61 results on '"F, My"'
Search Results
2. Genetic profile and clinical application of chromosomal microarray in children with intellectual disability in Hong Kong
- Author
-
P Yt Chan, HM Luk, F My Lee, and I Fm Lo
- Subjects
0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Microarray ,Referral ,Autism Spectrum Disorder ,Severe disease ,Pilot Projects ,Severity of Illness Index ,Genetic profile ,03 medical and health sciences ,Intellectual Disability ,Intellectual disability ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Medical diagnosis ,Child ,health care economics and organizations ,Oligonucleotide Array Sequence Analysis ,business.industry ,General Medicine ,Genetic Profile ,medicine.disease ,humanities ,030104 developmental biology ,Cross-Sectional Studies ,Autism spectrum disorder ,Child, Preschool ,Cohort ,Hong Kong ,Female ,business - Abstract
INTRODUCTION Chromosomal microarray (CMA) is recommended as a first-tier genetic investigation for intellectual disability (ID), developmental delay, or autism spectrum disorder due to its higher diagnostic yield with respect to conventional karyotyping. The aim of the present study was to investigate the genetic profile and diagnostic yield of CMA in children with moderate, severe and profound ID. METHODS A pilot cross-sectional study was performed by the Child Assessment Service and the Clinical Genetic Service in Hong Kong from July 2016 to June 2017. Children with unexplained ID were recruited for CMA testing by an expedited referral pathway. Children who were existing clients of the Clinical Genetic Service were also recruited. RESULTS Of 225 children included in this study, 68 (30.2%) had genetic diagnoses. Among the 138 children who underwent CMA testing, 53 (38%) children were referred to the Clinical Genetic Service by the expedited referral pathway. The respective diagnostic yields of CMA in moderate, severe, and profound ID were 8.7%, 17.6%, and 23.5% (P
- Published
- 2018
3. Reasons driving treatment modification in Parkinson's disease: results from the cross-sectional phase of the REASON study
- Author
-
Michele, Tinazzi, Giovanni, Abbruzzese, Antonini, Angelo, Roberto, Ceravolo, Giovanni, Fabbrini, Patrizia, Lessi, Barone, Paolo, Giovanni, Abruzzese, Venezia, Lido, M A, B Melone, Schettino, C, Califano, F, G Ceravolo, M, Capecci, M, Andrenelli, E, Iemolo, F, Spadaro, D, Carnemolla, A, E Pontieri, F, Pellicano, C, Benincasa, D, Fabbrini, G, Pietracupa, S, Latorre, A, Tedeschi, G, Tessitore, A, Giordano, A, Bonuccelli, U, Frosini, D, Vanelli, F, Comi, G, A Volonté, M, Spagnolo, F, Scaglioni, A, Abrignani, G, Abbruzzese, G, Avanzino, L, Tamburini, T, Antonini, A, Facchini, S, Biundo, R, C Altavista, M, Roberti, C, Asteggiano, G, R L'Episcopo, M, Saracco, E, Avarello, T, Bono, G, Riboldazzi, G, Leva, S, M Del Sette, Carabelli, E, Traverso, E, Michelucci, R, Nassetti, S, Pasini, E, Padovani, A, Cottini, E, Bigni, B, Ruggieri, S, Modugno, N, Fischetti, M, Stefani, A, Pierantozzi, M, M Stampanoni Bassi, Tinazzi, M, Ottaviani, S, Ajena, D, Trianni, G, F, My, Caggiula, M, Valenti, G, Grioli, S, I La Farina, S Zambito Marsala, Marchini, C, Gioulis, M, Barone, P, Picillo, M, Moccia, M, Denaro, A, Sebastianelli, L, Onofrj, M, Thomas, A, Marini, C, F De Santis, Spagnoli, V, L'Erario, R, Passadore, P, Belgrado, E, Mucchiut, M, Priori, A, Cogiamanian, F, and Marchet, A
- Published
- 2013
4. Adherence to anti-Parkinson drug therapy in the 'REASON' sample of Italian patients with Parkinson's disease: the linguistic validation of the Italian version of the 'Morisky Medical Adherence Scale-8 items'
- Author
-
Fabbrini, G, Abbruzzese, G, Barone, P, Antonini, A, Tinazzi, M, Castegnaro, G, Rizzoli, S, E Morisky, D, Lessi, P, Ceravolo, R, Giovanni, Abbruzzese, Antonini, Angelo, Barone, Paolo, Roberto, Ceravolo, Giovanni, Fabbrini, Michele, Tinazzi, M A, B Melone, Schettino, C, Califano, F, G Ceravolo, M, Capecci, M, Andrenelli, E, Iemolo, F, Spadaro, D, Carnemolla, A, E Pontieri, F, Pellicano, C, Benincasa, D, Pietracupa, S, Latorre, A, Tedeschi, G, Tessitore, A, Giordano, A, Bonuccelli, U, Frosini, D, Vanelli, F, Comi, G, A Volonté, M, Spagnolo, F, Scaglioni, A, Abrignani, G, Avanzino, L, Tamburini, T, Facchini, S, Biundo, R, C Altavista, M, Roberti, C, Asteggiano, G, R L'Episcopo, M, Saracco, E, Avarello, T, Bono, G, Riboldazzi, G, Leva, S, M Del Sette, Carabelli, E, Traverso, E, Michelucci, R, Nassetti, S, Pasini, E, Padovani, A, Cottini, E, Bigni, B, Ruggieri, S, Modugno, N, Fischetti, M, Stefani, A, Pierantozzi, M, M Stampanoni Bassi, Ottaviani, S, Ajena, D, Trianni, G, F, My, Caggiula, M, Valenti, G, Grioli, S, I La Farina, S Zambito Marsala, Marchini, C, Gioulis, M, Picillo, M, Moccia, M, Denaro, A, Sebastianelli, L, Onofrj, M, Thomas, A, Marini, C, F De Santis, Spagnoli, V, L'Erario, R, Passadore, P, Belgrado, E, Mucchiut, M, Priori, A, Cogiamanian, F, Marchet, A, Patrizia, Lessi, Ori, A, Pirondi, S, Roncari, B, Sala, S, Sgarbi, S, Simoni, L, Trevisan, F, and Zanoli, L
- Published
- 2013
5. L-dopa effects on preprogramming and control activity in a skilled motor act in Parkinson's disease
- Author
-
Mariano Serrao, Francesco Pierelli, F My, A. Morocutti, S. Del Monte, M. Mostarda, Giuseppe Amabile, Leoluca Parisi, and Francesco Fattapposta
- Subjects
Male ,medicine.medical_specialty ,Levodopa ,Parkinson's disease ,bereitschaftspotential ,l-dopa ,motor learning ,movement related potentials ,parkinson's disease ,skilled performance positivity ,education ,Central nervous system disease ,Antiparkinson Agents ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Aged ,Dopaminergic ,Motor control ,Body movement ,Parkinson Disease ,Middle Aged ,medicine.disease ,Evoked Potentials, Motor ,Sensory Systems ,Endocrinology ,Neurology ,Motor Skills ,Bereitschaftspotential ,Female ,Neurology (clinical) ,Psychology ,Motor learning ,Neuroscience ,Psychomotor Performance ,medicine.drug - Abstract
The authors investigated whether preprogramming (Bereitschaftspotential, BP) and control activity (skilled performance positivity, SPP) in a bimanual, sequential skilled performance task (SPT) is sensitive to L-dopa administration in non-demented Parkinson's disease (PD) patients.Movement related potentials (MRPs) were recorded in 12 non-demented parkinsonian patients before and after acute L-dopa administration, and in 17 control subjects, all of whom were performing SPT for the first time. BP, SPP and correct performances were evaluated both as a grand average and in sequential blocks in order to verify the learning effect.After L-dopa administration the PD patients scored a significantly higher percentage of correct performances (P0.05), linked to a decreased BP amplitude (P0.001) and an increased SPP amplitude (P0.005), than before therapy. Dynamic evaluation through the block analysis did not show any learning effect in off-therapy patients but showed that L-dopa intake improved learning, linked to a BP amplitude decrease (P0.005) and a SPP amplitude increase (P0.05). Furthermore, L-dopa minimized differences in the learning trend between off-therapy PD patients and controls.Our findings suggest that skilled motor learning is impaired in non-demented untreated PD patients. Dopaminergic drug administration seems to restore the ability of PD patients to use more automatic motor strategies, as demonstrated by the electrophysiological and behavioural pattern, which became more similar to that of normal subjects.
