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1.
Thorax ; 73(1): 78-81, 2018 01.
Article in English | MEDLINE | ID: mdl-28258249

ABSTRACT

Lung function tests have a major role in respiratory medicine. Training in lung function tests is variable within the European Union. In this study, we have shown that an internship in a lung function tests laboratory significantly improved the technical and diagnostic skills of French respiratory trainees.


Subject(s)
Clinical Competence , Internship and Residency , Pulmonary Medicine/education , Respiratory Function Tests , Respiratory Physiological Phenomena , Adult , Cross-Sectional Studies , Female , France , Humans , Male
2.
Neuroimage ; 149: 233-243, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28159689

ABSTRACT

Computational anatomy studies typically use T1-weighted magnetic resonance imaging contrast to look at local differences in cortical thickness or grey matter volume across time or subjects. This type of analysis is a powerful and non-invasive tool to probe anatomical changes associated with neurodevelopment, aging, disease or experience-induced plasticity. However, these comparisons could suffer from biases arising from vascular and metabolic subject- or time-dependent differences. Differences in blood flow and volume could be caused by vasodilation or differences in vascular density, and result in a larger signal contribution of the blood compartment within grey matter voxels. Metabolic changes could lead to differences in dissolved oxygen in brain tissue, leading to T1 shortening. Here, we analyze T1 maps and T1-weighted images acquired during different breathing conditions (ambient air, hypercapnia (increased CO2) and hyperoxia (increased O2)) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O2 concentration in computational anatomy studies. Results show that increased blood volume from vasodilation during hypercapnia is associated with an overestimation of cortical thickness (1.85%) and grey matter volume (3.32%), and that both changes in O2 concentration and blood volume lead to changes in the T1 value of tissue. These results should be taken into consideration when interpreting existing morphometry studies and in future study design. Furthermore, this study highlights the overlap in structural and physiological MRI, which are conventionally interpreted as two independent modalities.


Subject(s)
Brain Mapping/methods , Brain/diagnostic imaging , Adult , Brain/blood supply , Brain/metabolism , Cerebrovascular Circulation/physiology , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Young Adult
3.
Mol Psychiatry ; 21(9): 1215-24, 2016 09.
Article in English | MEDLINE | ID: mdl-26239292

ABSTRACT

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.


Subject(s)
Autism Spectrum Disorder/metabolism , Stem Cells/metabolism , Sulfurtransferases/metabolism , Adult , Animals , Autism Spectrum Disorder/genetics , Caenorhabditis elegans , Female , France , Humans , Male , Mice , Mice, Inbred C57BL , Olfactory Mucosa/metabolism , Olfactory Receptor Neurons/metabolism , Olfactory Receptor Neurons/physiology , Stem Cells/physiology , Sulfurtransferases/therapeutic use
4.
Encephale ; 43(1): 32-40, 2017 Feb.
Article in French | MEDLINE | ID: mdl-26995150

ABSTRACT

OBJECTIVE: Face and gaze avoidance are among the most characteristic and salient symptoms of autism spectrum disorders (ASD). Studies using eye tracking highlighted early and lifelong ASD-specific abnormalities in attention to face such as decreased attention to internal facial features. These specificities could be partly explained by disorders in the perception and integration of rapid and complex information such as that conveyed by facial movements and more broadly by biological and physical environment. Therefore, we wish to test whether slowing down facial dynamics may improve the way children with ASD attend to a face. METHODS: We used an eye tracking method to examine gaze patterns of children with ASD aged 3 to 8 (n=23) and TD controls (n=29) while viewing the face of a speaker telling a story. The story was divided into 6 sequences that were randomly displayed at 3 different speeds, i.e. a real-time speed (RT), a slow speed (S70=70% of RT speed), a very slow speed (S50=50% of RT speed). S70 and S50 were displayed thanks to software called Logiral™, aimed at slowing down visual and auditory stimuli simultaneously and without tone distortion. The visual scene was divided into four regions of interest (ROI): eyes region; mouth region; whole face region; outside the face region. The total time, number and mean duration of visual fixations on the whole visual scene and the four ROI were measured between and within the two groups. RESULTS: Compared to TD children, children with ASD spent significantly less time attending to the visual scenes and, when they looked at the scene, they spent less time scanning the speaker's face in general and her mouth in particular, and more time looking outside facial area. Within the ASD group mean duration of fixation increased on the whole scene and particularly on the mouth area, in R50 compared to RT. Children with mild autism spent more time looking at the face than the two other groups of ASD children, and spent more time attending to the face and mouth as well as longer mean duration of visual fixation on mouth and eyes, at slow speeds (S50 and/or S70) than at RT one. CONCLUSIONS: Slowing down facial dynamics enhances looking time on face, and particularly on mouth and/or eyes, in a group of 23 children with ASD and particularly in a small subgroup with mild autism. Given the crucial role of reading the eyes for emotional processing and that of lip-reading for language processing, our present result and other converging ones could pave the way for novel socio-emotional and verbal rehabilitation methods for autistic population. Further studies should investigate whether increased attention to face and particularly eyes and mouth is correlated to emotional/social and/or verbal/language improvements.


