and whole plasma were further analysed using ELISA and their presence in sections from human cadaver eyes was examined using immunofluorescence. All six proteins were found to be present in the RPE/choroid interface, and four of these (FHR1, FHR3, APOC4 and PZP) were associated with spherules in sub-RPE space. This study provides qualitative and quantitative information relating to the degree by which plasma proteins may contribute to sub-RPE deposit formation through binding to HAP spherules and how genetic differences might contribute to deposit formation.
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http://dx.doi.org/10.1016/j.exer.2018.03.023DOI Listing
July 2018

Arrhythmias and sudden death among older children and young adults following tetralogy of Fallot repair in the current era: are previously reported risk factors still applicable?

Congenit Heart Dis 2014 Sep-Oct;9(5):407-14. Epub 2013 Dec 9.

Section of Pediatric Cardiology, Carmen and Ann Adams Department of Pediatrics, The Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Mich, USA.

Background: Young adult patients (pts) with repaired tetralogy of Fallot (TOF) remain at risk for arrhythmias (Ar) and sudden cardiac death (SCD). Based on past studies with earlier pt subsets, Ar/SCD events were associated with right ventricular (RV) systolic pressures >60 mm Hg, outflow tract gradients >20 mm Hg, and QRS duration >180 ms. However, there are limited recent studies to evaluate these risk factors in the current patient generation.

Methods: Patients with TOF followed over the past 50 years were grouped by presence of any arrhythmias (group 1), absence of arrhythmias (group 2), and presence of SCD or significant ventricular arrhythmias (group 3) and correlated with current pt age, gender, age at repair, repair types, echocardiogram, cardiac magnetic resonance imaging, electrocardiogram/Holter, hemodynamics, and electrophysiology findings.

Results: Of 109 pts, 52 were male aged 17-58 years. Of these, 59 (54%) had Ar, two of whom had SCD. These 59 pts were chronologically older at the time of analysis, with repair at an older age and wider QRS duration (78-240, mean 158 ms) when compared with those without Ar. However, there was no correlation with surgical era, surgical repair, gender, RV pressure >60 mm Hg, right ventricular outflow tract gradient >20 mm Hg, or RV end-diastolic volume on CMRI.

Conclusions: Ar/SCD risk continues to correlate with repair age and advancing pt age. QRS duration is longer in these patients but at a shorter interval (mean 158 ms) and less RV pressure (mean 43 mm Hg) than previously reported. In the current TOF patient generation, neither surgical era, type of repair, RV outflow gradient nor RV volume correlate with Ar/SCD. Electrophysiologic testing to verify and identify arrhythmias remains clinically effective.
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http://dx.doi.org/10.1111/chd.12153DOI Listing
June 2015

Truncated hemoglobin, HbN, is post-translationally modified in Mycobacterium tuberculosis and modulates host-pathogen interactions during intracellular infection.

J Biol Chem 2013 Oct 27;288(41):29987-99. Epub 2013 Aug 27.

From the Council of Scientific and Industrial Research (CSIR)-Institute of Microbial Technology, Sector 39A, Chandigarh 160036, India.

Mycobacterium tuberculosis (Mtb) is a phenomenally successful human pathogen having evolved mechanisms that allow it to survive within the hazardous environment of macrophages and establish long term, persistent infection in the host against the control of cell-mediated immunity. One such mechanism is mediated by the truncated hemoglobin, HbN, of Mtb that displays a potent O2-dependent nitric oxide dioxygenase activity and protects its host from the toxicity of macrophage-generated nitric oxide (NO). Here we demonstrate for the first time that HbN is post-translationally modified by glycosylation in Mtb and remains localized on the cell membrane and the cell wall. The glycan linkage in the HbN was identified as mannose. The elevated expression of HbN in Mtb and M. smegmatis facilitated their entry within the macrophages as compared with isogenic control cells, and mutation in the glycan linkage of HbN disrupted this effect. Additionally, HbN-expressing cells exhibited higher survival within the THP-1 and mouse peritoneal macrophages, simultaneously increasing the intracellular level of proinflammatory cytokines IL-6 and TNF-α and suppressing the expression of co-stimulatory surface markers CD80 and CD86. These results, thus, suggest the involvement of HbN in modulating the host-pathogen interactions and immune system of the host apart from protecting the bacilli from nitrosative stress inside the activated macrophages, consequently driving cells toward increased infectivity and intracellular survival.
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http://dx.doi.org/10.1074/jbc.M113.507301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795296PMC
October 2013

Primary endocardial fibroelastosis presenting in a young child as incessant ventricular tachycardia and dilated cardiomyopathy.