- Published
- 2002
6. Psychophysiological approach in Parkinson's disease: L-dopa effects on preprogramming and control activity
- Author
-
Francesco Fattapposta, Giuseppe Amabile, Leoluca Parisi, M. Mostarda, Nicoletta Locuratolo, Francesco Pierelli, F My, S. Del Monte, and Mariano Serrao
- Subjects
Male ,medicine.medical_specialty ,Parkinson's disease ,Neurology ,Movement ,Dermatology ,Movement-related potentials ,Antiparkinson Agents ,Levodopa ,Internal medicine ,medicine ,Humans ,Aged ,Dopaminergic ,Drug administration ,Parkinson Disease ,General Medicine ,Middle Aged ,medicine.disease ,Control subjects ,Psychiatry and Mental health ,Endocrinology ,Motor Skills ,Bereitschaftspotential ,Case-Control Studies ,Physical therapy ,Female ,Neurology (clinical) ,Psychology ,Psychomotor Performance - Abstract
To investigate whether preprogramming (Bereitschaftspotential, BP) and control activity (skilled performance positivity, SPP) in a complex task are sensitive to L-dopa, movement related potentials (MRPs) were recorded in 12 non-demented Parkinson's disease (PD) patients before and after acute L-dopa administration, and in 17 control subjects. After L-dopa administration, the PD patients scored a significantly higher percentage of correct performances (p
- Published
- 2002
7. Preprogramming and control activity of bimanual self paced motor task in Parkinson's disease
- Author
-
F My, G. Soldati, J Osborn, M. Mostarda, Giuseppe Amabile, Francesco Pierelli, C. D'alessio, G Traversa, and Francesco Fattapposta
- Subjects
Male ,medicine.medical_specialty ,Parkinson's disease ,education ,Video Recording ,Motor program ,Electromyography ,Physical medicine and rehabilitation ,Reference Values ,Physiology (medical) ,Evoked Potentials, Somatosensory ,medicine ,Humans ,Attention ,Motor skill ,Aged ,Brain Mapping ,medicine.diagnostic_test ,Motor control ,Brain ,Electroencephalography ,Parkinson Disease ,Electrooculography ,Middle Aged ,medicine.disease ,Hand ,Sensory Systems ,Neurology ,Motor Skills ,Bereitschaftspotential ,Female ,Neurology (clinical) ,Psychology ,Motor learning ,Neuroscience ,Psychomotor Performance - Abstract
Objective : The authors investigated programming (Bereitschaftspotential or BP) and control activity (Skilled Performance Positivity or SPP) of a bimanual, sequential, skilled motor act in off-therapy Parkinson's disease (PD) patients. Methods : We recorded Movement Related Potentials (MRPs) in 12, non-demented, off-therapy parkinsonian patients and in 17 control subjects who were performing a skilled, time-locked motor act, which was not routine in their everyday life but had to be learned: the Skilled Performance Task (SPT). BP, SPP and correct performances were evaluated in grand average waveforms and in sequential blocks. Results : The analysis of correct performances showed that accuracy in PD patients was significantly lower than in the control group and this accuracy did not improve throughout the blocks. A significantly low level of performances was associated with an increased BP amplitude ( P P Conclusion : Our findings suggest that skill motor learning is impaired in non-demented unmedicated PD patients. We discuss the view that PD patients may allocate more attentional resources, as suggested by the increased BP amplitude, the decreased SPP amplitude and the low correct performances, in order to perform a new skilled motor act.
- Published
- 2000
8. Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.
- Author
-
Gentile L, Mazzeo A, Briani C, Casagrande S, De Luca M, Fabrizi GM, Gagliardi C, Gemelli C, Forcina F, Grandis M, Guglielmino V, Iabichella G, Leonardi L, Lozza A, Manganelli F, Mussinelli R, My F, Occhipinti G, Fenu S, Russo M, Romano A, Salvalaggio A, Tagliapietra M, Tozza S, Palladini G, Obici L, and Luigetti M
- Subjects
- Humans, Italy, Male, Female, Middle Aged, Retrospective Studies, Aged, Treatment Outcome, RNA, Small Interfering therapeutic use, Quality of Life, Amyloid Neuropathies, Familial drug therapy, Amyloid Neuropathies, Familial complications
- Abstract
Background: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP., Methods: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed., Results: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m
2 ; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged., Conclusions: Patisiran largely stabilised disease in patients with ATTRv amyloidosis., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
9. Correction to: Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.
- Author
-
Gentile L, Mazzeo A, Briani C, Casagrande S, De Luca M, Fabrizi GM, Gagliardi C, Gemelli C, Forcina F, Grandis M, Guglielmino V, Iabichella G, Leonardi L, Lozza A, Manganelli F, Mussinelli R, My F, Occhipinti G, Fenu S, Russo M, Romano A, Salvalaggio A, Tagliapietra M, Tozza S, Palladini G, Obici L, and Luigetti M
- Published
- 2024
- Full Text
- View/download PDF
10. Synthesis, structural characterization, antioxidant and antidiabetic activities, DFT calculation, and molecular docking of novel substituted phenolic and heterocyclic compounds.
- Author
-
Lahmidi S, Anouar EH, Mortada S, El Hafi M, My El Abbes F, Essassi EM, and Mague JT
- Subjects
- Antioxidants pharmacology, Antioxidants chemistry, Molecular Docking Simulation, Density Functional Theory, Phenols pharmacology, alpha-Amylases metabolism, Hypoglycemic Agents pharmacology, Hypoglycemic Agents chemistry, Heterocyclic Compounds
- Abstract
The current work describes the preparation of three unexpected compounds: a tetrasubstituted phenolic compound, an isocoumarin, and a pyranopyridine, bearing various substituent groups obtained through the condensation of 6-methyl-4-hydroxypyran-2-one 1 with 2-aminopyridine 2 under mild conditions. Plausible mechanisms explaining the formation of these compounds have been presented. Their structures have been elucidated using spectral data and confirmed by crystallographic studies. Furthermore, optimized geometries of and electronic distribution of FMOs orbitals are investigated in the PCM solvent model at the B3LYP/6-311++G(d,p) level of theory. The compounds were tested for their antioxidant and antidiabetic activities. Moreover, the binding interactions between the compounds and α -glucosidase and α -amylase were determined through their docking into the binding sites of the target enzymes using the Autodock package.Communicated by Ramaswamy H. Sarma.
- Published
- 2023
- Full Text
- View/download PDF
11. Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy.
- Author
-
Luigetti M, Antonini G, Di Paolantonio A, Gentile L, Grandis M, Leonardi L, Lozza A, Manganelli F, Mazzeo A, Mussinelli R, My F, Obici L, Maria Pennisi E, Romozzi M, Russo M, Sabatelli M, Salvalaggio A, Tagliapietra M, and Tozza S
- Subjects
- Humans, Italy, Oligonucleotides, Phenotype, Prealbumin genetics, Quality of Life, Retrospective Studies, Amyloid Neuropathies, Familial drug therapy, Amyloid Neuropathies, Familial genetics, Thrombocytopenia complications
- Abstract
Background and Purpose: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult-onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene-silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early-access program was opened in Italy, and in this article, we present the long-term outcome of a cohort of Italian ATTRv patients who received inotersen within this program., Methods: This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early-access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life-Diabetic Neuropathy, troponin, N-terminal pro-brain natriuretic peptide, interventricular septum thickness, and body mass index., Results: In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug-related hypotension, and amyloid-negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow-up available., Conclusions: The long-term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
- Published
- 2022
- Full Text
- View/download PDF
12. Recurrent Miller-Fisher syndrome overlapping Guillain-Barrè syndrome and Bickerstaff brainstem encephalitis: A case report.
- Author
-
Barbagallo G, Caggiula M, Lupo A, Rizzo A, My F, Marulli D, and Barbarini L
- Subjects
- Adult, Autoantibodies immunology, Autoantigens immunology, Brain Stem, Female, Gangliosides immunology, Humans, Recurrence, Encephalitis immunology, Encephalitis physiopathology, Guillain-Barre Syndrome immunology, Guillain-Barre Syndrome physiopathology, Miller Fisher Syndrome immunology, Miller Fisher Syndrome physiopathology
- Abstract
Miller-Fisher syndrome (MFS) together with Guillan-Barré syndrome (GBS) and Bickerstaff brainstem encephalitis (BBE) are considered to form a continuous clinical spectrum of the same disease, possibly affecting the peripheral and/or central nervous systems, with monophasic symptoms. The frequency of overlapping clinical signs and the risk of recurrence are independent and very low, but no cases of GQ1b-seropositive recurrent MFS overlapping with GBS and BBE have been described so far. Here, we describe for the first time an atypical case of recurrent GQ1b-seropositive MFS overlapping GBS and BBE, 12 years after a previous GQ1b-seronegative typical MFS episode. Our case expands the clinical spectrum of recurrent MFS, and it should prompt clinicians to investigate the presence of anti-ganglioside antibodies in recurrent MFS even when these were negative in the previous episode, especially in those presenting with overlapping spectrum symptoms and a critically ill picture during the second episode., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
13. ATTRv amyloidosis Italian Registry: clinical and epidemiological data.
- Author
-
Russo M, Obici L, Bartolomei I, Cappelli F, Luigetti M, Fenu S, Cavallaro T, Chiappini MG, Gemelli C, Pradotto LG, Manganelli F, Leonardi L, My F, Sampaolo S, Briani C, Gentile L, Stancanelli C, Di Buduo E, Pacciolla P, Salvi F, Casagrande S, Bisogni G, Calabrese D, Vanoli F, Di Iorio G, Antonini G, Santoro L, Mauro A, Grandis M, Di Girolamo M, Fabrizi GM, Pareyson D, Sabatelli M, Perfetto F, Rapezzi C, Merlini G, Mazzeo A, and Vita G
- Subjects
- Adult, Aged, Aged, 80 and over, Amyloid Neuropathies, Familial diagnosis, Amyloid Neuropathies, Familial genetics, Amyloid Neuropathies, Familial pathology, Cardiomyopathies epidemiology, Cardiomyopathies pathology, Female, Genotype, Humans, Italy epidemiology, Male, Middle Aged, Mutation, Phenotype, Polyneuropathies epidemiology, Polyneuropathies pathology, Prealbumin genetics, Prevalence, Registries, Amyloid Neuropathies, Familial epidemiology
- Abstract
Introduction: ATTRv amyloidosis is worldwide spread with endemic foci in Portugal and Sweden, Japan, Brazil, Maiorca, and Cyprus. A national Registry was developed to characterise the epidemiology and genotype-phenotype correlation of ATTRv amyloidosis in Italy and to allow a better planning of diagnostic and therapeutic services., Methods: Fifteen Italian referral centres for amyloidosis spread all over the country have contributed to the Registry., Results: Four-hundred-forty-seven subjects were enrolled, 187 asymptomatic carriers and 260 affected patients. Thirty-one different mutations were recorded. The seven most represented genetic variants were significantly different in terms of age at onset, clinical features and geographical distribution. National prevalence is 4.33/million with higher values in Southern Italy. Overall symptoms of polyneuropathy were present at disease onset in about half of the patients, symptoms of cardiomyopathy in a quarter of patients, the rest referring carpal tunnel syndrome, dysautonomia or lumbar spinal stenosis. 52.6% of patients were in FAP stage 1, 20.4% in stage 2 and 13.5% in stage 3, while 13.5% patients had no neuropathy, presenting only cardiological symptoms., Conclusions: We presented an epidemiological study based on collaboration among referral centres for ATTRv amyloidosis spread in all the Italian territory, using web-based Registry. It provided a detailed map of the regional distribution of the disease. The increased awareness of the disease among general practitioners and medical specialists has contributed to reduce the diagnostic delay and the rate of misdiagnosis. The Registry will allow to collect also future information about clinical and instrumental follow-up.
