39 results on '"Ferrandino G"'
Search Results
2. DNAJC17 is localized in nuclear speckles and interacts with splicing machinery components
- Author
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Pascarella, A., Ferrandino, G., Credendino, S. C., Moccia, C., D'Angelo, F., Miranda, B., D'Ambrosio, C., Bielli, P., Spadaro, O., Ceccarelli, M., Scaloni, A., Sette, C., De Felice, M., De Vita, G., Amendola, E., Sette, C. (ORCID:0000-0003-2864-8266), Pascarella, A., Ferrandino, G., Credendino, S. C., Moccia, C., D'Angelo, F., Miranda, B., D'Ambrosio, C., Bielli, P., Spadaro, O., Ceccarelli, M., Scaloni, A., Sette, C., De Felice, M., De Vita, G., Amendola, E., and Sette, C. (ORCID:0000-0003-2864-8266)
- Abstract
DNAJC17 is a heat shock protein (HSP40) family member, identified in mouse as susceptibility gene for congenital hypothyroidism. DNAJC17 knockout mouse embryos die prior to implantation. In humans, germline homozygous mutations in DNAJC17 have been found in syndromic retinal dystrophy patients, while heterozygous mutations represent candidate pathogenic events for myeloproliferative disorders. Despite widespread expression and involvement in human diseases, DNAJC17 function is still poorly understood. Herein, we have investigated its function through high-throughput transcriptomic and proteomic approaches. DNAJC17-depleted cells transcriptome highlighted genes involved in general functional categories, mainly related to gene expression. Conversely, DNAJC17 interactome can be classified in very specific functional networks, with the most enriched one including proteins involved in splicing. Furthermore, several splicing-related interactors, were independently validated by co-immunoprecipitation and in vivo co-localization. Accordingly, co-localization of DNAJC17 with SC35, a marker of nuclear speckles, further supported its interaction with spliceosomal components. Lastly, DNAJC17 up-regulation enhanced splicing efficiency of minigene reporter in live cells, while its knockdown induced perturbations of splicing efficiency at whole genome level, as demonstrated by specific analysis of RNAseq data. In conclusion, our study strongly suggests a role of DNAJC17 in splicing-related processes and provides support to its recognized essential function in early development.
- Published
- 2018
3. ROLE OF CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY (CCTA) IN SPONTANEOUS CORONARY ARTERY DISSECTION (SCAD)
- Author
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Dell‘Aversana, F, Tedeschi, C, Ferrandino, G, Tuccillo, A, Scotto di Uccio, F, Tuccillo, B, and Liguori, C
- Abstract
Spontaneous Coronary Artery Dissection (SCAD) is a rare but insidious cause of myocardial infarction and sudden cardiac death especially in those who lacks of traditional cardiovascular risk factors. Although the most appropriate management of patients with SCAD is not clearly defined, it‘s essential to make an early diagnosis in order to follow a conservative approach. Nowadays, the role of Coronary Computed Tomography Angiography (CCTA) is consolidated in the study of atherosclerotic coronary pathology but its contribution in the diagnosis and follow–up of patients with SCAD does not apperar to be defined. The purpose of this study was to retrospectively investigate the diagnostic performance of CCTA and its role in the follow–up of patients with diagnosis of SCAD. We examined 307 patients admitted to emergency department for acute chest pain and an ECG diagnosis of STEMI from March 2021 to July 2023. 1 patient was diagnosed with type 2 SCAD on invasive coronary angiography (ICA) and 2 patients received a suspected diagnosis of SCAD at ICA and CCTA examination was performed to confirm the suspicion. CCTA examination showed the acute presence of Intramural hematoma (IMH) of the wall of left anterior descending artery (LAD) in 2 patients, confirming the angiographic suspect of SCAD type 2. All 3 patients were treated with conservatie therapy and subsequentely underwent CCTA of follow–up. The examination performed respectively 3 months, 45 days and 1 month after the acute event demonstrated the complete resolution of IMH in all patients and the patency of the vessel lumens. CCTA seems to be a feasible and effective imaging modality to detect the main findings of SCAD. It may play a crucial role in the management of patients with acute chest pain at low–intermediate risk of ACS in order to reduce the number of misdiagnoses. Furthermore, CCTA could facilitate follow–up of patients with diagnosis of SCAD given the high recurrency rate of this pathology. However, further large prospective studies are needed to clarify the role of CCTA in the diagnosis and in the follow–up of SCAD.
- Published
- 2024
- Full Text
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4. THE ROLE OF ADVANCED NON–INVASIVE CARDIAC IMAGING IN THE DIAGNOSIS AND THE MANAGEMENT OF ACUTE CHEST PAIN IN WOMEN
- Author
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Dell‘Aversana, F, Tedeschi, C, Ferrandino, G, Tuccillo, A, Scotto di Uccio, F, Tuccillo, B, and Liguori, C
- Abstract
Over the last years the awareness of gender differences in cardiovascular disease has gradually increased. Gender differences can be highlighted in the spectrum of clinical manifestations of ischemic cardiovascular disease in women and in the higher incidence in female sex of specific pathologies such as Takotsubo Syndrome (TTS), myocardial infarction without significant coronary obstruction (MINOCA) and Spontaneous coronary artery dissection (SCAD). Advanced cardiac imaging is gaining a relevant role also in the acute patient scenario and it can allows the identification of the pathologies that can most frequently cause acute chest pain in women. We included 102 female patients admitted to our emergency department with acute chest pain who underwent advanced cardiac imaging examinations. 72 women had Cardiac Magnetic Resonance Imaging (CMR) for acute myocardial injury after excluding Acute Coronary Syndrome (ACS). 30 women underwent Coronary Computed Tomography Angiography (CCTA) for suspected ACS with low or intermediate risk of Coronary Artery Disease (CAD). In 25/72 patients undergoing CMR was found an ischemic pattern: 19 (26.4%) patients received a diagnosis of myocardial infarction with associated afferent coronary obstruction, in 5 (7%) patients the diagnosis was compatible with MINOCA and in 1 case (4%) the diagnosis of aborted heart attack was made. A non–ischemic pattern was found in 37 patients: 12 (16.7%) patients were diagnosed with Takotsubo Syndrome, 21 (29.2%) patients were affected by myocarditis and 4 (5.5%) patients had signs of pericarditis. In 10 (13.8%) cases CMR was negative. Of the 30 patients who underwent CCTA, 11 (36.7%) had normal coronary arteries, 9 (30%) had non–obstructive CAD (stenosis <50%), 8 (26.6%) had obstructive CAD (stenosis >50%) and 2 (6.6%) patients were diagnosed with SCAD. According to our experience, CMR can play a central role in the diagnosis and management of non–coronary ischemic heart disease which typically affects women. In fact, in females the etiopathogenesis of myocardial ischemia is much more complex and heterogeneous than in males, making non–invasive cardiac imaging decisive to identify the underlying causes of acute chest pain. Furthermore, the use of CCTA as a first–instance diagnostic test in an acute scenario allows us to improve the diagnosis of clinically significant CAD and to adequately direct the therapeutic process.