Tex Heart Inst J 2012 ;39(5):714-8

Section of Pediatric Cardiology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan 48201, USA.

Endocardial fibroelastosis is a cardiomyopathy not commonly seen in the present age. We describe the case of a 4-year-old girl who presented with sustained incessant ventricular tachycardia, a severely dilated left ventricle, and cardiac dysfunction refractory to all medical management and even to ablation; she eventually underwent cardiac transplantation. The diagnosis was made only after histopathologic examination of the explanted heart showed clear evidence of endocardial fibroelastosis. Through this report, we would like to highlight the fact that primary endocardial fibroelastosis can masquerade as idiopathic dilated cardiomyopathy and that associated frequent premature ventricular contractions and nonsustained ventricular tachycardia require close monitoring. Progressive ventricular dilation and ventricular dysfunction can convey a poor prognosis. Sustained recalcitrant ventricular tachycardia in these patients can be a life-threatening event that requires emergent mechanical support and heart transplantation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461649PMC
April 2013

Successful Ablation of Antero-septal Accessory Pathway in the Non-Coronary Cusp in a Child.

Indian Pacing Electrophysiol J 2012 May 20;12(3):124-30. Epub 2012 May 20.

Division of Pediatric Cardiology, Children's Hospital of Michigan, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.

A 15-year-old boy with Wolff-Parkinson-White syndrome underwent an electrophysiology study for symptoms of palpitations and persistence of pre-excitation during peak exercise. He was detected to have right antero-septal accessory pathway with relatively long effective refractory period and no inducible tachycardia. He had only transient normalization with cryoablation. Eight months later, he presented again with two episodes of seizures with preceding palpitations. Neurology evaluation was unremarkable with a normal electroencephalogram. In view of his symptoms in association with evidence of pre-excitation, he underwent a second electrophysiology study with ablation. Cryoablation in the anterior septum again achieved only transient normalization. Mapping in the non-coronary cusp identified an earliest accessory pathway potential. RF ablation was performed in the non-coronary cusp with immediate normalization of his electrocardiogram. At 6 month follow-up, he continues to have no pre-excitation on his EKG. Ablation of the anteroseptal accessory pathway in the non-coronary cusp can be safely performed in patients' refractory to conventional ablation sites and techniques.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356592PMC
http://dx.doi.org/10.1016/s0972-6292(16)30506-xDOI Listing
May 2012

Epstein Barr virus-associated acute acalculous cholecystitis: a rare occurrence but favorable outcome.

Clin Pediatr (Phila) 2010 Aug 31;49(8):799-804. Epub 2010 Mar 31.

Wayne State University, Detroit, MI, USA.

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http://dx.doi.org/10.1177/0009922810363729DOI Listing
August 2010

Central venous catheter-associated pericardial tamponade in a 6-day old: a case report.

Int J Pediatr 2009 9;2009:910208. Epub 2010 Feb 9.

The Carman and Ann Adams Department of Pediatrics, Wayne State University and Division of Pediatric Cardiology, Children's Hospital of Michigan, Detroit, MI 48201, USA.