Subject(s)
Attention/physiology , Autism Spectrum Disorder , Face , Fixation, Ocular/physiology , Pursuit, Smooth/physiology , Visual Perception/physiology , Autism Spectrum Disorder/physiopathology , Autism Spectrum Disorder/psychology , Child , Child, Preschool , Female , Humans , Male , Pilot Projects , Recognition, Psychology/physiology , Time Factors
5.
J Endocrinol Invest ; 39(6): 635-42, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26694707

ABSTRACT

PURPOSE: The aims were to: (1) compare peak oxygen uptake ([Formula: see text]peak) predicted from four standard equations to actual [Formula: see text]peak measured from a cardiopulmonary exercise test (CPET) in obese patients with metabolic syndrome (MetS), and (2) develop a new equation to accurately estimate [Formula: see text]peak in obese women with MetS. METHODS: Seventy-five obese patients with MetS performed a CPET. Anthropometric data were also collected for each participant. [Formula: see text]peak was predicted from four prediction equations (from Riddle et al., Hansen et al., Wasserman et al. or Gläser et al.) and then compared with the actual [Formula: see text]peak measured during the CPET. The accuracy of the predictions was determined with the Bland-Altman method. When accuracy was low, a new prediction equation including anthropometric variables was proposed. RESULTS: [Formula: see text]peak predicted from the equation of Wasserman et al. was not significantly different from actual [Formula: see text]peak in women. Moreover, a significant correlation was found between the predicted and actual values (p < 0.001, r = 0.69). In men, no significant difference was noted between actual [Formula: see text]peak and [Formula: see text]peak predicted from the prediction equation of Gläser et al., and these two values were also correlated (p = 0.03, r = 0.44). However, the LoA95% was wide, whatever the prediction equation or gender. Regression analysis suggested a new prediction equation derived from age and height for obese women with MetS. CONCLUSIONS: The methods of Wasserman et al. and Gläser et al. are valid to predict [Formula: see text]peak in obese women and men with MetS, respectively. However, the accuracy of the predictions was low for both methods. Consequently, a new prediction equation including age and height was developed for obese women with MetS. However, new prediction equation remains to develop in obese men with MetS.


Subject(s)
Biomarkers/analysis , Metabolic Syndrome/etiology , Metabolic Syndrome/physiopathology , Obesity/complications , Oxygen Consumption , Oxygen/metabolism , Adolescent , Adult , Anthropometry , Exercise Test , Female , Humans , Male , Middle Aged , Models, Theoretical , Regression Analysis , Young Adult
6.
Neuroimage ; 114: 71-87, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25896931

ABSTRACT

This work presents a novel approach for modelling laminar myelin patterns in the human cortex in brain MR images on the basis of known cytoarchitecture. For the first time, it is possible to estimate intracortical contrast visible in quantitative ultra-high resolution MR images in specific primary and secondary cytoarchitectonic areas. The presented technique reveals different area-specific signatures which may help to study the spatial distribution of cortical T1 values and the distribution of cortical myelin in general. It may lead to a new discussion on the concordance of cyto- and myeloarchitectonic boundaries, given the absence of such concordance atlases. The modelled myelin patterns are quantitatively compared with data from human ultra-high resolution in-vivo 7T brain MR images (9 subjects). In the validation, the results are compared to one post-mortem brain sample and its ex-vivo MRI and histological data. Details of the analysis pipeline are provided. In the context of the increasing interest in advanced methods in brain segmentation and cortical architectural studies, the presented model helps to bridge the gap between the microanatomy revealed by classical histology and the macroanatomy visible in MRI.