- Published
- 2024
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5. DNAJC17 is localized in nuclear speckles and interacts with splicing machinery components
- Author
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Pascarella, A., primary, Ferrandino, G., additional, Credendino, S. C., additional, Moccia, C., additional, D’Angelo, F., additional, Miranda, B., additional, D’Ambrosio, C., additional, Bielli, P., additional, Spadaro, O., additional, Ceccarelli, M., additional, Scaloni, A., additional, Sette, C., additional, De Felice, M., additional, De Vita, G., additional, and Amendola, E., additional
- Published
- 2018
- Full Text
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6. A new gene predisposing to congenital hypothyroidism
- Author
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Pascarella A., Ferrandino G., Basile M., Spadaro O., D'Angelo F., D'Ambrosio C., Scaloni A., De Felice M., Di Lauro R., De Vita G., Amendola E., Pascarella, A., Ferrandino, G., Basile, M., Spadaro, O., D'Angelo, F., D'Ambrosio, C., Scaloni, A., De Felice, M., Di Lauro, R., De Vita, G., and Amendola, E.
- Published
- 2014
7. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine
- Author
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Nagarajah, J., Le, M., Knauf, J.A., Ferrandino, G., Montero-Conde, C., Pillarsetty, N., Bolaender, A., Irwin, C., Krishnamoorthy, G.P., Saqcena, M., Larson, S.M., Ho, A.L., Seshan, V., Ishii, N., Carrasco, N., Rosen, N., Weber, W.A., Fagin, J.A., Nagarajah, J., Le, M., Knauf, J.A., Ferrandino, G., Montero-Conde, C., Pillarsetty, N., Bolaender, A., Irwin, C., Krishnamoorthy, G.P., Saqcena, M., Larson, S.M., Ho, A.L., Seshan, V., Ishii, N., Carrasco, N., Rosen, N., Weber, W.A., and Fagin, J.A.
- Abstract
Item does not contain fulltext, Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
- Published
- 2016
8. Contabilità dei materiali. Nuovo metodo per un sistema di salvaguardia ambientale
- Author
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Aparo, M, Dionisi, M, Ferrandino, G, Lombardi, V, Remetti, Romolo, and Zeppa, P.
- Subjects
POLLUTION ,Material Accountancy - Published
- 1990
9. N-Methyl-D-aspartic Acid (NMDA) in the nervous system of the amphioxus Branchiostoma lanceolatum
- Author
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Garcia-Fernàndez Jordi, Ferrandino Gabriele, Topo Enza, Fisher George H, D'Aniello Salvatore, and D'Aniello Antimo
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background NMDA (N-methyl-D-aspartic acid) is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone) in the hypothalamus, and of LH (Luteinizing Hormone) and PRL (Prolactin) in the pituitary gland. Results In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 ± 0.37 nmol/g tissue in the nerve cord and 10.52 ± 1.41 nmol/g tissue in the cephalic vesicle). As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp) by a NMDA synthase (also called D-aspartate methyl transferase). Conclusion Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.
- Published
- 2007
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10. DNAJC17 is localized in nuclear speckles and interacts with splicing machinery components
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Elena Amendola, Andrea Scaloni, G. Ferrandino, C. Sette, A. Pascarella, G De Vita, Sara Carmela Credendino, M De Felice, O. Spadaro, P. Bielli, Michele Ceccarelli, Chiara D'Ambrosio, B. Miranda, Carmen Moccia, Fulvio D'Angelo, Pascarella, A., Ferrandino, G., Credendino, S. C., Moccia, C., D'Angelo, F., Miranda, B., D'Ambrosio, C., Bielli, P., Spadaro, O., Ceccarelli, M., Scaloni, A., Sette, C., De Felice, M., De Vita, G., and Amendola, E.
- Subjects
0301 basic medicine ,Proteomics ,lcsh:Medicine ,Biology ,Interactome ,Article ,Transcriptome ,03 medical and health sciences ,Protein Interaction Mapping ,Humans ,lcsh:Science ,Gene ,Cell Nucleus ,Gene knockdown ,Settore BIO/16 ,Multidisciplinary ,Alternative Splicing ,HSP40 Heat-Shock Proteins ,HeLa Cells ,Spliceosomes ,Alternative splicing ,lcsh:R ,Cell biology ,030104 developmental biology ,RNA splicing ,Knockout mouse ,lcsh:Q ,Minigene - Abstract
DNAJC17 is a heat shock protein (HSP40) family member, identified in mouse as susceptibility gene for congenital hypothyroidism. DNAJC17 knockout mouse embryos die prior to implantation. In humans, germline homozygous mutations in DNAJC17 have been found in syndromic retinal dystrophy patients, while heterozygous mutations represent candidate pathogenic events for myeloproliferative disorders. Despite widespread expression and involvement in human diseases, DNAJC17 function is still poorly understood. Herein, we have investigated its function through high-throughput transcriptomic and proteomic approaches. DNAJC17-depleted cells transcriptome highlighted genes involved in general functional categories, mainly related to gene expression. Conversely, DNAJC17 interactome can be classified in very specific functional networks, with the most enriched one including proteins involved in splicing. Furthermore, several splicing-related interactors, were independently validated by co-immunoprecipitation and in vivo co-localization. Accordingly, co-localization of DNAJC17 with SC35, a marker of nuclear speckles, further supported its interaction with spliceosomal components. Lastly, DNAJC17 up-regulation enhanced splicing efficiency of minigene reporter in live cells, while its knockdown induced perturbations of splicing efficiency at whole genome level, as demonstrated by specific analysis of RNAseq data. In conclusion, our study strongly suggests a role of DNAJC17 in splicing-related processes and provides support to its recognized essential function in early development.
- Published
- 2018
- Full Text
- View/download PDF
11. A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid
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Roberto Di Lauro, Tina Di Palma, Mario De Felice, Antonella Galvan, Elena Amendola, Giuseppe Ferrandino, Giacomo Manenti, Marzia Scarfò, Mariastella Zannini, Nina A. Dathan, Remo Sanges, Francesca Maria Alvino, Tommaso A. Dragani, Amendola, E., Sanges, R., Galvan, A., Dathan, N., Manenti, G., Ferrandino, G., Alvino, F. M., Di Palma, T., Scarfò, M., Zannini, M., Dragani, T., DE FELICE, Mario, and DI LAURO, Roberto
- Subjects
Nonsynonymous substitution ,Thyroid Gland ,PROTEIN ,Thyrotropin ,Mice ,0302 clinical medicine ,Endocrinology ,Settore BIO/13 - Biologia Applicata ,HOMEOBOX GENE ,Missense mutation ,TRANSCRIPTION ,Cells, Cultured ,Genetics ,QUANTITATIVE TRAIT LOCI ,0303 health sciences ,Cultured ,Reverse Transcriptase Polymerase Chain Reaction ,Blotting ,Thyroid ,Chromosome Mapping ,Immunohistochemistry ,Congenital hypothyroidism ,OF-FUNCTION MUTATION ,medicine.anatomical_structure ,Essential gene ,030220 oncology & carcinogenesis ,Chromosomal region ,Western ,medicine.medical_specialty ,PHENOTYPIC VARIABILITY ,Cells ,Blotting, Western ,Locus (genetics) ,Biology ,Chromosomes ,03 medical and health sciences ,MISSENSE MUTATION ,Internal medicine ,medicine ,Congenital Hypothyroidism ,Animals ,Genetic Predisposition to Disease ,Genetic Association Studies ,030304 developmental biology ,Mammalian ,HSP40 Heat-Shock Proteins ,medicine.disease ,PAX8 ,Chromosomes, Mammalian ,DYSGENESIS - Abstract
We report here the mapping of a chromosomal region responsible for strain-specific development of congenital hypothyroidism in mice heterozygous for null mutations in genes encoding Nkx2-1/Titf1 and Pax8. The two strains showing a differential predisposition to congenital hypothyroidism contain several single-nucleotide polymorphisms in this locus, one of which leads to a nonsynonymous amino acid change in a highly conserved region of Dnajc17, a member of the type III heat-shock protein-40 (Hsp40) family. We demonstrate that Dnajc17 is highly expressed in the thyroid bud and had an essential function in development, suggesting an important role of this protein in organogenesis and/or function of the thyroid gland.