- Published
- 2020
- Full Text
- View/download PDF
14. Low Sensitivity of Bone Scintigraphy in Detecting Phe64Leu Mutation-Related Transthyretin Cardiac Amyloidosis.
- Author
-
Musumeci MB, Cappelli F, Russo D, Tini G, Canepa M, Milandri A, Bonfiglioli R, Di Bella G, My F, Luigetti M, Grandis M, Autore C, Perlini S, Perfetto F, and Rapezzi C
- Subjects
- Aged, Amyloid Neuropathies, Familial genetics, Cardiomyopathies genetics, Female, Genetic Predisposition to Disease, Humans, Italy, Male, Middle Aged, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Technetium Tc 99m Medronate administration & dosage, Amyloid Neuropathies, Familial diagnostic imaging, Bone and Bones diagnostic imaging, Cardiomyopathies diagnostic imaging, Diphosphonates administration & dosage, Mutation, Prealbumin genetics, Radionuclide Imaging, Radiopharmaceuticals administration & dosage, Technetium Compounds administration & dosage, Technetium Tc 99m Medronate analogs & derivatives, Whole Body Imaging
- Abstract
Objectives: The aim of this study was to assess the diagnostic accuracy of bone scintigraphy in a large multicenter cohort of patients with cardiac amyloidotic involvement and Phe64Leu transthyretin (TTR) mutation., Background: Diagnostic accuracy of bone scintigraphy for transthyretin-related cardiac amyloidosis (TTR-CA) is considered extremely high, enabling this technique to be the noninvasive diagnostic standard for TTR-CA. Nevertheless, this approach has not been systematically validated across the entire spectrum of TTR mutations., Methods: A total of 55 patients with Phe64Leu TTR mutation were retrospectively analyzed and evaluated between 1993 and 2018 at 7 specialized Italian tertiary centers. Cardiac involvement was defined as presence of an end-diastolic interventricular septum thickness ≥12 mm, without other possible causes of left ventricular hypertrophy (i.e., arterial hypertension or valvulopathies). A technetium-99m (99mTc)-diphosphonate (DPD) or 99mTc-hydroxyl-methylene-diphosphonate (HMDP) bone scintigraphy was reviewed, and visual scoring was evaluated according to Perugini's method., Results: Among 26 patients with definite cardiac involvement, 19 underwent 99mTc-DPD or 99mTc-HMDP bone scintigraphy. Of them, 17 (89.5%) patients had low or absent myocardial bone tracer uptake, whereas only 2 (10.5%) showed high-grade myocardial uptake. The sensitivity and the accuracy of bone scintigraphy in detecting TTR-CA were 10.5% and 37%, respectively. Patients with cardiac involvement and low or absent bone tracer uptake were similar to those with high-grade myocardial uptake in terms of age, sex, and electrocardiographic and echocardiographic findings., Conclusions: The sensitivity of bone scintigraphy (DPD and HMDP) in detecting TTR-CA is extremely low in patients with Phe64Leu TTR mutation, suggesting the need to assess diagnostic accuracy of bone scintigraphy to identify cardiac involvement across a wider spectrum of TTR mutations., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
15. Genetic profile and clinical application of chromosomal microarray in children with intellectual disability in Hong Kong.
- Author
-
Chan PY, Luk HM, Lee FM, and Lo IF
- Subjects
- Autism Spectrum Disorder genetics, Child, Child, Preschool, Cross-Sectional Studies, Female, Genetic Profile, Genetic Testing, Hong Kong, Humans, Male, Oligonucleotide Array Sequence Analysis, Pilot Projects, Severity of Illness Index, Genetic Predisposition to Disease, Intellectual Disability genetics
- Abstract
Introduction: Chromosomal microarray (CMA) is recommended as a first-tier genetic investigation for intellectual disability (ID), developmental delay, or autism spectrum disorder due to its higher diagnostic yield with respect to conventional karyotyping. The aim of the present study was to investigate the genetic profile and diagnostic yield of CMA in children with moderate, severe and profound ID., Methods: A pilot cross-sectional study was performed by the Child Assessment Service and the Clinical Genetic Service in Hong Kong from July 2016 to June 2017. Children with unexplained ID were recruited for CMA testing by an expedited referral pathway. Children who were existing clients of the Clinical Genetic Service were also recruited., Results: Of 225 children included in this study, 68 (30.2%) had genetic diagnoses. Among the 138 children who underwent CMA testing, 53 (38%) children were referred to the Clinical Genetic Service by the expedited referral pathway. The respective diagnostic yields of CMA in moderate, severe, and profound ID were 8.7%, 17.6%, and 23.5% (P<0.05). Children with dysmorphic features demonstrated a much higher yield from CMA (45.8% vs 4.4%, P<0.05). CONCLUSTION. The overall diagnostic yield (11.6%) of CMA in this cohort is comparable with that of other international cohorts. This further supports the use of CMA as a first-tier genetic investigation for children with ID, developmental delay, or autism spectrum disorder, particularly for those with severe disease.
- Published
- 2018
- Full Text
- View/download PDF
16. [A case of Anderson-Fabry disease: a multidisciplinary approach for diagnosis and follow up].
- Author
-
Zito A, De Pascalis A, Armeni A, Ria P, Barbarini L, Caggiula M, My F, Barbarini S, Trianni G, and Napoli M
- Subjects
- Cerebral Hemorrhage etiology, Early Diagnosis, Enzyme Replacement Therapy, Fabry Disease complications, Fabry Disease drug therapy, Genetic Testing, Humans, Hypertrophy, Left Ventricular etiology, Kidney Failure, Chronic etiology, Kidney Failure, Chronic therapy, Male, Middle Aged, Mutation, Missense, Pedigree, Point Mutation, alpha-Galactosidase genetics, alpha-Galactosidase therapeutic use, Fabry Disease diagnosis
- Abstract
Fabry disease (also known as Anderson-Fabry disease, angiocheratoma corporis diffusum, diffuse angiocheratoma) is a rare tesaurismosis linked to the deficiency of the lysosomal enzyme alpha-galactosidase A, required for the physiological catabolism of glycosphingolipids. The related clinical signs show a multisystemic feature and define a degenerative and disabling pathology, whose approach requires a close multidisciplinary specialist collaboration. Currently, the renewed interest in the disease is aimed at the need to provide an early diagnosis, in order to early begin the enzyme replacement therapy and to slow down or avoid the establishment of irreparable organ damage. For this reason, the diagnostic suspicion becomes crucial and arises from the careful observation and research of the symptoms, together with the anamnesis and the overall clinical evaluation of the patient., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)
- Published
- 2018
17. Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis.
- Author
-
Iorio A, De Lillo A, De Angelis F, Di Girolamo M, Luigetti M, Sabatelli M, Pradotto L, Mauro A, Mazzeo A, Stancanelli C, Perfetto F, Frusconi S, My F, Manfellotto D, Fuciarelli M, and Polimanti R
- Subjects
- Amyloidosis diagnosis, Female, Genotype, Heterozygote, Humans, Male, Prealbumin metabolism, Amyloidosis genetics, Mutation, Phenotype, Prealbumin genetics
- Abstract
Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.
- Published
- 2017
- Full Text
- View/download PDF
18. Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis.
- Author
-
Iorio A, De Angelis F, Di Girolamo M, Luigetti M, Pradotto LG, Mazzeo A, Frusconi S, My F, Manfellotto D, Fuciarelli M, and Polimanti R
- Subjects
- Genotype, Humans, Phenotype, Amyloidosis genetics, Amyloidosis pathology, Gene Expression Regulation, Prealbumin genetics
- Abstract
Background: Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project., Results: We observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10
-6 ). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10-28 ; Left Ventricle p = 6.54*10-35 )., Conclusions: Genetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.- Published
- 2017
- Full Text
- View/download PDF
19. Goodbyes Are Not Forever.
- Author
-
Kong MY
- Subjects
- Child, Death, Humans, Mothers, Attitude to Death, Grief, Physician-Patient Relations, Physicians psychology
- Published
- 2017
- Full Text
- View/download PDF
20. Love at First Sight.
- Author
-
Kong MY
- Published
- 2016
- Full Text
- View/download PDF
21. The C-terminal 18 Amino Acid Region of Dengue Virus NS5 Regulates its Subcellular Localization and Contains a Conserved Arginine Residue Essential for Infectious Virus Production.
- Author
-
Tay MY, Smith K, Ng IH, Chan KW, Zhao Y, Ooi EE, Lescar J, Luo D, Jans DA, Forwood JK, and Vasudevan SG
- Subjects
- Active Transport, Cell Nucleus, Amino Acid Substitution, Animals, Cell Line, Cell Nucleus virology, Cricetinae, Humans, Mutation, Missense, Nuclear Localization Signals genetics, Protein Domains, Viral Nonstructural Proteins genetics, Cell Nucleus metabolism, Dengue Virus physiology, Nuclear Localization Signals metabolism, Viral Nonstructural Proteins metabolism, Virus Replication
- Abstract
Dengue virus NS5 is the most highly conserved amongst the viral non-structural proteins and is responsible for capping, methylation and replication of the flavivirus RNA genome. Interactions of NS5 with host proteins also modulate host immune responses. Although replication occurs in the cytoplasm, an unusual characteristic of DENV2 NS5 is that it localizes to the nucleus during infection with no clear role in replication or pathogenesis. We examined NS5 of DENV1 and 2, which exhibit the most prominent difference in nuclear localization, employing a combination of functional and structural analyses. Extensive gene swapping between DENV1 and 2 NS5 identified that the C-terminal 18 residues (Cter18) alone was sufficient to direct the protein to the cytoplasm or nucleus, respectively. The low micromolar binding affinity between NS5 Cter18 and the nuclear import receptor importin-alpha (Impα), allowed their molecular complex to be purified, crystallised and visualized at 2.2 Å resolution using x-ray crystallography. Structure-guided mutational analysis of this region in GFP-NS5 clones of DENV1 or 2 and in a DENV2 infectious clone reveal residues important for NS5 subcellular localization. Notably, the trans conformation adopted by Pro-884 allows proper presentation for binding Impα and mutating this proline to Thr, as present in DENV1 NS5, results in mislocalizaion of NS5 to the cytoplasm without compromising virus fitness. In contrast, a single mutation to alanine at NS5 position R888, a residue conserved in all flaviviruses, resulted in a completely non-viable virus, and the R888K mutation led to a severely attenuated phentoype, even though NS5 was located in the nucleus. R888 forms a hydrogen bond with Y838 that is also conserved in all flaviviruses. Our data suggests an evolutionarily conserved function for NS5 Cter18, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
- Full Text
- View/download PDF
22. IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline.
- Author
-
Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, and Ip NY
- Subjects
- Alzheimer Disease diagnosis, Animals, Brain drug effects, Cognition Disorders diagnosis, Cytokines metabolism, Female, Male, Mice, Mice, Transgenic, Neuroprotective Agents administration & dosage, Treatment Outcome, Alzheimer Disease drug therapy, Alzheimer Disease physiopathology, Brain physiopathology, Cognition Disorders drug therapy, Cognition Disorders physiopathology, Interleukin-33 administration & dosage
- Abstract
Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.