Introduction. Pericardial effusion (PCE) and tamponade can cause significant morbidity and mortality in neonates. Such cases have been reported in the literature in various contexts. Case Presentation. A 6-day old neonate with meconium aspiration syndrome and persistent pulmonary hypertension of newborn on high frequency oscillator ventilation and inhaled nitric oxide was referred to our hospital with a large pericardial effusion causing hemodynamic compromise. Prompt pericardiocentesis led to significant improvement in the cardio-respiratory status and removal of the central line prevented the fluid from reaccumulating. Cellular and biochemical analysis aided in the diagnosis of catheter related etiology with possibility of infusate diffusion into the pericardial space. Conclusion. We present this paper to emphasize the importance of recognizing this uncommon but serious complication of central venous catheters in intensive care units. We also discuss the proposed hypothesis for the mechanism of production of PCE.
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http://dx.doi.org/10.1155/2009/910208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821761PMC
July 2011

Role of Pre-A motif in nitric oxide scavenging by truncated hemoglobin, HbN, of Mycobacterium tuberculosis.

J Biol Chem 2009 May 27;284(21):14457-68. Epub 2009 Mar 27.

Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.

Mycobacterium tuberculosis truncated hemoglobin, HbN, is endowed with a potent nitric-oxide dioxygenase activity and has been found to relieve nitrosative stress and enhance in vivo survival of a heterologous host, Salmonella enterica Typhimurium, within the macrophages. These findings implicate involvement of HbN in the defense of M. tuberculosis against nitrosative stress. The protein carries a tunnel system composed of a short and a long tunnel branch that has been proposed to facilitate diatomic ligand migration to the heme and an unusual Pre-A motif at the N terminus, which does not contribute significantly to the structural integrity of the protein, as it protrudes out of the compact globin fold. Strikingly, deletion of Pre-A region from the M. tuberculosis HbN drastically reduces its ability to scavenge nitric oxide (NO), whereas its insertion at the N terminus of Pre-A lacking HbN of Mycobacterium smegmatis improved its nitric-oxide dioxygenase activity. Titration of the oxygenated adduct of HbN and its mutants with NO indicated that the stoichiometric oxidation of protein is severalfold slower when the Pre-A region is deleted in HbN. Molecular dynamics simulations show that the excision of Pre-A motif results in distinct changes in the protein dynamics, which cause the gate of the tunnel long branch to be trapped into a closed conformation, thus impeding migration of diatomic ligands toward the heme active site. The present study, thus, unequivocally demonstrates vital function of Pre-A region in NO scavenging and unravels its unique role by which HbN might attain its efficient NO-detoxification ability.
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http://dx.doi.org/10.1074/jbc.M807436200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682894PMC
May 2009

Genetic relatedness of six North-Indian butterfly species (Lepidoptera :Pieridae) based on 16S rRNA sequence analysis.

Mol Cell Biochem 2007 Jan 2;295(1-2):145-51. Epub 2006 Sep 2.

Department of Biotechnology, Panjab University, Chandigarh, 160014, India.

The present work involves the assessment of level of genetic relatedness or divergence amongst the six North-Indian species of Lepidoptera belonging to family Pieridae and sub family Pierinae on the basis of sequence variation of 16S ribosomal RNA. The PCR amplified products of these species were directly sequenced using ABI Prism BigDye Terminator Sequencing Kits (Applied Biosystems). The multiple nucleotide sequence alignment analysis has revealed several differences across these species. Significantly high percentage of A + T base composition content ranging between 73.13% (Ixias pyrene ) and 79.20 % (Pieris brassica) was observed in studied species. The percentage divergence in the investigated species of Pieridae family varied from 5.5% to 21.7%. The two species of Catopsilia revealed minimum sequence divergence of only 5.5%, whereas the other two groups of Ixias and Pieris revealed 15.5% and 8.6% sequence divergence, respectively. Pieris canidia and Ixias pyrene are genetically most divergent (21.7%) amongst the studied lepidopteran species. Phylogenetic analysis based on 16S rRNA nucleotide sequence revealed grouping of six species of Lepidoptera in the form of two different clusters, each cluster being represented by two species from the same genera. The separate taxonomic grouping of these Indian species has been observed when compared with several species of Piernae and Coliadinae subfamilies from other country isolates.
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http://dx.doi.org/10.1007/s11010-006-9284-6DOI Listing
January 2007
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