- Published
- 2010
12. D-aspartic acid in the nervous system of Aplysia limacina: possible role in neurotransmission
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Euan R. Brown, Biagio D'Aniello, Antimo D'Aniello, Patrizia Spinelli, George H. Fisher, Gabriella Chieffi Baccari, Pier Giorgio Montarolo, Gabriele Ferrandino, Rakesh K. Rastogi, Margherita Branno, Enrico D'Aniello, Spinelli, P., E. R., Brown, G., Ferrandino, M., Branno, P. G., Montarolo, E., D'Aniello, R. K., Rastogi, D'Aniello, Biagio, G. C., Baccari, G., Fisher, A., D'Aniello, Brown, E., Ferrandino, G., Branno, M., Montarolo, P., Rastogi, R., D'Aniello, B., Chieffi, Gabriella, Fisher, G., and D'Aniello, A.
- Subjects
Nervous system ,Physiology ,Clinical Biochemistry ,Racemases and Epimerases ,Aplysia limacina ,Aspartate racemase ,Biology ,Neurotransmission ,Synaptic vesicle ,Models, Biological ,Nervous System ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Aplysia ,medicine ,Cyclic AMP ,Animals ,030304 developmental biology ,chemistry.chemical_classification ,Cell Nucleus ,0303 health sciences ,Ionomycin ,D-Aspartic Acid ,Depolarization ,Cell Biology ,biology.organism_classification ,Immunohistochemistry ,Neurosecretory Systems ,3. Good health ,Amino acid ,Microscopy, Electron ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Potassium ,Neurotransmissio ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
In the marine mollusk Aplysia limacina, a substantial amount of endogenous D-aspartic acid (D-Asp) was found following its synthesis from L-aspartate by an aspartate racemase. Concentrations of D-Asp between 3.9 and 4.6 μmol/g tissue were found in the cerebral, abdominal, buccal, pleural, and pedal ganglia. In non nervous tissues, D-Asp occurred at a very low concentration compared to the nervous system. Immunohistochemical studies conducted on cultured Aplysia neurons using an anti-D-aspartate antibody demonstrated that D-Asp occurs in the soma, dendrites, and in synaptic varicosities. Synaptosomes and synaptic vesicles from cerebral ganglia were prepared and characterized by electron microscopy. HPLC analysis revealed high concentrations of D-Asp together with L-aspartate and L-glutamate in isolated synaptosomes. In addition, D-Asp was released from synaptosomes by K+ depolarization or by ionomycin. D-Asp was one of the principal amino acids present in synaptic vesicles representing about the 25% of total amino acids present in these cellular organelles. Injection of D-Asp into live animals or addition to the incubation media of cultured neurons, caused an increase in cAMP content. Taken as a whole, these findings suggest a possible role of D-Asp in neurotransmission in the nervous system of Aplysia limacina. © 2005 Wiley-Liss, Inc.
- Published
- 2005
13. Stage III xanthogranulomatous pyelonephritis with sarcomatoid degeneration.
- Author
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Roberta A, Comune R, Mazzei F, Ferrandino G, Galluzzo M, Pinto F, Stavolo C, Scaglione M, and Tamburrini S
- Abstract
Xanthogranulomatous pyelonephritis (XGP) is an uncommon chronic condition characterized by destructive granulomatous disease of the kidney with uncertain etiology. Significant risk factors for XGP are represented by the coexistence of history of nephrolithiasis, diabetes mellitus, recurrent urinary tract infections and other immunocompromised conditions. It is also associated with higher risk of malignancy, reported in up to 11% of patients. We report a case of a 76-year-old female who presented to the emergency department with an insidious onset of abdominal and right lower back pain. She had a history of renal stones and diabetes mellitus. On physical examination, a painful fistulous orifice in skin on the right lumbar region was found. CT images showed a nonfunctioning right kidney replaced by multiple necrotic cavities with inflammatory involvement of the right hepatic lobe and a nephron-cutaneous fistula. These CT findings were strongly suggestive of XGP (III state). CT images obtained before and after the administration of intravenous contrast material showed also a hyper-vascularized renal mass with irregularly thickened walls confirmed by a targeted CEUS examination and suspicious for malignancy. Pathologic examination confirmed the chronic pyelonephritis and revealed evidence of a concomitant sarcomatoid lesion. This case underlines the central role of a multimodality imaging approach in the emergency department and how this affects the correct management and treatment of patients. In fact, MDCT is considered the current gold standard for the diagnosis and the staging of XPG but the contrast-enhanced ultrasound (CEUS) in selected patients can increase the diagnostic accuracy in the uncertain small renal masses detected on CT scans., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
- Published
- 2024
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14. Exogenous Volatile Organic Compound (EVOC ® ) Breath Testing Maximizes Classification Performance for Subjects with Cirrhosis and Reveals Signs of Portal Hypertension.
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Ferrandino G, Ricciardi F, Murgia A, Banda I, Manhota M, Ahmed Y, Sweeney K, Nicholson-Scott L, McConville L, Gandelman O, Allsworth M, Boyle B, Smolinska A, Ginesta Frings CA, Contreras J, Asenjo-Lobos C, Barrientos V, Clavo N, Novoa A, Riviotta A, Jerez M, and Méndez L
- Abstract
Background: Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based on dynamic breath testing. Methods: We enrolled 29 subjects with cirrhosis (Child-Pugh A and B), and 29 controls. All subjects fasted overnight. Breath samples were taken using Breath Biopsy
® before and at different time points after the administration of 100 mg limonene. Absolute limonene breath levels were measured using gas chromatography-mass spectrometry. Results: All subjects showed a >100-fold limonene spike in breath after administration compared to baseline. Limonene breath kinetics showed first-order decay in >90% of the participants, with higher bioavailability in the cirrhosis group. At the Youden index, baseline limonene levels showed classification performance with an area under the roc curve (AUROC) of 0.83 ± 0.012, sensitivity of 0.66 ± 0.09, and specificity of 0.83 ± 0.07. The best performing timepoint post-administration was 60 min, with an AUROC of 0.91, sensitivity of 0.83 ± 0.07, and specificity of 0.9 ± 0.06. In the cirrhosis group, limonene bioavailability showed a correlation with MELD and fibrosis indicators, and was associated with signs of portal hypertension. Conclusions: Dynamic limonene breath testing enhances diagnostic performance for cirrhosis compared to static testing. The correlation with disease severity suggests potential for monitoring therapeutic interventions. Given the non-invasive nature of breath collection, a dynamic limonene breath test could be implemented in primary care.- Published
- 2023
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15. Advanced Cardiac Imaging and Women's Chest Pain: A Question of Gender.
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Dell'Aversana F, Tedeschi C, Comune R, Gallo L, Ferrandino G, Basco E, Tamburrini S, Sica G, Masala S, Scaglione M, and Liguori C
- Abstract
Awareness of gender differences in cardiovascular disease (CVD) has increased: both the different impact of traditional cardiovascular risk factors on women and the existence of sex-specific risk factors have been demonstrated. Therefore, it is essential to recognize typical aspects of ischemic heart disease (IHD) in women, who usually show a lower prevalence of obstructive coronary artery disease (CAD) as a cause of acute coronary syndrome (ACS). It is also important to know how to recognize pathologies that can cause acute chest pain with a higher incidence in women, such as spontaneous coronary artery dissection (SCAD) and myocardial infarction with non-obstructive coronary arteries (MINOCA). Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance imaging (CMR) gained a pivotal role in the context of cardiac emergencies. Thus, the aim of our review is to investigate the most frequent scenarios in women with acute chest pain and how advanced cardiac imaging can help in the management and diagnosis of ACS.