- Published
- 2016
- Full Text
- View/download PDF
23. Acupoint Stimulation on Weight Reduction for Obesity: A Randomized Sham-Controlled Study.
- Author
-
Yeh ML, Chu NF, Hsu MY, Hsu CC, and Chung YC
- Subjects
- Acupuncture Points, Adolescent, Adult, Female, Humans, Male, Middle Aged, Young Adult, Acupuncture, Ear, Obesity therapy, Weight Loss
- Abstract
Auricular acupoint stimulation has become a popular weight loss method. However, its efficacy for obesity treatment has not been fully studied. This study aimed to investigate the effect of a 10-week intervention of auricular electrical stimulation combined with auricular acupressure on weight reduction in obese outpatients. In this single-blind randomized sham-controlled study, 134 participants were randomly assigned to an experimental group receiving stimulation at true acupoints, or a sham group receiving stimulation delivered in the same manner but at sham acupoints. Each participant received nutrition counseling by a nutritionist weekly. The results showed significant differences in body mass index, blood pressure, total cholesterol, triglyceride, and leptin or adiponectin over time within the group, but not between the groups. This study could not exclude the effect of placebo and dietary consultation. Further study that adds a control group receiving no treatment is therefore needed to confirm the effects of auricular acupressure., (© The Author(s) 2014.)
- Published
- 2015
- Full Text
- View/download PDF
24. Rapid anti-depressant and anxiolytic actions following dopamine D1-D2 receptor heteromer inactivation.
- Author
-
Shen MY, Perreault ML, Bambico FR, Jones-Tabah J, Cheung M, Fan T, Nobrega JN, and George SR
- Subjects
- Analysis of Variance, Animals, Disease Models, Animal, Dopamine Agents pharmacology, Dose-Response Relationship, Drug, Feeding Behavior drug effects, Food Preferences drug effects, Gene Products, tat metabolism, Male, Maze Learning drug effects, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Reaction Time drug effects, Stress, Psychological drug therapy, Sucrose administration & dosage, Swimming psychology, Anti-Anxiety Agents therapeutic use, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism, Stress, Psychological metabolism
- Abstract
A role for the mesolimbic dopaminergic system in the pathophysiology of depression has become increasingly evident. Specifically, brain-derived neurotrophic factor (BDNF) has been shown to be elevated in the nucleus accumbens of depressed patients and to positively contribute to depression-like behaviour in rodents. The dopamine D1-D2 receptor heteromer exhibits significant expression in NAc and has also been shown to enhance BDNF expression and signalling in this region. We therefore examined the effects of D1-D2 heteromer stimulation in rats by SKF 83959, or its inactivation by a selective heteromer-disrupting TAT-D1 peptide on depression- and anxiety-like behaviours in non-stressed animals and in animals exposed to chronic unpredictable stress. SKF 83959 treatment significantly enhanced the latency to immobility in the forced swim test, increased the latency to drink condensed milk and reduced total milk consumption in the novelty-induced hypophagia test, and additionally reduced the total time spent in the open arms in the elevated plus maze test. These pro-depressant and anxiogenic effects of SKF 83959 were consistently abolished or attenuated by TAT-D1 peptide pre-treatment, signifying the behaviours were mediated by the D1-D2 heteromer. More importantly, in animals exposed to chronic unpredictable stress (CUS), TAT-D1 peptide treatment alone induced significant and rapid anxiolytic and antidepressant-like effects in two tests for CUS-induced anhedonia-like reactivity and in the novelty-suppressed feeding test. Together these findings indicate a positive role for the D1-D2 heteromer in mediating depression- and anxiety-like behaviours and suggest its possible value as a novel therapeutic target., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
25. Chromobacterium Violaceum Sepsis: Rethinking Conventional Therapy to Improve Outcome.
- Author
-
Richard KR, Lovvorn JJ, Oliver SE, Ross SA, Benner KW, and Kong MY
- Subjects
- Child, Gram-Negative Bacterial Infections diagnosis, Gram-Negative Bacterial Infections drug therapy, Humans, Male, Sepsis diagnosis, Sepsis drug therapy, Anti-Bacterial Agents therapeutic use, Chromobacterium isolation & purification, Gram-Negative Bacterial Infections microbiology, Sepsis microbiology
- Abstract
Background: Chromobacterium violaceum (C. violaceum) is a facultative anaerobic gram-negative bacterium found in soil and water, especially in tropical and subtropical areas. Although infection in humans is rare, it is associated with significant morbidity. The bacterium is known for its resistance to multiple antimicrobials, and the possibility of relapse and reinfection. Presence of bacteremia, disseminated infection, and ineffective antimicrobial agents are predictors of mortality., Case Report: We report the case of a previously healthy 11-year-old male with C. violaceum sepsis who was exposed to stagnant water. He presented with severe septic shock and developed multi-organ system failure. Initial presumptive diagnosis was staphylococcal infection secondary to presence of skin abscesses resulting in antibiotic coverage with vancomycin, clindamycin, nafcillin and ceftriaxone. He also had multiple lung and liver abscesses. Once C. violaceum was identified, he received meropenem and ciprofloxacin, and was later discharged on ertapenem and trimethoprim-sulfamethoxazole (TMP-SMX) to complete a total of six months of antibiotics. He was diagnosed with chronic granulomatous disease (CGD) and is currently on prophylactic TMP-SMX and itraconazole. He has not had any relapses since his initial presentation., Conclusions: This case highlights the importance of considering C. violaceum as a relevant human pathogen, and considering it early in temperate regions, particularly in cases of fulminant sepsis associated with multi-organ abscesses. Once C. violaceum is identified, appropriate antimicrobial therapy should be started promptly, and sufficient duration of treatment is necessary for successful therapy.
- Published
- 2015
- Full Text
- View/download PDF
26. Balance is in the Moment.
- Author
-
Kong MY
- Published
- 2015
- Full Text
- View/download PDF
27. Addendum: Kong, M.Y.; Whitley, R.J.; Peng, N.; Oster, R.; Schoeb, T.R.; Sullender, W.; Ambalavanan, N.; Clancy, J.P.; Gaggar, A.; Blalock J.E. Matrix Metalloproteinase-9 Mediates RSV Infection in Vitro and in Vivo. Viruses 2015, 30, 7, 4230–4253.
- Author
-
Kong MY, Whitley RJ, Peng N, Oster R, Schoeb TR, Sullender W, Ambalavanan N, Clancy JP, Gaggar A, and Blalock JE
- Published
- 2015
- Full Text
- View/download PDF
28. Genotypic characterization of Brazilian patients with infantile and juvenile forms of metachromatic leukodystrophy.
- Author
-
Virgens MY, Siebert M, Bock H, Burin M, Giugliani R, and Saraiva-Pereira ML
- Subjects
- Brazil, Cerebroside-Sulfatase genetics, Child, Child, Preschool, Female, Gene Frequency, Genetic Association Studies, Genotype, Humans, Infant, Male, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Leukodystrophy, Metachromatic genetics
- Abstract
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder inherited as an autosomal recessive trait. MLD is caused by the deficiency of arylsulfatase A (ARSA), a lysosomal enzyme that catalyzes the first step in the degradation of sulfated glycolipids, which are essential components of the myelin sheet. Notably, between 7% and 15% of healthy individuals show in vitro deficiency of ARSA, a condition called ARSA pseudodeficiency (ARSA-PD). To date, 151 ARSA-MLD mutations have been reported in the gene encoding ARSA (ARSA), among which IVS2+1G>A and P426L occur at high frequencies in most of the studied populations. The aim of this work was to identify ARSA mutant alleles in a cohort of 27 unrelated Brazilian MLD patients. The most frequent ARSA-MLD mutation, IVS2+1G>A, and the ARSA-PD polymorphisms, N350S and 1524+95A>G, were detected using real-time PCR, while the remaining mutations were detected using direct sequencing of ARSA. In concordance with previous reports, IVS2+1G>A and P426L were the most common ARSA-MLD mutations in our cohort of MLD patients, found at frequencies of 0.05 and 0.08, respectively. Interestingly, two mutations previously reported as rare, 103_110del8 and 1190_1191insC, were found at higher frequencies in our cohort of MLD patients, 0.08 and 0.06, respectively. Additionally, 11 other rare ARSA-MLD mutations were found at lower frequencies in our cohort of MLD patients. To our knowledge, this is the first systematic genotypic characterization of MLD patients from Latin America. This work highlights the genetic heterogeneity of MLD, and supports genotype-phenotype associations, which become more important as specific treatments are being developed for this devastating disorder., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
29. Matrix Metalloproteinase-9 Mediates RSV Infection in Vitro and in Vivo.
- Author
-
Kong MY, Whitley RJ, Peng N, Oster R, Schoeb TR, Sullender W, Ambalavanan N, Clancy JP, Gaggar A, and Blalock JE
- Subjects
- Animals, Cells, Cultured, Epithelial Cells virology, Gene Silencing, Humans, Lung pathology, Matrix Metalloproteinase 9 genetics, Mice, Inbred C57BL, Mice, Knockout, RNA, Small Interfering metabolism, Viral Load, Host-Pathogen Interactions, Matrix Metalloproteinase 9 metabolism, Respiratory Syncytial Viruses physiology
- Abstract
Respiratory Syncytial Virus (RSV) is an important human pathogen associated with substantial morbidity and mortality. The present study tested the hypothesis that RSV infection would increase matrix metalloproteinase (MMP)-9 expression, and that MMP-9 inhibition would decrease RSV replication both in vitro and in vivo. RSV A2 infection of human bronchial epithelial cells increased MMP-9 mRNA and protein release. Cells transfected with siRNA against MMP-9 following RSV infection had lower viral titers. In RSV infected wild-type (WT) mice, MMP-9, airway resistance and viral load peaked at day 2 post infection, and remained elevated on days 4 and 7. RSV infected MMP-9 knockout (KO) mice had decreased lung inflammation. On days 2 and 4 post inoculation, the RSV burden was lower in the MMP-9 KO mice compared to WT controls. In conclusion, our studies demonstrate that RSV infection is a potent stimulus of MMP-9 expression both in vitro and in vivo. Reduction of MMP-9 (via siRNA knockdown, and in MMP-9 KO mice) resulted in decreased viral replication. Our findings suggest MMP-9 is a potential therapeutic target for RSV disease.