Subject(s)
Brain Mapping/methods , Cerebral Cortex/cytology , Magnetic Resonance Imaging/methods , Myelin Sheath , Adult , Female , Humans , Image Processing, Computer-Assisted , Male , Motor Cortex/cytology , Somatosensory Cortex/cytology , Young Adult
7.
J Sports Med Phys Fitness ; 51(2): 283-91, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21681164

ABSTRACT

AIM: This study examined the effects of an exercise training program on ventilatory function at rest and the exercise cardiorespiratory pattern in relation to body composition in obese individuals (53.4±7.6 years; 158.6±6.7 cm). METHODS: After initial tests (exercise testing and anthropometric assessment), ten women participated in a 12-week training program combining strength exercise and aerobic exercise at the ventilatory threshold, three times per week for 90 minutes. RESULTS: The post-training mean ventilatory efficiency (ΔE/ΔCO(2)) and cardiac efficiency (ΔHR/ΔO(2)) were improved (P<0.05, respectively). Decreased fat mass (-1.2 kg, P<0.01), increased lean body mass (+1 kg, P<0.01), and decreased waist and hip circumferences (-5.5 cm and -5 cm, respectively, P<0.05) were also obtained after training. CONCLUSION: The program significantly improved a number of physiological variables in our obese patients, although not to sedentary healthy levels. The results show that a functional exercise program has the potential to improve physiological variables and dynamic cardiorespiratory response to exercise in obese women.


Subject(s)
Exercise/physiology , Obesity/physiopathology , Obesity/therapy , Oxygen Consumption/physiology , Pulmonary Ventilation/physiology , Body Mass Index , Female , Humans , Middle Aged , Waist Circumference/physiology
8.
Rev Mal Respir ; 38(4): 418-422, 2021 Apr.
Article in French | MEDLINE | ID: mdl-33832809

ABSTRACT

INTRODUCTION: Vocal Cord Dysfunction (VCD) is a syndrome characterized by paradoxical adduction of the vocal folds during breathing. Its non-specific clinical manifestations frequently lead to misdiagnosis and delay in its treatment. The treatment of VCD is not pharmacological but rehabilitative and remains poorly appreciated. OBSERVATION: In this clinical case we describe a 16-year-old female judoka who presented with effort intolerance associated with occasional dyspnea, which had suddenly worsened over the preceding few months so that in now produced sudden respiratory difficulty, mainly during intense and sudden efforts. After a period where her symptoms were confused with asthma, she was diagnosed with exercise-induced VCD. Her treatment was aimed to: (a) rehabilitate respiratory mechanics in order to eliminate abdominal-thoracic asynchrony, (b) rehabilitate naso-nasal breathing, (c) train her to control abdominal-diaphragmatic breathing at rest and then during effort, (d) train her to use ventilatory control as soon as prodromal symptoms appear in order to prevent the development of stridor or complete closure of the vocal folds (at rest and then progressively during exercise). CONCLUSION: Following the implementation of these rehabilitation strategies to correct her ventilatory and dyskinetic issues, the patient no longer develops respiratory discomfort during exercise, including during judo competitions.


Subject(s)
Vocal Cord Dysfunction , Adolescent , Athletes , Diagnosis, Differential , Dyspnea/diagnosis , Dyspnea/etiology , Female , Humans , Respiratory Sounds , Vocal Cord Dysfunction/diagnosis , Vocal Cords
9.
Med Phys ; 36(4): 1442-51, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19472651

ABSTRACT

In MRI, a trade-off exists between resolution and signal-to-noise ratio, since different fractions of the available scan time can be used to acquire data at higher spatial frequencies and to perform signal averaging. By comparing a wide variety of 3D isotropic MR scans with different combinations of SNR, resolution, and scan duration, the impact of this trade-off on the image information content was assessed. The information content of mouse brain, mouse whole-body, and human brain images was evaluated using a simple numerical approach, which sums the information contribution of each individual k-space data point. Results show that, with a fixed receiver bandwidth and field of view, the information content of trade-off images is always maximized when the SNR is equal to about 16. The optimal imaging resolution is dependent on the scan duration, as well as certain MR system properties, such as field strength and coil sensitivity. These properties are, however, easily accounted for with the acquisition of a single scout MR image, and the optimal imaging resolution can then be calculated using a simple mathematical relationship. If the imaging task is approached with a predetermined resolution requirement, the same scout scan can be used to calculate the scan duration that will provide the maximum possible information. Using these relationships to maximize the image information content is an excellent technique for guiding the initial selection of imaging parameters.


Subject(s)
Brain/diagnostic imaging , Brain/pathology , Imaging, Three-Dimensional/methods , Magnetic Resonance Imaging/methods , Algorithms , Animals , Brain/metabolism , Brain Mapping/methods , Contrast Media/pharmacology , Humans , Image Processing, Computer-Assisted/methods , Information Storage and Retrieval , Mice , Models, Statistical , Radiography
10.
J Gynecol Obstet Hum Reprod ; 47(1): 17-21, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29102706