- Published
- 2023
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16. ECG-Gated CCTA in the Assessment of Post-Procedural Complications.
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Liguori C, Lassandro G, Ferrandino G, Picchi SG, Tamburrini S, Toro G, Tamburro F, Masala S, and Scaglione M
- Abstract
Introduction: The aim of our study was to assess the role of ECG-gated coronary CT angiography (CCTA) in the diagnosis, imaging follow-up, and treatment guidance in post-procedural/surgical interventions in the heart and thoracic aorta (PTCA, TAVI, PMK/ICD placement, CABGs)., Materials and Methods: We retrospectively evaluated 294 ECG-gated CCTA studies performed in our center from January 2020 to January 2023. CCTA studies were acquired to detect/exclude possible complications related to the endovascular or surgical procedure., Results: There were 27 cases (9.2%) of post-procedural complications. Patients enrolled in the study were 18 males and 9 females (male/female ratio: 2), with age ranging from 47 to 86 years (mean age, 68.3 years). Among percutaneous coronary intervention (PCI) complications, coronary intimal dissection with ascending aorta involvement was found to be the most frequent complication after PTCA (22.2%). Vascular wall pseudoaneurysm formation (11.1%) and coronary stent misalignment or displacement (14.8%) were complications less frequently encountered after PTCA. Right atrial or ventricular perforation with associated hemopericardium were the most common complications (18.5%) after pacemaker implantation. Complications encountered after aortic valve interventions were loosening and dislocation of the prosthesis associated with aortic root pseudoaneurysm (7.4%), para-valvular leak (11.1%), and hemopericardium (7.4%). In one patient who underwent transcatheter repair of patent foramen ovale (3.7%), CTTA detected the dislocation of the Amplatzer septal occluder., Conclusions: ECG-gated CCTA is a fundamental diagnostic tool for the detection of post-procedural endovascular/surgical complications to enable optimal patient management. Radiologists must be familiar with the use of cardiac synchronization in the course of CT and must be aware of all possible complications that can occur in the context of acute settings or routine follow-up studies.
- Published
- 2023
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17. Breath Biopsy ® to Identify Exhaled Volatile Organic Compounds Biomarkers for Liver Cirrhosis Detection.
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Ferrandino G, De Palo G, Murgia A, Birch O, Tawfike A, Smith R, Debiram-Beecham I, Gandelman O, Kibble G, Lydon AM, Groves A, Smolinska A, Allsworth M, Boyle B, van der Schee MP, Allison M, Fitzgerald RC, Hoare M, and Snowdon VK
- Abstract
Background and Aims: The prevalence of chronic liver disease in adults exceeds 30% in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare burden. Breath is a rich sampling matrix that offers non-invasive solutions suitable for early-stage detection and disease monitoring. Having previously investigated targeted analysis of a single biomarker, here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical use., Methods: To identify candidate biomarkers we compared 46 breath samples from cirrhosis patients and 42 from controls. Collection and analysis used Breath Biopsy OMNI™, maximizing signal and contrast to background to provide high confidence biomarker detection based upon gas chromatography mass spectrometry (GC-MS). Blank samples were also analyzed to provide detailed information on background volatile organic compounds (VOCs) levels., Results: A set of 29 breath VOCs differed significantly between cirrhosis and controls. A classification model based on these VOCs had an area under the curve (AUC) of 0.95±0.04 in cross-validated test sets. The seven best performing VOCs were sufficient to maximize classification performance. A subset of 11 VOCs was correlated with blood metrics of liver function (bilirubin, albumin, prothrombin time) and separated patients by cirrhosis severity using principal component analysis., Conclusions: A set of seven VOCs consisting of previously reported and novel candidates show promise as a panel for liver disease detection and monitoring, showing correlation to disease severity and serum biomarkers at late stage., Competing Interests: Giuseppe Ferrandino, Giovanna De Palo, Antonio Murgia, Owen Birch, Rob Smith, Ahmed Tawfike, Olga Gandelman, Max Allsworth, and Billy Boyle, are/were employees of Owlstone Medical Ltd., (© 2023 Authors.)
- Published
- 2023
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18. Lower Limb Ischemia as Acute Onset of Primary Aortic Occlusion: CTA Imaging and Management.
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Lassandro G, Tamburrini S, Liguori C, Picchi SG, Pezzullo F, Ferrandino G, Spinetti F, Vigliotti G, Marano I, and Scaglione M
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- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Treatment Outcome, Ischemia, Erectile Dysfunction, Arterial Occlusive Diseases, Aortic Diseases surgery, Thrombosis complications, Thrombosis therapy
- Abstract
Primary aortic occlusion (PAO) is defined as acute occlusion in the absence of aortic atherosclerosis or aneurysm. PAO is a rare disease with acute onset and can determine massive parenchymal ischemia and distal arterial embolization. The aim of our study was to focus on the assessment of clinical characteristic, CT signs, medical and surgical treatment, complication rates and the overall survival of PAO., Materials and Methods: We retrospectively analyzed the data of all patients with acute lower limb ischemia and a final surgical or discharge diagnosis of PAO who underwent aortic CT angiography in ER settings in our hospital from January 2019 to November 2022., Results: A total of 11 patients (8 males/3 females; male/female ratio, 2.66:1, age range 49 to 79 years-old, mean age 65.27 y/o) with acute onset of lower limb impotence or ischemia were diagnosed with PAO. The etiology was thrombosis in all patients. The aortic occlusion was always located in the abdominal aorta and extended bilaterally through the common iliac arteries. The upper limit of the thrombosis was detected in the aortic subrenal tract in 81.8% of the cases, and in the infrarenal tract in 18.2%. A total of 81.8% of the patients were referred to the ER for symptoms related to lower limb: bilateral acute pain, hypothermia and sudden onset of functional impotence. Two patients (18.2%) died before undergoing surgery for multi-organ failure determined by the severe acute ischemia. The other patients (81.8%) underwent surgical treatment that included aortoiliac embolectomy (54.5%), aortoiliac embolectomy + aorto-femoral bypass (18.2%) and aortoiliac embolectomy and right lower limb amputation (9.1%). The overall mortality was 36.4% while the estimated survival at 1 year was 63.6%., Conclusions: PAO is a rare entity with high morbidity and mortality rates if not recognized and treated promptly. Acute onset of lower limb impotence is the most common clinical presentation of PAO. Aortic CT angiography is the first-choice imaging technique for the early diagnosis of this disease and for the surgical treatment, planning and assessment of any complications. Combined with surgical treatment, anticoagulation is considered the first-line medical therapy at the time of diagnosis, during surgical treatment and after at discharge.
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- 2023
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19. Breathing new life into clinical testing and diagnostics: perspectives on volatile biomarkers from breath.