- Published
- 2015
- Full Text
- View/download PDF
30. Diagnosis and History Taking in Children with Autism Spectrum Disorder: Dealing with the Challenges.
- Author
-
Kong MY
- Published
- 2015
- Full Text
- View/download PDF
31. A crystal structure of the Dengue virus NS5 protein reveals a novel inter-domain interface essential for protein flexibility and virus replication.
- Author
-
Zhao Y, Soh TS, Zheng J, Chan KW, Phoo WW, Lee CC, Tay MY, Swaminathan K, Cornvik TC, Lim SP, Shi PY, Lescar J, Vasudevan SG, and Luo D
- Subjects
- Crystallography, X-Ray, Protein Structure, Tertiary, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Dengue Virus chemistry, Dengue Virus physiology, Viral Nonstructural Proteins chemistry, Virus Replication physiology
- Abstract
Flavivirus RNA replication occurs within a replication complex (RC) that assembles on ER membranes and comprises both non-structural (NS) viral proteins and host cofactors. As the largest protein component within the flavivirus RC, NS5 plays key enzymatic roles through its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent-RNA polymerase (RdRp) domains, and constitutes a major target for antivirals. We determined a crystal structure of the full-length NS5 protein from Dengue virus serotype 3 (DENV3) at a resolution of 2.3 Å in the presence of bound SAH and GTP. Although the overall molecular shape of NS5 from DENV3 resembles that of NS5 from Japanese Encephalitis Virus (JEV), the relative orientation between the MTase and RdRp domains differs between the two structures, providing direct evidence for the existence of a set of discrete stable molecular conformations that may be required for its function. While the inter-domain region is mostly disordered in NS5 from JEV, the NS5 structure from DENV3 reveals a well-ordered linker region comprising a short 310 helix that may act as a swivel. Solution Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) analysis reveals an increased mobility of the thumb subdomain of RdRp in the context of the full length NS5 protein which correlates well with the analysis of the crystallographic temperature factors. Site-directed mutagenesis targeting the mostly polar interface between the MTase and RdRp domains identified several evolutionarily conserved residues that are important for viral replication, suggesting that inter-domain cross-talk in NS5 regulates virus replication. Collectively, a picture for the molecular origin of NS5 flexibility is emerging with profound implications for flavivirus replication and for the development of therapeutics targeting NS5.
- Published
- 2015
- Full Text
- View/download PDF
32. Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer.
- Author
-
Perreault ML, Shen MY, Fan T, and George SR
- Subjects
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine analogs & derivatives, 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine pharmacology, Animals, Brain drug effects, Cell Count, Dimerization, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Immunohistochemistry, Male, Neurons drug effects, Neurons metabolism, Rats, Sprague-Dawley, Brain metabolism, Proto-Oncogene Proteins c-fos metabolism, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism
- Abstract
The dopamine D1 and D2 receptors form the D1-D2 receptor heteromer in a subset of neurons and couple to the Gq protein to regulate intracellular calcium signaling. In the present study the effect of D1-D2 heteromer activation and disruption on neuronal activation in the rat brain was mapped. This was accomplished using the dopamine agonist SKF 83959 to activate the D1-D2 heteromer in combination with a TAT-D1 disrupting peptide we developed, and which has been shown to disrupt the D1/D2 receptor interaction and antagonize D1-D2 heteromer-induced cell signaling and behavior. Acute SKF 83959 administration to rats induced significant c-fos expression in the nucleus accumbens that was significantly inhibited by TAT-D1 pretreatment. No effects of SKF 83959 were seen in caudate putamen. D1-D2 heteromer disruption by TAT-D1 did not have any effects in any striatal subregions, but induced significant c-fos immunoreactivity in a number of cortical regions including the orbitofrontal cortex, prelimbic and infralimbic cortices and piriform cortex. The induction of c-fos by TAT-D1 was also evident in the anterior olfactory nucleus, as well as the lateral habenula and thalamic nuclei. These findings show for the first time that the D1-D2 heteromer can differentially regulate c-fos expression in a region-dependent manner either through its activation or through tonic inhibition of neuronal activity., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
33. The C-terminal 50 amino acid residues of dengue NS3 protein are important for NS3-NS5 interaction and viral replication.
- Author
-
Tay MY, Saw WG, Zhao Y, Chan KW, Singh D, Chong Y, Forwood JK, Ooi EE, Grüber G, Lescar J, Luo D, and Vasudevan SG
- Subjects
- Animals, Antiviral Agents chemistry, Binding Sites, Cell Line, Cell Line, Tumor, Cricetinae, DNA, Complementary metabolism, Enzyme-Linked Immunosorbent Assay, Humans, Lysine chemistry, Mutagenesis, Site-Directed, Mutation, Plasmids metabolism, Protein Binding, Protein Interaction Mapping, Protein Structure, Tertiary, RNA-Dependent RNA Polymerase, Scattering, Radiation, Dengue Virus physiology, RNA, Viral chemistry, Serine Endopeptidases chemistry, Viral Nonstructural Proteins chemistry, Virus Replication
- Abstract
Dengue virus multifunctional proteins NS3 protease/helicase and NS5 methyltransferase/RNA-dependent RNA polymerase form part of the viral replication complex and are involved in viral RNA genome synthesis, methylation of the 5'-cap of viral genome, and polyprotein processing among other activities. Previous studies have shown that NS5 residue Lys-330 is required for interaction between NS3 and NS5. Here, we show by competitive NS3-NS5 interaction ELISA that the NS3 peptide spanning residues 566-585 disrupts NS3-NS5 interaction but not the null-peptide bearing the N570A mutation. Small angle x-ray scattering study on NS3(172-618) helicase and covalently linked NS3(172-618)-NS5(320-341) reveals a rigid and compact formation of the latter, indicating that peptide NS5(320-341) engages in specific and discrete interaction with NS3. Significantly, NS3:Asn-570 to alanine mutation introduced into an infectious DENV2 cDNA clone did not yield detectable virus by plaque assay even though intracellular double-stranded RNA was detected by immunofluorescence. Detection of increased negative-strand RNA synthesis by real time RT-PCR for the NS3:N570A mutant suggests that NS3-NS5 interaction plays an important role in the balanced synthesis of positive- and negative-strand RNA for robust viral replication. Dengue virus infection has become a global concern, and the lack of safe vaccines or antiviral treatments urgently needs to be addressed. NS3 and NS5 are highly conserved among the four serotypes, and the protein sequence around the pinpointed amino acids from the NS3 and NS5 regions are also conserved. The identification of the functionally essential interaction between the two proteins by biochemical and reverse genetics methods paves the way for rational drug design efforts to inhibit viral RNA synthesis., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
34. The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization.
- Author
-
Shen MY, Perreault ML, Fan T, and George SR
- Subjects
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine analogs & derivatives, 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine pharmacology, Amphetamine-Related Disorders physiopathology, Amphetamine-Related Disorders psychology, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Central Nervous System Stimulants pharmacology, Dopamine Antagonists pharmacology, Dopamine D2 Receptor Antagonists pharmacology, Male, Multiprotein Complexes chemistry, Multiprotein Complexes physiology, Peptide Fragments pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1 antagonists & inhibitors, Receptors, Dopamine D1 chemistry, Receptors, Dopamine D2 chemistry, Reward, Amphetamine pharmacology, Motor Activity drug effects, Motor Activity physiology, Receptors, Dopamine D1 physiology, Receptors, Dopamine D2 physiology
- Abstract
A role for the dopamine D1-D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1-D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioral model widely used to study the neuroadaptations associated with psychostimulant addiction. D1-D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1-D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1-D2 receptor heteromer exerts a tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1-D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
35. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism.
- Author
-
Hasbi A, Perreault ML, Shen MY, Zhang L, To R, Fan T, Nguyen T, Ji X, O'Dowd BF, and George SR
- Subjects
- Animals, Brain metabolism, Dopamine metabolism, Dopamine D2 Receptor Antagonists pharmacology, Male, Neurons drug effects, Peptides metabolism, Rats, Sprague-Dawley, Receptors, Dopamine D1 antagonists & inhibitors, Calcium Signaling physiology, Neurons metabolism, Protein Multimerization, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism
- Abstract
Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues (404)Glu and (405)Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment., (© FASEB.)
- Published
- 2014
- Full Text
- View/download PDF
36. Biphasic assembly of the contractile apparatus during the first two cell division cycles in zebrafish embryos.
- Author
-
Webb SE, Goulet C, Chan CM, Yuen MY, and Miller AL
- Subjects
- Actins metabolism, Actomyosin metabolism, Animals, Cardiac Myosins metabolism, Embryo, Nonmammalian ultrastructure, Microscopy, Confocal, Myosin Light Chains metabolism, Phosphorylation, Cell Division physiology, Embryo, Nonmammalian cytology, Embryo, Nonmammalian physiology, Zebrafish embryology
- Abstract
The large and optically clear embryos of the zebrafish provide an excellent model system in which to study the dynamic assembly of the essential contractile band components, actin and myosin, via double fluorescent labelling in combination with confocal microscopy. We report the rapid appearance (i.e. within <2 min) of a restricted arc of F-actin patches along the prospective furrow plane in a central, apical region of the blastodisc cortex. These patches then fused with each other end-to-end forming multiple actin cables, which were subsequently bundled together forming an F-actin band. During this initial assembly phase, the F-actin-based structure did not elongate laterally, but was still restricted to an arc extending ~15° either side of the blastodisc apex. This initial assembly phase was then followed by an extension phase, where additional F-actin patches were added to each end of the original arc, thus extending it out to the edges of the blastodisc. The dynamics of phosphorylated myosin light chain 2 (MLC2) recruitment to this F-actin scaffold also reflect the two-phase nature of the contractile apparatus assembly. MLC2 was not associated with the initial F-actin arc, but MLC2 clusters were recruited and assembled into the extending ends of the band. We propose that the MLC2-free central region of the contractile apparatus acts to position and then extend the cleavage furrow in the correct plane, while the actomyosin ends alone generate the force required for furrow ingression. This biphasic assembly strategy may be required to successfully divide the early cells of large embryos.
- Published
- 2014
- Full Text
- View/download PDF
37. Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus.
- Author
-
Kong MY, Clancy JP, Peng N, Li Y, Szul TJ, Xu X, Oster R, Sullender W, Ambalavanan N, Blalock JE, and Gaggar A
- Subjects
- Biomarkers metabolism, Cells, Cultured, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Intubation, Leukocyte Elastase metabolism, Male, Oxygen therapeutic use, Peroxidase metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism, Gene Expression Regulation, Enzymologic, Lung enzymology, Matrix Metalloproteinase 9 metabolism, Respiration, Artificial methods, Respiratory Syncytial Virus Infections enzymology, Respiratory Syncytial Virus, Human
- Abstract
Respiratory syncytial virus (RSV) infection is a potent stimulus for airway epithelial expression of matrix metalloproteinase (MMP)-9. MMP-9 activity in vivo is a predictor of disease severity in children with RSV-induced respiratory failure. Human airway epithelial cells were infected with RSV A2 strain and analysed for MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 (a natural inhibitor of MMP-9) release. In addition, endotracheal samples from children with RSV-RF and controls (non-RSV pneumonia and nonlung disease controls) were analysed for MMP-9, TIMP-1, human neutrophil elastase and myeloperoxidase activity. RSV infection of airway epithelia was sufficient to rapidly induce MMP-9 transcription and protein release. Pulmonary MMP-9 activity peaked at 48 h in infants with RSV-induced respiratory failure. In the RSV group, MMP-9 activity and MMP-9/TIMP-1 ratio imbalance predicted higher oxygen requirement and worse paediatric risk of mortality scores. The highest levels of human neutrophil elastase and myeloperoxidase activity were measured in the RSV cohort; however, unlike MMP-9, these neutrophil markers failed to predict disease severity. These results support the hypothesis that RSV is a potent stimulus for MMP-9 expression and release from human airway epithelium, and that MMP-9 is an important biomarker of disease severity in mechanically ventilated children with RSV lung infection.
- Published
- 2014
- Full Text
- View/download PDF
38. Quantifying psychological distress among cancer patients in interventions and scales: a systematic review.
- Author
-
Yeh ML, Chung YC, Hsu MY, and Hsu CC
- Subjects
- Anxiety etiology, Anxiety therapy, Cognitive Behavioral Therapy methods, Complementary Therapies methods, Depression etiology, Depression therapy, Exercise Therapy methods, Fatigue psychology, Fatigue therapy, Humans, Neoplasms therapy, Pain etiology, Pain Management methods, Quality of Life psychology, Randomized Controlled Trials as Topic, Surveys and Questionnaires, Survivors psychology, Anxiety diagnosis, Depression diagnosis, Fatigue etiology, Neoplasms psychology, Pain diagnosis, Stress, Psychological complications, Stress, Psychological diagnosis, Stress, Psychological etiology, Stress, Psychological therapy
- Abstract
The management of cancer-related psychological distress has been addressed in numerous studies, which have examined both the development of interventions to alleviate psychological distress as well as scales for evaluating their efficacy. In this systematic review, we examine results from randomized controlled trials (RCTs) on the relative effectiveness of interventions in reducing cancer-related psychological distress and the scales employed to measure this distress. An electronic database search for RCTs of psychological interventions in cancer patients from October 2008 to July 2013 was conducted using PubMed, MEDLINE, and CINAHL. Data was independently extracted and assessed by two researchers. Nineteen RCTs on interventions for psychological distress were identified and analyzed, among which eight studies reported that the interventions had a positive effect and improved the symptoms of psychological distress, and in which seven main instruments were used to measure psychological distress. The most frequently employed interventions were exercise training, cognitive behavioral therapy, and complementary therapy, followed by meeting with a psychologist and a combination of keeping a written journal and peer counseling. The three most frequently employed scales were the Profile of Mood States-Short Form (POMS-SF), Distress Thermometer (DT), and Hospital Anxiety and Depression (HADS). The majority of cancer patients experience considerable psychological and emotional distress at some time during the course of the disease. Reports have shown that interventions such as exercise training, cognitive behavioral therapy, and complementary therapy can assist oncology personnel in alleviating this distress. Future studies should consider optimizing such interventions. The POMS-SF scale, which has frequently been employed to measure the effects of psychological distress, could be incorporated into elements of screening programs for measuring unfulfilled needs, desire for assistance, clinical response, and longitudinal outcomes.
- Published
- 2014
- Full Text
- View/download PDF
39. Identification and molecular characterization of human antibody fragments specific for dengue NS5 protein.
- Author
-
Zhao Y, Moreland NJ, Tay MY, Lee CC, Swaminathan K, and Vasudevan SG
- Subjects
- Amino Acid Sequence, Cross Reactions, Dengue immunology, Dengue Virus classification, Dengue Virus genetics, Dengue Virus immunology, Epitope Mapping, Humans, Immunoglobulin Fab Fragments analysis, Immunoglobulin Fab Fragments genetics, Immunoglobulin Fab Fragments immunology, Methyltransferases genetics, Methyltransferases immunology, Molecular Sequence Data, RNA-Dependent RNA Polymerase genetics, RNA-Dependent RNA Polymerase immunology, Sequence Alignment, Species Specificity, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins immunology, Virus Replication, Dengue virology, Dengue Virus enzymology, Methyltransferases chemistry, RNA-Dependent RNA Polymerase chemistry, Viral Nonstructural Proteins chemistry
- Abstract
The multifunctional dengue nonstructural (NS) protein 5 from the four serotypes of dengue virus (DENV1-4) is essential for viral replication and harbors a methyl transferase (MTase) and a RNA-dependent RNA-polymerase domain (RdRp). There are limited comparative studies of NS5 from the four DENV serotypes and this is further hampered by a lack of cross-reactive NS5 antibodies. In this study, recombinant NS5 proteins were expressed, purified, enzymatically characterized, and used strategically as bait in biopanning experiments with a naïve human Fab phage-display library to identify serotype specific or cross-reactive Fab fragments. Using a combination of peptide competition ELISA and peptide phage display the epitopes of the cross-reactive Fabs were mapped to the first alpha helix of the MTase domain (5M1) and the priming loop of the RdRp domain (5R3). The epitope of a third, serotype-specific Fab (5M3) was mapped to aa19-30 of the DENV3 MTase domain. Together the recombinant proteins and specific antibodies will facilitate further mechanistic studies of the DENV replication complex., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
40. Identification of dengue-specific human antibody fragments using phage display.
- Author
-
Tay MY, Lee CC, Vasudevan SG, and Moreland NJ
- Subjects
- Antigens, Viral immunology, Biotinylation, Cross Reactions immunology, Enzyme-Linked Immunosorbent Assay, Humans, Resins, Synthetic metabolism, Species Specificity, Streptavidin metabolism, Antibodies, Viral immunology, Cell Surface Display Techniques methods, Dengue Virus immunology, Immunoglobulin Fragments immunology
- Abstract
High-affinity antibodies are valuable tools for dengue research. A method for the selection of dengue-specific, human antibody fragments using naïve repertoires displayed on M13 filamentous bacteriophage is described. Naïve repertoires are unbiased, thus enabling the identification of antibodies to dengue structural and nonstructural proteins from the same library. Dengue-specific clones are enriched by binding to an immobilized dengue antigen, followed by washing, elution, and amplification of phage for subsequent rounds of selection. Dengue virus has four antigenically related serotypes, and the serotype of the antigen can be kept constant or alternated during the selection process depending on whether serotype-specific or cross-reactive antibodies are required. After the selection process, clones are screened, and specific clones are identified by phage ELISA and Western blot.