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Haworth JJ, Pitcher CK, Ferrandino G, Hobson AR, Pappan KL, and Lawson JLD
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- Biomarkers analysis, Breath Tests methods, Humans, Helicobacter Infections, Helicobacter pylori, Volatile Organic Compounds analysis
- Abstract
Human breath offers several benefits for diagnostic applications, including simple, noninvasive collection. Breath is a rich source of clinically-relevant biological information; this includes a volatile fraction, where greater than 1,000 volatile organic compounds (VOCs) have been described so far, and breath aerosols that carry nucleic acids, proteins, signaling molecules, and pathogens. Many of these factors, especially VOCs, are delivered to the lung by the systemic circulation, and diffusion of candidate biomarkers from blood into breath allows systematic profiling of organismal health. Biomarkers on breath offer the capability to advance early detection and precision medicine in areas of global clinical need. Breath tests are noninvasive and can be performed at home or in a primary care setting, which makes them well-suited for the kind of public screening program that could dramatically improve the early detection of conditions such as lung cancer. Since measurements of VOCs on breath largely report on metabolic changes, this too aids in the early detection of a broader range of illnesses and can be used to detect metabolic shifts that could be targeted through precision medicine. Furthermore, the ability to perform frequent sampling has envisioned applications in monitoring treatment responses. Breath has been investigated in respiratory, liver, gut, and neurological diseases and in contexts as diverse as infectious diseases and cancer. Preclinical research studies using breath have been ongoing for some time, yet only a few breath-based diagnostics tests are currently available and in widespread clinical use. Most recently, tests assessing the gut microbiome using hydrogen and methane on breath, in addition to tests using urea to detect Helicobacter pylori infections have been released, yet there are many more applications of breath tests still to be realized. Here, we discuss the strengths of breath as a clinical sampling matrix and the technical challenges to be addressed in developing it for clinical use. Historically, a lack of standardized methodologies has delayed the discovery and validation of biomarker candidates, resulting in a proliferation of early-stage pilot studies. We will explore how advancements in breath collection and analysis are in the process of driving renewed progress in the field, particularly in the context of gastrointestinal and chronic liver disease. Finally, we will provide a forward-looking outlook for developing the next generation of clinically relevant breath tests and how they may emerge into clinical practice.
- Published
- 2022
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20. Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment.
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Rechtzigel MJ, Meyerink BL, Leppert H, Johnson TB, Cain JT, Ferrandino G, May DG, Roux KJ, Brudvig JJ, and Weimer JM
- Abstract
Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e., SNAREs and tethers) and altered synaptic SNARE complexing in vivo , demonstrating a novel shared etiology., Competing Interests: JB and JW are employees of Amicus Therapeutics Inc. and hold equity in the company in the form of stock-based compensation. JW receives sponsored research support for the Sanford laboratory from Amicus Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rechtzigel, Meyerink, Leppert, Johnson, Cain, Ferrandino, May, Roux, Brudvig and Weimer.)
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- 2022
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21. Role of CT and MRI in Cardiac Emergencies.
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Liguori C, Tamburrini S, Ferrandino G, Leboffe S, Rosano N, and Marano I
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- Chest Pain diagnostic imaging, Chest Pain etiology, Humans, Magnetic Resonance Imaging, Tomography, X-Ray Computed, Acute Coronary Syndrome complications, Acute Coronary Syndrome diagnostic imaging, Emergencies
- Abstract
Current strategies for the evaluation of patients with chest pain have significantly changed thanks to the implemented potentiality of CT and MRI. The possible fatal consequences and high malpractice costs of missed acute coronary syndromes lead to unnecessary hospital admissions every year. CT provides consistent diagnostic support, mainly in suspected coronary disease in patients with a low or intermediate pre-test risk. Moreover, it can gain information in the case of cardiac involvement in pulmonary vascular obstructive disease. MRI, on the other hand, has a leading role in the condition of myocardial damage irrespective of the underlying inflammatory or stress related etiology. This article discusses how radiology techniques (CT and MRI) can impact the diagnostic workflow of the most common cardiac and vascular pathologies that are responsible for non-traumatic chest pain admissions to the Emergency Department.
- Published
- 2022
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22. Advanced cardiac imaging in athlete's heart: unravelling the grey zone between physiologic adaptation and pathology.
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Palmisano A, Darvizeh F, Cundari G, Rovere G, Ferrandino G, Nicoletti V, Cilia F, De Vizio S, Palumbo R, Esposito A, and Francone M
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- Heart diagnostic imaging, Humans, Adaptation, Physiological physiology, Athletes, Cardiomegaly, Exercise-Induced physiology, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic physiopathology, Computed Tomography Angiography methods, Magnetic Resonance Imaging methods
- Abstract
Over the last decades, interest toward athlete's heart has progressively increased, leading to improve the knowledge on exercise-induced heart modifications. Sport may act as a trigger for life-threatening arrhythmias in patients with structural or electrical abnormalities, hence requiring to improve the diagnostic capability to differentiate physiological from pathological remodeling. Pathological alterations are often subtle at the initial stages; therefore, the challenge is to promptly identify athletes at risk of sudden cardiac death during the pre-participation screening protocols. Advanced imaging modalities such as coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) can non-invasively depict coronary vessels and provide a deep morpho-functional and structural characterization of the myocardium, in order to rule out pathological life threatening alterations, which may overlap with athletes' heart remodeling. The purpose of the present narrative review is to provide an overview of most frequent diagnostic challenges, defining the boundaries between athlete's heart remodeling and pathological structural alteration with a focus on the role and importance of CCTA and CMR., (© 2021. Italian Society of Medical Radiology.)
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- 2021
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23. Breath-Taking Perspectives and Preliminary Data toward Early Detection of Chronic Liver Diseases.
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Murgia A, Ahmed Y, Sweeney K, Nicholson-Scott L, Arthur K, Allsworth M, Boyle B, Gandelman O, Smolinska A, and Ferrandino G
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The gold standard method for chronic liver diseases diagnosis and staging remains liver biopsy, despite the spread of less invasive surrogate modalities based on imaging and blood biomarkers. Still, more than 50% of chronic liver disease cases are detected at later stages when patients exhibit episodes of liver decompensation. Breath analysis represents an attractive means for the development of non-invasive tests for several pathologies, including chronic liver diseases. In this perspective review, we summarize the main findings of studies that compared the breath of patients with chronic liver diseases against that of control subjects and found candidate biomarkers for a potential breath test. Interestingly, identified compounds with best classification performance are of exogenous origin and used as flavoring agents in food. Therefore, random dietary exposure of the general population to these compounds prevents the establishment of threshold levels for the identification of disease subjects. To overcome this limitation, we propose the exogenous volatile organic compounds (EVOCs) probe approach, where one or multiple of these flavoring agent(s) are administered at a standard dose and liver dysfunction associated with chronic liver diseases is evaluated as a washout of ingested compound(s). We report preliminary results in healthy subjects in support of the potential of the EVOC Probe approach.
- Published
- 2021
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24. Liver Impairment-The Potential Application of Volatile Organic Compounds in Hepatology.
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Stavropoulos G, van Munster K, Ferrandino G, Sauca M, Ponsioen C, van Schooten FJ, and Smolinska A
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Liver diseases are currently diagnosed through liver biopsy. Its invasiveness, costs, and relatively low diagnostic accuracy require new techniques to be sought. Analysis of volatile organic compounds (VOCs) in human bio-matrices has received a lot of attention. It is known that a musty odour characterises liver impairment, resulting in the elucidation of volatile chemicals in the breath and other body fluids such as urine and stool, which may serve as biomarkers of a disease. Aims: This study aims to review all the studies found in the literature regarding VOCs in liver diseases, and to summarise all the identified compounds that could be used as diagnostic or prognostic biomarkers. The literature search was conducted on ScienceDirect and PubMed, and each eligible publication was qualitatively assessed by two independent evaluators using the SANRA critical appraisal tool. Results: In the search, 58 publications were found, and 28 were kept for inclusion: 23 were about VOCs in the breath, one in the bile, three in urine, and one in faeces. Each publication was graded from zero to ten. A graphical summary of the metabolic pathways showcasing the known liver disease-related VOCs and suggestions on how VOC analysis on liver impairment could be applied in clinical practice are given.