- Published
- 2014
- Full Text
- View/download PDF
41. Sepsis-associated cholestasis in adult patients: a prospective study.
- Author
-
Fan HB, Yang DL, Chen AS, Li Z, Xu LT, Ma XJ, Zhou H, Tian ZF, Wu JJ, and Yan FM
- Subjects
- APACHE, Adult, Age Factors, Aged, China epidemiology, Cholestasis mortality, Female, Gram-Negative Bacteria classification, Gram-Negative Bacteria isolation & purification, Gram-Positive Bacteria classification, Gram-Positive Bacteria isolation & purification, Hospitalization, Humans, Incidence, Male, Middle Aged, Morbidity, Organ Dysfunction Scores, Prospective Studies, Risk Factors, Sepsis microbiology, Sepsis mortality, Cholestasis epidemiology, Cholestasis microbiology, Sepsis complications, Sepsis epidemiology
- Abstract
Background: Sepsis-associated cholestasis is a common problem in neonatal patients. However, there are limited data related to sepsis-associated cholestasis in adults. In this study, the authors assessed the clinical characteristics, risk factors and outcome of adult patients with sepsis-associated cholestasis., Methods: An observational prospective single-center study was conducted. A total of 608 patients with sepsis (66 patients with cholestasis and 542 without evidence of cholestasis) from January 1, 2005, to December 31, 2011, were included from the infectious disease unit. Demographic, clinical and laboratory information were recorded on admission for all patients. Additional data were also collected on the day of the 1st episode of bacteremia for patients who developed cholestasis. Accordingly, the organ dysfunction scores (Acute Physiology and Chronic Health Evaluation [APACHE] II and Sequential Organ Failure Assessment [SOFA]) were assessed on the same day., Results: The mean age of the 608 patients was 49.3 ± 11.4 years (range, 22-83 years); 312 (51.3%) patients were men, 296 (48.7%) were women. The mean APACHE II and SOFA score were 15.2 ± 6 and 5.6 ± 2.3, respectively. Sepsis-associated cholestasis was strongly associated with older age, biomarkers of organ dysfunction and clinical composite scores (APACHE II and SOFA). Mortality was higher in patients with sepsis-associated cholestasis (10.6%) compared with subjects with sepsis without cholestasis (1.5%) (P < 0.05)., Conclusions: The authors found that sepsis-associated cholestasis affects the outcome of patients with sepsis in the infectious disease unit. Additional clinical studies are necessary to elucidate the pathology and pathophysiology of sepsis-associated cholestasis.
- Published
- 2013
- Full Text
- View/download PDF
42. Isocitrate dehydrogenase 1 is a novel plasma biomarker for the diagnosis of non-small cell lung cancer.
- Author
-
Sun N, Chen Z, Tan F, Zhang B, Yao R, Zhou C, Li J, Gao Y, Liu Z, Tan X, Zhou F, He MY, Shao K, Li N, Qiu B, Sun J, Yu Y, Wang S, Zhao Y, Shi X, and He J
- Subjects
- Adenocarcinoma blood, Adult, Aged, Aged, 80 and over, Antigens, Neoplasm blood, Area Under Curve, CA-125 Antigen blood, Carcinoembryonic Antigen blood, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Squamous Cell blood, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Humans, Keratin-19 blood, Lung Neoplasms blood, Male, Membrane Proteins blood, Middle Aged, Neoplasm Staging, Prognosis, ROC Curve, Adenocarcinoma diagnosis, Biomarkers, Tumor blood, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Squamous Cell diagnosis, Isocitrate Dehydrogenase blood, Lung Neoplasms diagnosis
- Abstract
Purpose: Effective biomarkers for the diagnosis of non-small cell lung cancer (NSCLC) are needed. We previously showed that isocitrate dehydrogenase 1 (IDH1) is significantly increased in NSCLC tumors. This study aimed to examine the plasma levels of IDH1 in a large patient population to evaluate its effectiveness in NSCLC diagnosis., Experimental Design: The plasma levels of IDH1, CA125, Cyfra21-1, and CEA were assayed by ELISA. Blood samples were obtained from 1,422 participants (943 patients with NSCLC and 479 healthy controls). The samples were randomly divided into a training set and a test set. Receiver operating characteristic and binary logistic regression analyses were applied to evaluate diagnostic efficacy and establish diagnostic mathematical models., Results: Plasma IDH1 levels were significantly higher in patients with NSCLCs than in healthy controls (P < 0.001). The diagnostic use of IDH1 in lung adenocarcinoma [area under curve (AUC): 0.858 and 0.810; sensitivity: 77.1% and 76.2%; specificity: 82.9% and 76.6%; in the training set and test set, respectively] was significantly greater than that of CA125, Cyfra21-1, or CEA (P < 0.001). The model combining IDH1 with CEA, CA125, and Cyfra21-1 was more effective for lung adenocarcinoma diagnosis than IDH1 alone (sensitivity and specificity in the training set: 75.8%, 89.6%; test set: 86.3%, 70.7%). In addition, the plasma levels of IDH1 could contribute to the diagnostic model of lung squamous cell carcinoma., Conclusions: IDH1 can be used as a plasma biomarker for the diagnosis of NSCLCs, particularly lung adenocarcinoma, with relatively high sensitivity and specificity., (©2013 AACR.)
- Published
- 2013
- Full Text
- View/download PDF
43. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin.
- Author
-
Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, Vasudevan SG, and Jans DA
- Subjects
- Cytoplasm virology, Dengue drug therapy, Dengue Virus classification, Dengue Virus genetics, Dengue Virus metabolism, Humans, Protein Transport drug effects, Viral Nonstructural Proteins genetics, Antiviral Agents pharmacology, Cell Nucleus virology, Dengue virology, Dengue Virus drug effects, Ivermectin pharmacology, Viral Nonstructural Proteins metabolism
- Abstract
Infection by one of the 4 distinct serotypes of dengue virus (DENV) threatens >40% of the world's population, with no efficacious vaccine or antiviral agent currently available. DENV replication through the virus-encoded nonstructural protein (NS) 5 protein occurs in the infected cell cytoplasm, but NS5 from DENV2 has thus far been shown to localize strongly in the nucleus throughout infection. Here we use specific antibodies cross-reactive with NS5 from DENV1-4 to demonstrate nuclear localization of NS5 from all DENV serotypes for the first time in both infected as well as transfected cells, although to differing extents. The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/β in vitro, and protected against infection from DENV1-4. Ivermectin thus has potential in the clinical setting as a dengue antiviral., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
44. Characterization of Ca(2+) signaling in the external yolk syncytial layer during the late blastula and early gastrula periods of zebrafish development.
- Author
-
Yuen MY, Webb SE, Chan CM, Thisse B, Thisse C, and Miller AL
- Subjects
- Aequorin metabolism, Animals, Calcium Channels metabolism, Cell Nucleus metabolism, Egg Yolk cytology, Embryo, Nonmammalian cytology, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum ultrastructure, Inositol 1,4,5-Trisphosphate Receptors metabolism, Microscopy, Confocal, Microscopy, Fluorescence, Multiphoton, Signal Transduction, Zebrafish metabolism, Zebrafish Proteins metabolism, Blastula metabolism, Calcium Signaling physiology, Egg Yolk metabolism, Embryo, Nonmammalian metabolism, Gastrula metabolism, Zebrafish embryology
- Abstract
Preferential loading of the complementary bioluminescent (f-aequorin) and fluorescent (Calcium Green-1 dextran) Ca(2+) reporters into the yolk syncytial layer (YSL) of zebrafish embryos, revealed the generation of stochastic patterns of fast, short-range, and slow, long-range Ca(2+) waves that propagate exclusively through the external YSL (E-YSL). Starting abruptly just after doming (~4.5h post-fertilization: hpf), and ending at the shield stage (~6.0hpf) these distinct classes of waves propagated at mean velocities of ~50 and ~4μm/s, respectively. Although the number and pattern of these waves varied between embryos, their initiation site and arcs of propagation displayed a distinct dorsal bias, suggesting an association with the formation and maintenance of the nascent dorsal-ventral axis. Wave initiation coincided with a characteristic clustering of YSL nuclei (YSN), and their associated perinuclear ER, in the E-YSL. Furthermore, the inter-YSN distance (IND) appeared to be critical such that Ca(2+) wave propagation occurred only when this was <~8μm; an IND >~8μm was coincidental with wave termination at shield stage. Treatment with the IP3R antagonist, 2-APB, the Ca(2+) buffer, 5,5'-dibromo BAPTA, and the SERCA-pump inhibitor, thapsigargin, resulted in a significant disruption of the E-YSL Ca(2+) waves, whereas exposure to the RyR antagonists, ryanodine and dantrolene, had no significant effect. These findings led us to propose that the E-YSL Ca(2+) waves are generated mainly via Ca(2+) release from IP3Rs located in the perinuclear ER, and that the clustering of the YSN is an essential step in providing a CICR pathway required for wave propagation. This article is part of a Special Issue entitled: 12th European Symposium on Calcium., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
45. Monoclonal antibodies against dengue NS2B and NS3 proteins for the study of protein interactions in the flaviviral replication complex.
- Author
-
Moreland NJ, Tay MY, Lim E, Rathore AP, Lim AP, Hanson BJ, and Vasudevan SG
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Viral immunology, Enzyme-Linked Immunosorbent Assay methods, Humans, Immunoglobulin G immunology, Immunoglobulin G isolation & purification, Immunohistochemistry methods, Immunoprecipitation methods, Mice, Protein Binding, RNA Helicases immunology, RNA Helicases metabolism, Reproducibility of Results, Sensitivity and Specificity, Serine Endopeptidases immunology, Serine Endopeptidases metabolism, Viral Nonstructural Proteins immunology, Antibodies, Monoclonal isolation & purification, Antibodies, Viral isolation & purification, Dengue Virus physiology, Protein Interaction Mapping, Viral Nonstructural Proteins metabolism
- Abstract
The replication of dengue virus (DENV) RNA requires at least two viral non-structural (NS) proteins, NS3 and NS5. To facilitate the study of the DENV replication complex, human monoclonal IgG that are specific for NS proteins have been generated and characterised. The anti-NS3 IgG, 3F8, binds a conserved epitope (aa526-531) in the NS3 helicase domain, and cross-reacts with NS3 from all four DENV serotypes and the related yellow fever virus. The anti-NS2B IgG, 3F10, binds aa49-66 of NS2B (CF18), which forms part of the 47 aa hydrophilic cofactor region required for NS3 protease activity. The specificity of the IgG for their respective non-structural proteins has been demonstrated by immunofluorescence of cells infected with DENV and Western blotting. 3F8 is able to co-immunoprecipitate NS3 and NS5 from BHK-21 cells infected with DENV2, and 3F10 is able to detect an interaction between recombinant NS2B(CF18)NS3 full-length protein and the NS5 RNA-dependent RNA polymerase (RdRp) domain in an ELISA-based binding assay. The assay is specific and highly reproducible, with a clear binding curve seen when RdRp is incubated with increasing amounts of full-length NS3, but not the NS3 protease domain. The NS3 helicase domain competes with NS3 full-length for NS5 RdRp binding, with a K(d.) of 2.5μM. Since NS3 and NS5 are required for DENV replication, this fascile assay could be used to screen for non-nucleoside, allosteric inhibitors that disrupt the interaction between the two proteins., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
46. Prolonged peri-firing compression with a linear stapler prevents pancreatic fistula in laparoscopic distal pancreatectomy.
- Author
-
Nakamura M, Ueda J, Kohno H, Aly MY, Takahata S, Shimizu S, and Tanaka M
- Subjects
- Adolescent, Adult, Aged, Amylases blood, Equipment Design, Female, Humans, Incidence, Laparotomy, Length of Stay statistics & numerical data, Male, Middle Aged, Pancreatic Fistula epidemiology, Postoperative Complications epidemiology, Pressure, Retrospective Studies, Suction, Young Adult, Laparoscopy methods, Pancreatectomy methods, Pancreatic Fistula prevention & control, Postoperative Complications prevention & control, Surgical Staplers, Surgical Stapling methods
- Abstract
Background: Laparoscopic distal pancreatectomy (Lap-DP) is one of the most accepted laparoscopic procedures in the field of pancreatic surgery. However, pancreatic fistula remains a major and frequent complication in Lap-DP, as in open surgery. The aim of this retrospective study is to clarify the advantages of prolonged peri-firing compression (PFC) with a linear stapler for prevention of pancreatic fistula after laparoscopic distal pancreatectomy., Patients and Methods: Incidence of pancreatic fistula in clinical levels (equivalent to grades B and C defined by the International Study Group of Pancreatic Fistula (ISGPF)) was retrospectively compared between patients who underwent Lap-DP with PFC (PFC group, n = 17) and those who underwent Lap-DP without PFC (no-PFC group, n = 25)., Results: Incidence of clinical pancreatic fistula was significantly lower in the PFC group than in the no-PFC group. Consistent with the results for pancreatic fistula, peritoneal drainage period and postoperative hospital stay were shorter in the PFC group than in the no-PFC group., Conclusions: Our data show that PFC effectively prevents pancreatic fistula and shortens postoperative hospital stay after Lap-DP.
- Published
- 2011
- Full Text
- View/download PDF
47. Early elevation of matrix metalloproteinase-8 and -9 in pediatric ARDS is associated with an increased risk of prolonged mechanical ventilation.
- Author
-
Kong MY, Li Y, Oster R, Gaggar A, and Clancy JP
- Subjects
- Acute Disease, Adolescent, Biomarkers metabolism, Child, Child, Preschool, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infant, Leukocyte Elastase metabolism, Lung Diseases pathology, Male, Matrix Metalloproteinase Inhibitors, Peroxidase metabolism, Risk Assessment, Risk Factors, Syndrome, Time Factors, Tissue Inhibitor of Metalloproteinase-1 metabolism, Trachea drug effects, Trachea enzymology, Trachea pathology, Lung Diseases enzymology, Lung Diseases therapy, Matrix Metalloproteinase 8 metabolism, Matrix Metalloproteinase 9 metabolism, Respiration, Artificial
- Abstract
Background: Matrix metalloproteinases (MMP) -8 and -9 may play key roles in the modulation of neutrophilic lung inflammation seen in pediatric Acute Respiratory Distress Syndrome (ARDS). We aimed to perform a comprehensive analysis of MMP-8 and MMP-9 activity in tracheal aspirates of pediatric ARDS patients compared with non-ARDS controls, testing whether increased MMP-8 and -9 activities were associated with clinical outcomes., Methods: Tracheal aspirates were collected from 33 pediatric ARDS patients and 21 non-ARDS controls at 48 hours of intubation, and serially for those who remained intubated greater than five days. MMPs, tissue inhibitor of metalloproteinases (TIMPs), human neutrophil elastase (HNE) and myeloperoxidase (MPO) activity were measured by ELISA, and correlated with clinical indicators of disease severity such as PRISM (Pediatric Risk of Mortality) scores, oxygen index (OI), multi-organ system failure (MOSF) and clinical outcome measures including length of intubation, ventilator-free days (VFDs) and mortality in the Pediatric Intensive Care Unit (PICU)., Results: Active MMP-9 was elevated early in pediatric ARDS subjects compared to non-ARDS controls. Higher MMP-8 and active MMP-9 levels at 48 hours correlated with a longer course of mechanical ventilation (r = 0.41, p = 0.018 and r = 0.75, p<0.001; respectively) and fewer number of VFDs (r = -0.43, p = 0.013 and r = -0.76, p<0.001; respectively), independent of age, gender and severity of illness. Patients with the highest number of ventilator days had the highest levels of active MMP-9. MMP-9 and to a lesser extent MMP-8 activities in tracheal aspirates from ARDS subjects were sensitive to blockade by small molecule inhibitors., Conclusions: Higher MMP-8 and active MMP-9 levels at 48 hours of disease onset are associated with a longer duration of mechanical ventilation and fewer ventilator-free days among pediatric patients with ARDS. Together, these results identify early biomarkers predictive of disease course and potential therapeutic targets for this life threatening disease.
- Published
- 2011
- Full Text
- View/download PDF
48. High affinity human antibody fragments to dengue virus non-structural protein 3.
- Author
-
Moreland NJ, Tay MY, Lim E, Paradkar PN, Doan DN, Yau YH, Geifman Shochat S, and Vasudevan SG
- Subjects
- Antibodies, Viral genetics, Antibody Specificity, Dengue virology, Dengue Virus genetics, Dengue Virus physiology, HEK293 Cells, Humans, Immunoglobulin Fab Fragments genetics, RNA Helicases genetics, RNA Helicases immunology, Serine Endopeptidases genetics, Serine Endopeptidases immunology, Viral Nonstructural Proteins genetics, Virus Replication, Antibodies, Viral immunology, Dengue immunology, Dengue Virus immunology, Immunoglobulin Fab Fragments immunology, Viral Nonstructural Proteins immunology
- Abstract
Background: The enzyme activities catalysed by flavivirus non-structural protein 3 (NS3) are essential for virus replication. They are distributed between the N-terminal protease domain in the first one-third and the C-terminal ATPase/helicase and nucleoside 5' triphosphatase domain which forms the remainder of the 618-aa long protein., Methodology/principal Findings: In this study, dengue full-length NS3 protein with residues 49 to 66 of NS2B covalently attached via a flexible linker, was used as bait in biopanning with a naïve human Fab phage-display library. Using a range of truncated constructs spanning the NS2B cofactor region and the full-length NS3, 10 unique Fab were identified and characterized. Of these, monoclonal Fab 3F8 was shown to bind α3″ (residues 526 through 531) within subdomain III of the helicase domain. The antibody inhibits the ATPase and helicase activites of NS3 in biochemical assays and reduces DENV replication in HEK293 cells that were previously transfected with Fab 3F8 compared with mock transfected cells., Conclusions/significance: Antibodies such as 3F8 are valuable tools for studying the molecular mechanisms of flaviviral replication and for the monospecific detection of replicating dengue virus in vivo.
- Published
- 2010
- Full Text
- View/download PDF
49. Comparative study of laparoscopic and open distal pancreatectomy.
- Author
-
Aly MY, Tsutsumi K, Nakamura M, Sato N, Takahata S, Ueda J, Shimizu S, Redwan AA, and Tanaka M
- Subjects
- Adult, Aged, Female, Humans, Laparoscopy, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Pancreatectomy methods, Pancreatic Diseases surgery
- Abstract
Background: Laparoscopic distal pancreatectomy (LDP) has been shown to be an effective surgical option for benign lesions in the body and tail of the pancreas. However, its advantages and disadvantages have not been well characterized. In this study, we compared the outcomes of LDP and open pancreatectomy performed in our clinic., Materials and Methods: Peri- and postoperative outcomes were retrospectively compared between patients with benign pancreatic disorders who underwent open distal pancreatectomy (ODP) (n = 35) and those who underwent LDP (n = 40). The peri- and postoperative factors analyzed included operative time, blood loss, hospital stay, postoperative recovery, biochemical findings, and complications., Results: LDP was associated with significantly less operative blood loss (363 versus 606 mL; P = 0.001) and shorter hospital stay (22 versus 27 day; P = 0.009), but longer operative time (342 versus 250 min; P = 0.000), compared with ODP. There were no significant differences between the two groups in complication rates or postoperative recovery, except for the significantly shorter duration of postoperative pain-killer intake and earlier improvement of the biochemical analysis in LDP than in ODP., Conclusions: LDP appears to be a safe, desirable procedure for the management of benign pancreatic diseases, with outcomes similar to ODP.
- Published
- 2010
- Full Text
- View/download PDF
50. Matrix metalloproteinase activity in pediatric acute lung injury.
- Author
-
Kong MY, Gaggar A, Li Y, Winkler M, Blalock JE, and Clancy JP
- Subjects
- Adolescent, Blotting, Western, Child, Child, Preschool, Female, Humans, Infant, Male, Matrix Metalloproteinase 11 metabolism, Matrix Metalloproteinase 12 metabolism, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 3 metabolism, Matrix Metalloproteinase 8 metabolism, Matrix Metalloproteinase 9 metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism, Acute Lung Injury enzymology, Matrix Metalloproteinases metabolism
- Abstract
Pediatric Acute Lung Injury (ALI) is associated with a high mortality and morbidity, and dysregulation of matrix metalloproteinases (MMPs) may play an important role in the pathogenesis and evolution of ALI. Here we examined MMP expression and activity in pediatric ALI compared with controls. MMP-8, -9, and to a lesser extent, MMP-2, -3, -11 and -12 were identified at higher levels in lung secretions of pediatric ALI patients compared with controls. Tissue Inhibitor of Matrix metalloproteinase-1 (TIMP-1), a natural inhibitor of MMPs was detected in most ALI samples, but MMP-9:TIMP-1 ratios were high relative to controls. In subjects who remained intubated for >or=10 days, MMP-9 activity decreased, with > 80% found in the latent form. In contrast, almost all MMP-8 detected at later disease course was constitutively active. Discriminating MMP-9:TIMP-1 ratios were found in those who had a prolonged ALI course. These results identify a specific repertoire of MMP isoforms in the lung secretions of pediatric ALI patients, and demonstrate inverse changes in MMPs -8 and -9 with protracted disease.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.