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- 2021
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25. Malignant Gastric Outlet Obstruction Caused by Duodenal Cervix Metastasis in a Young Woman: Rendezvous Technique.
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Marra E, Quassone P, Tammaro P, Cardalesi C, D'Avino R, Cipolletta F, Del Prete A, Travaglino A, Tamburrini S, Ferrandino G, Sarti G, Iannuzzi M, Maida P, and Santini G
- Subjects
- Adult, Cervix Uteri, Female, Humans, Retrospective Studies, Stents, Treatment Outcome, Cholestasis, Duodenal Obstruction etiology, Duodenal Obstruction surgery, Gastric Outlet Obstruction etiology, Gastric Outlet Obstruction surgery
- Abstract
Background : Malignant gastric outlet obstruction (MGOD) is an extremely rare expression of advanced extra-gastrointestinal cancer, such as squamous cell carcinoma (SCC) of the cervix, and only sixcases are described in the literature.Because of the short life expectancyand the high surgical risk involving these patients, less invasive approaches have been developed over time, such asthe use of an enteral stent or less invasive surgical techniques (i.e., laparoscopic gastrojejunostomy). However, MGOD could make it difficult to perform an endoscopic retrograde cholangio-pancreatography (ERCP) for standard endoscopic drainage, so in this case a combined endoscopic-percutaneous technique may be performed. This article, therefore, aims to highlight the presence in the doctor's armamentarium of the "rendezvous technique", few case reports of whichare described in the literature, and, moreover, this article aims to underline the technique'sfeasibility. Case Presentation: The case is that of a 38-year-old woman who presented with MGOD three years after the diagnosis of SCC of the cervix, who successfully underwent the rendezvous technique with the resolution of duodenal obstruction. Endoscopic enteral stenting treatment with the placement of a metal stent (SEMSs) represents the mainstay of MGOD treatment compared withsurgery due to its lower morbidity, mortality, shorter hospitalization and earlier symptom relief. However, in patients with both duodenal and biliary obstruction, a combined endoscopic-percutaneous approach may be necessary because of the difficulty in passing the duodenal stricture or in accessing the papilla through the mesh of the duodenal SEMS. Conclusion : The rendezvous procedure is a technicallyfeasible and minimally invasive approach to the double stenting of biliary and duodenal strictures. It achieves the desired therapeutic result while avoiding the need to perform more invasive procedures that could have a negative impact on the patient'sprognosis.
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- 2021
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26. Pleural empyema secondary to nephropleural fistula in complicated pyonephrosis.
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Tamburrini S, Lugarà M, Saturnino PP, Ferrandino G, Quassone P, Leboffe S, Sarti G, Rocco C, Panico C, Raffaele F, Cesarano T, Iannuzzi M, Cagini L, and Marano I
- Abstract
Pleural empyema of extra pulmonary origin is uncommon and empyema secondary to a fistula between the urinary tract and thorax is extremely rare. We report a case of nephropleural fistula causing massive pleural empyema in a 64-year-old woman with a long history of urological problems, including nephrolitiasis and urinary tract infection. She was admitted with sepsis, fever, chills, tachypnea, productive cough and pyuria. At clinical examination, breath sounds were reduced over the left hemithorax. CT revealed a fistulous connection from the upper left calyceal group and the pleural space. Drainage of thoracic and perinephric collection was carried out, but nephrectomy and pleural decortication were required due to haemopurulent urine and decreased hemoglobin levels during the hospitalization. This case demonstrates the unusual and prolonged evolution of an obstructive hydroureteronephrosis complicated by pyonephrosis, culminating in retroperitoneal abscess that fistulized into the pleural space, leading to empyema., (© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
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- 2021
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27. Iatrogenic superior vena cava syndrome with concomitant deep vein thrombosis of azygos and hemiazygos veins.
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Picascia O, Fiorini V, Vitale G, Quassone P, Scognamiglio M, Ferrandino G, Pelella I, Rosano N, De Simone F, Sarti G, Camocardi A, Tamburrini S, and Marano I
- Abstract
Iatrogenic superior vena cava syndrome (SVCs) represents an emergent diagnostic entity and its correlation with deep vein thrombosis is extremely rare. Recently, the increased use of indwelling lines, pacemakers and intracardiac devices has led to more cases of SVC syndrome also associated with a higher frequency of DVT. We report an unusual complication in a 74-year-old female, who has been undergoing hemodialysis via CVC for 14 years, who referred at our Emergency Department complaining of shortness of breath, headache, face and neck swelling. She underwent chest Computed Tomography Angiography (CTA), that showed a thrombus extending from the superior vena cava to the azygos and hemiazygos veins. Acute SVCs should be suspected in emergency settings in symptomatic patients with indwelling central lines, catheters and pacemakers. CTA represents an accurate and quick imaging modality for the diagnosis and the assessment of the extension of the thrombus., (© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
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- 2021
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28. "Bulb-like" sign: Small bowel closed loop obstruction in incarcerated Spigelian hernia.
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Cesaro E, Rocco C, Rosano N, Ferrandino G, Marra E, Rispoli C, Maio D, Lugarà M, Tamburrini S, and Marano I
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A Spigelian hernia is a rare hernia, making up approximately 0.1% of all abdominal wall hernias. This hernia goes through a defect in the Spigelian fascia which is the part of the transversus abdominis aponeurosis lateral to the rectus muscle, often at the level of the arcuate line, where the fascia is widest and weakest. Clinical diagnosis is difficult in patients without obvious abdominal mass but imaging can be a valuable adjunct in diagnosis. We report the case of a 64-year-old male who presented to our hospital with small bowel obstruction secondary to an incarcerated Spigelian hernia who was pre-operatively diagnosed with ultrasound and computed tomography. At ultrasound and computed tomography a closed loop obstruction in a Spigelian Hernia was detected, resembling on both imaging modalities a "bulb-like" appearance., (© 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
- Published
- 2020
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29. Myocarditis: imaging up to date.
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Liguori C, Farina D, Vaccher F, Ferrandino G, Bellini D, and Carbone I
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- Acute Disease, Adult, Asymptomatic Diseases, Betacoronavirus, Bioprospecting, COVID-19, Chronic Disease, Coronavirus Infections complications, Coronavirus Infections epidemiology, Female, Humans, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Multidetector Computed Tomography, Myocarditis etiology, Myocarditis pathology, Pandemics, Pericarditis diagnostic imaging, Pericarditis etiology, Pneumonia, Viral complications, Pneumonia, Viral epidemiology, Prognosis, SARS-CoV-2, Cardiac Imaging Techniques methods, Endocardium pathology, Magnetic Resonance Imaging methods, Myocarditis diagnostic imaging
- Abstract
Myocarditis is an inflammatory disease of the heart muscle, diagnosed by histological, immunological, and immunohistochemical criteria. Endomyocardial biopsy represents the diagnostic gold standard for its diagnosis but is infrequently used. Due to its noninvasive ability to detect the presence of myocardial edema, hyperemia and necrosis/fibrosis, Cardiac MR imaging is routinely used in the clinical practice for the diagnosis of acute myocarditis. Recently pixel-wise mapping of T1 and T2 relaxation time have been introduced into the clinical Cardiac MR protocol increasing its accuracy. Our paper will review the role of MR imaging in the diagnosis of acute myocarditis.
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- 2020
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30. Breath Biopsy Assessment of Liver Disease Using an Exogenous Volatile Organic Compound-Toward Improved Detection of Liver Impairment.
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Ferrandino G, Orf I, Smith R, Calcagno M, Thind AK, Debiram-Beecham I, Williams M, Gandelman O, de Saedeleer A, Kibble G, Lydon AM, Mayhew CA, Allsworth M, Boyle B, van der Schee MP, Allison M, Hoare M, and Snowdon VK
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers analysis, Breath Tests, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular physiopathology, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Liver pathology, Liver physiopathology, Liver Cirrhosis pathology, Liver Cirrhosis physiopathology, Liver Function Tests methods, Liver Neoplasms pathology, Liver Neoplasms physiopathology, Male, Middle Aged, Prospective Studies, Severity of Illness Index, Carcinoma, Hepatocellular diagnosis, Limonene analysis, Liver Cirrhosis diagnosis, Liver Neoplasms diagnosis, Volatile Organic Compounds analysis
- Abstract
Introduction: Liver cirrhosis and its complication - hepatocellular carcinoma (HCC) - have been associated with increased exhaled limonene. It is currently unclear whether this increase is more strongly associated with the presence of HCC or with the severity of liver dysfunction., Methods: We compared the exhaled breath of 40 controls, 32 cirrhotic patients, and 12 cirrhotic patients with HCC using the Breath Biopsy platform. Breath samples were analyzed by thermal desorption-gas chromatography-mass spectrometry. Limonene levels were compared between the groups and correlated to bilirubin, albumin, prothrombin time international normalized ratio, and alanine aminotransferase., Results: Breath limonene concentration was significantly elevated in subjects with cirrhosis-induced HCC (M: 82.1 ng/L, interquartile range [IQR]: 16.33-199.32 ng/L) and cirrhosis (M: 32.6 ng/L, IQR: 6.55-123.07 ng/L) compared with controls (M: 6.2 ng/L, IQR: 2.62-9.57 ng/L) (P value = 0.0005 and 0.0001, respectively) with no significant difference between 2 diseased groups (P value = 0.37). Levels of exhaled limonene correlated with serum bilirubin (R = 0.25, P value = 0.0016, r = 0.51), albumin (R = 0.58, P value = 5.3e-8, r = -0.76), and international normalized ratio (R = 0.29, P value = 0.0003, r = 0.51), but not with alanine aminotransferase (R = 0.01, P value = 0.36, r = 0.19)., Discussion: Exhaled limonene levels are primarily affected by the presence of cirrhosis through reduced liver functional capacity, as indicated by limonene correlation with blood metrics of impaired hepatic clearance and protein synthesis capacity, without further alterations observed in subjects with HCC. This suggests that exhaled limonene is a potential non-invasive marker of liver metabolic capacity (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A388).
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- 2020
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31. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms.
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Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, and Carrasco N
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- Adipose Tissue metabolism, Adipose Tissue physiopathology, Animals, Disease Models, Animal, Hypothyroidism etiology, Insulin metabolism, Insulin Secretion, Lipid Metabolism, Lipolysis physiology, Liver physiopathology, Male, Mice, Inbred C57BL, Mice, Knockout, Obesity complications, Symporters genetics, Hypothyroidism complications, Insulin Resistance, Insulin-Secreting Cells metabolism, Non-alcoholic Fatty Liver Disease etiology
- Abstract
Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism., Competing Interests: The authors declare no conflict of interest., (Published under the PNAS license.)
- Published
- 2017
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32. An extremely high dietary iodide supply forestalls severe hypothyroidism in Na + /I - symporter (NIS) knockout mice.
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Ferrandino G, Kaspari RR, Reyna-Neyra A, Boutagy NE, Sinusas AJ, and Carrasco N
- Subjects
- Animals, Biological Transport, Disease Models, Animal, Iodides metabolism, Mice, Knockout, Thyroid Hormones blood, Treatment Outcome, Dietary Supplements, Hypothyroidism prevention & control, Iodides administration & dosage, Symporters deficiency
- Abstract
The sodium/iodide symporter (NIS) mediates active iodide (I
- ) accumulation in the thyroid, the first step in thyroid hormone (TH) biosynthesis. Mutations in the SLC5A5 gene encoding NIS that result in a non-functional protein lead to congenital hypothyroidism due to I- transport defect (ITD). ITD is a rare autosomal disorder that, if not treated promptly in infancy, can cause mental retardation, as the TH decrease results in improper development of the nervous system. However, in some patients, hypothyroidism has been ameliorated by unusually large amounts of dietary I- . Here we report the first NIS knockout (KO) mouse model, obtained by targeting exons 6 and 7 of the Slc5a5 gene. In NIS KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and hence there is no active accumulation of the NIS substrate pertechnetate (99m TcO4 - ). NIS KO mice showed undetectable serum T4 and very low serum T3 levels when fed a diet supplying the minimum I- requirement for rodents. These hypothyroid mice displayed oxidative stress in the thyroid, but not in the brown adipose tissue or liver. Feeding the mice a high-I- diet partially rescued TH biosynthesis, demonstrating that, at high I- concentrations, I- enters the thyroid through routes other than NIS.- Published
- 2017
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33. The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications.
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Ravera S, Reyna-Neyra A, Ferrandino G, Amzel LM, and Carrasco N
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- Animals, Genes, Reporter genetics, Humans, Symporters genetics, Thyroid Gland metabolism, Thyroid Gland pathology, Thyroid Gland physiology, Thyroid Neoplasms metabolism, Thyroid Neoplasms pathology, Thyroid Neoplasms physiopathology, Iodides metabolism, Symporters metabolism
- Abstract
Active iodide (I
- ) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+ /I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. The molecular characterization of NIS in 1996 and the use of radioactive I- isotopes have led to significant advances in the diagnosis and treatment of thyroid cancer and provide the molecular basis for studies aimed at extending the use of radioiodide treatment in extrathyroidal malignancies. This review focuses on the most recent findings on I- homeostasis and I- transport deficiency-causing NIS mutations, as well as current knowledge of the structure/function properties of NIS and NIS regulatory mechanisms. We also discuss employing NIS as a reporter gene using viral vectors and stem cells in imaging, diagnostic, and therapeutic procedures.- Published
- 2017
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34. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
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Nagarajah J, Le M, Knauf JA, Ferrandino G, Montero-Conde C, Pillarsetty N, Bolaender A, Irwin C, Krishnamoorthy GP, Saqcena M, Larson SM, Ho AL, Seshan V, Ishii N, Carrasco N, Rosen N, Weber WA, and Fagin JA
- Subjects
- Amino Acid Substitution, Animals, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Iodides metabolism, MAP Kinase Signaling System genetics, Mice, Mice, Mutant Strains, Benzimidazoles pharmacology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Iodine Radioisotopes pharmacology, MAP Kinase Signaling System drug effects, Mutation, Missense, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Thyroid Neoplasms drug therapy, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism
- Abstract
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
- Published
- 2016
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35. Na+ coordination at the Na2 site of the Na+/I- symporter.
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Ferrandino G, Nicola JP, Sánchez YE, Echeverria I, Liu Y, Amzel LM, and Carrasco N
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- Amino Acids chemistry, Amino Acids genetics, Binding Sites, Humans, Iodine chemistry, Ion Transport genetics, Ions chemistry, Ligands, Models, Molecular, Symporters genetics, Thyroid Gland chemistry, Thyroid Hormones biosynthesis, Thyroid Hormones metabolism, Iodine metabolism, Sodium metabolism, Symporters metabolism, Thyroid Gland metabolism
- Abstract
The sodium/iodide symporter (NIS) mediates active I(-) transport in the thyroid-the first step in thyroid hormone biosynthesis-with a 2 Na(+): 1 I(-) stoichiometry. The two Na(+) binding sites (Na1 and Na2) and the I(-) binding site interact allosterically: when Na(+) binds to a Na(+) site, the affinity of NIS for the other Na(+) and for I(-) increases significantly. In all Na(+)-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na(+) ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues-S66, D191, Q194, and Q263-are also involved in Na(+) coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I(-) These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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36. A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid.
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Amendola E, Sanges R, Galvan A, Dathan N, Manenti G, Ferrandino G, Alvino FM, Di Palma T, Scarfò M, Zannini M, Dragani TA, De Felice M, and Di Lauro R
- Subjects
- Animals, Blotting, Western, Cells, Cultured, Chromosome Mapping, Chromosomes, Mammalian genetics, Congenital Hypothyroidism metabolism, Genetic Association Studies, HSP40 Heat-Shock Proteins metabolism, Immunohistochemistry, Mice, Reverse Transcriptase Polymerase Chain Reaction, Thyroid Gland metabolism, Thyrotropin blood, Congenital Hypothyroidism genetics, Genetic Predisposition to Disease genetics, HSP40 Heat-Shock Proteins genetics, Thyroid Gland abnormalities
- Abstract
We report here the mapping of a chromosomal region responsible for strain-specific development of congenital hypothyroidism in mice heterozygous for null mutations in genes encoding Nkx2-1/Titf1 and Pax8. The two strains showing a differential predisposition to congenital hypothyroidism contain several single-nucleotide polymorphisms in this locus, one of which leads to a nonsynonymous amino acid change in a highly conserved region of Dnajc17, a member of the type III heat-shock protein-40 (Hsp40) family. We demonstrate that Dnajc17 is highly expressed in the thyroid bud and had an essential function in development, suggesting an important role of this protein in organogenesis and/or function of the thyroid gland.
- Published
- 2010
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37. N-methyl-D-aspartic acid (NMDA) in the nervous system of the amphioxus Branchiostoma lanceolatum.
- Author
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D'Aniello S, Fisher GH, Topo E, Ferrandino G, Garcia-Fernàndez J, and D'Aniello A
- Subjects
- Animals, Chordata, Nonvertebrate metabolism, Chromatography, High Pressure Liquid methods, N-Methylaspartate biosynthesis, Nervous System metabolism, Chordata, Nonvertebrate chemistry, N-Methylaspartate analysis, Nervous System chemistry
- Abstract
Background: NMDA (N-methyl-D-aspartic acid) is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone) in the hypothalamus, and of LH (Luteinizing Hormone) and PRL (Prolactin) in the pituitary gland., Results: In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 +/- 0.37 nmol/g tissue in the nerve cord and 10.52 +/- 1.41 nmol/g tissue in the cephalic vesicle). As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp) by a NMDA synthase (also called D-aspartate methyl transferase)., Conclusion: Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.
- Published
- 2007
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38. D-aspartic acid in the nervous system of Aplysia limacina: possible role in neurotransmission.
- Author
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Spinelli P, Brown ER, Ferrandino G, Branno M, Montarolo PG, D'Aniello E, Rastogi RK, D'Aniello B, Baccari GC, Fisher G, and D'Aniello A
- Subjects
- Animals, Aplysia physiology, Cell Nucleus metabolism, Cyclic AMP metabolism, Immunohistochemistry, Ionomycin pharmacology, Microscopy, Electron, Models, Biological, Nervous System enzymology, Neurosecretory Systems physiology, Potassium pharmacology, Racemases and Epimerases metabolism, Signal Transduction, Aplysia metabolism, D-Aspartic Acid metabolism, Nervous System metabolism
- Abstract
In the marine mollusk Aplysia limacina, a substantial amount of endogenous D-aspartic acid (D-Asp) was found following its synthesis from L-aspartate by an aspartate racemase. Concentrations of D-Asp between 3.9 and 4.6 micromol/g tissue were found in the cerebral, abdominal, buccal, pleural, and pedal ganglia. In non nervous tissues, D-Asp occurred at a very low concentration compared to the nervous system. Immunohistochemical studies conducted on cultured Aplysia neurons using an anti-D-aspartate antibody demonstrated that D-Asp occurs in the soma, dendrites, and in synaptic varicosities. Synaptosomes and synaptic vesicles from cerebral ganglia were prepared and characterized by electron microscopy. HPLC analysis revealed high concentrations of D-Asp together with L-aspartate and L-glutamate in isolated synaptosomes In addition, D-Asp was released from synaptosomes by K+ depolarization or by ionomycin. D-Asp was one of the principal amino acids present in synaptic vesicles representing about the 25% of total amino acids present in these cellular organelles. Injection of D-Asp into live animals or addition to the incubation media of cultured neurons, caused an increase in cAMP content. Taken as a whole, these findings suggest a possible role of D-Asp in neurotransmission in the nervous system of Aplysia limacina., (Copyright 2005 Wiley-Liss, Inc.)
- Published
- 2006
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39. Cephalopod vision involves dicarboxylic amino acids: D-aspartate, L-aspartate and L-glutamate.
- Author
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D'Aniello S, Spinelli P, Ferrandino G, Peterson K, Tsesarskia M, Fisher G, and D'Aniello A
- Subjects
- Amino Acid Isomerases metabolism, Amino Acids, Dicarboxylic physiology, Animals, Aspartic Acid analogs & derivatives, Aspartic Acid metabolism, Aspartic Acid physiology, Biological Transport, Active physiology, Cattle, D-Aspartic Acid metabolism, D-Aspartic Acid physiology, Darkness, Decapodiformes physiology, Glutamic Acid metabolism, Glutamic Acid physiology, Kidney chemistry, Light, Neurosecretory Systems physiology, Octopodiformes physiology, Optic Lobe, Nonmammalian chemistry, Optic Lobe, Nonmammalian metabolism, Retina chemistry, Retina metabolism, Tritium metabolism, Amino Acids, Dicarboxylic metabolism, Mollusca physiology, Vision, Ocular physiology
- Abstract
In the present study, we report the finding of high concentrations of D-Asp (D-aspartate) in the retina of the cephalopods Sepia officinalis, Loligo vulgaris and Octopus vulgaris. D-Asp increases in concentration in the retina and optic lobes as the animal develops. In neonatal S. officinalis, the concentration of D-Asp in the retina is 1.8+/-0.2 micromol/g of tissue, and in the optic lobes it is 5.5+/-0.4 micromol/g of tissue. In adult animals, D-Asp is found at a concentration of 3.5+/-0.4 micromol/g in retina and 16.2+/-1.5 micromol/g in optic lobes (1.9-fold increased in the retina, and 2.9-fold increased in the optic lobes). In the retina and optic lobes of S. officinalis, the concentration of D-Asp, L-Asp (L-aspartate) and L-Glu (L-glutamate) is significantly influenced by the light/dark environment. In adult animals left in the dark, these three amino acids fall significantly in concentration in both retina (approx. 25% less) and optic lobes (approx. 20% less) compared with the control animals (animals left in a diurnal/nocturnal physiological cycle). The reduction in concentration is in all cases statistically significant (P=0.01-0.05). Experiments conducted in S. officinalis by using D-[2,3-3H]Asp have shown that D-Asp is synthesized in the optic lobes and is then transported actively into the retina. D-aspartate racemase, an enzyme which converts L-Asp into D-Asp, is also present in these tissues, and it is significantly decreased in concentration in animals left for 5 days in the dark compared with control animals. Our hypothesis is that the dicarboxylic amino acids, D-Asp, L-Asp and L-Glu, play important roles in vision.
- Published
- 2005
- Full Text
- View/download PDF
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