ABSTRACT

OBJECTIVES: Despite its simple definition, preeclampsia can have variable and atypical clinical presentations, an unpredictable course, and potential adverse maternal and fetal outcomes. No single test currently predicts risk or prognosis adequately. Scientific advances suggest that an angiogenic imbalance is involved in its pathophysiology. The objective of this study was to investigate the use of sFlt-1, PlGF, and their ratio in predicting preeclampsia. MATERIALS AND METHODS: In a single-center prospective observational study, we measured the angiogenic markers sFlt-1 and PlGF and calculated the sFlt-1/PlGF ratio in patients at risk of preeclampsia at 20 to 37 weeks of gestation. The main outcomes were the occurrence of preeclampsia and the interval before its onset. RESULTS: Of the 67 at risk patients included, 8 (12%) developed preeclampsia. For a sFlt-1/PlGF ratio ≥85, the specificity was 93%. The ratio was significantly higher (ratio=104±30) in women with an onset time less than 5 weeks than in those with later preeclampsia (ratio=10±2), P<0.001. CONCLUSION: In a high-risk population, angiogenic markers appear to be an interesting aid in predicting the onset of preeclampsia with high specificity and in estimating time to onset. However, due to small number of cases of PE, more studies are needed before recommendations to use these markers in daily practice.


Subject(s)
Placenta Growth Factor/blood , Pre-Eclampsia/blood , Vascular Endothelial Growth Factor Receptor-1/blood , Adult , Female , Gestational Age , Humans , Pregnancy , Prognosis , Prospective Studies , Risk
11.
Rev Mal Respir ; 33(6): 422-30, 2016 Jun.
Article in French | MEDLINE | ID: mdl-26520778

ABSTRACT

INTRODUCTION: Pulmonary rehabilitation is currently the gold standard treatment for patients with chronic obstructive pulmonary disease (COPD). However, the workload achieved may be insufficient to obtain physiological benefits because of the restricted respiratory capacity. BACKGROUND: In patients with COPD, changes in flow as well as biomechanical factors (distension) compromise respiratory adaptation to exertion. Some studies have shown that noninvasive ventilation (NIV) during exercise has a positive effect on respiratory muscle workload, physiological parameters and perceived exertion. However the evidence remains insufficient regarding the effects of the NIV during comprehensive pulmonary rehabilitation programs. OBJECTIVES: The identification of criteria which determine responsive patients is necessary in order to reduce human and time costs and to optimize the use of NIV during exercise. CONCLUSIONS: NIV is used during training to overcome dyspnoea and to increase muscle workload. Further studies are needed to verify the effectiveness of NIV in pulmonary rehabilitation.


Subject(s)
Noninvasive Ventilation , Pulmonary Disease, Chronic Obstructive/rehabilitation , Exercise/physiology , Exercise Tolerance/physiology , Humans , Noninvasive Ventilation/methods , Respiratory Mechanics/physiology , Respiratory Muscles/physiopathology
12.
Rev Mal Respir ; 32(9): 913-20, 2015 Nov.
Article in French | MEDLINE | ID: mdl-25511813

ABSTRACT

AIM: There are few data showing how pulmonary rehabilitation (PR) for COPD patients carried out at home impacts on health-related quality of life (HRQL). The aim of this study was to determine if PR conducted at home improves quality of life. METHODS: We compared the results of home-based PR versus PR performed in an outpatient center. The outcomes were the HRQL measured by the Saint-George's Hospital questionnaire and the 6-minute walk test distance (6MWT). Fifty-six COPD patients were included for PR either at home (n=27) or in the outpatient center (n=29) depending on distance from the center and patients preference. The two groups were similar for sex, age, BMI, lung function, and initial peak oxygen uptake. RESULTS: 6MWT showed a similar non-significant improvement in both groups after PR (+12±46m in home-based PR,+13±34m in outpatient center). HRQL was significantly improved in the home-based group in 2 domains : "Activity" (-8.6±6.4 vs -0.7±17.7, P<0.05), "Impact" (-8.4±6.5 vs 1.6±11.7, P<0.001) and total score (-8.2±4.0 vs 0.0±8.8, P<0.001). CONCLUSION: Pulmonary rehabilitation at home is associated with improvements in health-related quality of life, and thus can be considered where availability of treatment in specialized centers is limited.


Subject(s)
Ambulatory Care Facilities , Home Care Services , Pulmonary Disease, Chronic Obstructive/rehabilitation , Aged , Ambulatory Care Facilities/statistics & numerical data , Exercise Test , Exercise Tolerance , Female , Home Care Services/statistics & numerical data , Home Care Services, Hospital-Based/statistics & numerical data , Humans , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/psychology , Quality of Life , Retrospective Studies , Surveys and Questionnaires
13.
Gene ; 119(1): 17-28, 1992 Sep 21.
Article in English | MEDLINE | ID: mdl-1398087

ABSTRACT

The sequence of a 5633-bp EcoRI-PvuII DNA fragment from Clostridium cellulolyticum was determined. This fragment contains two complete endo-beta-1,4-glucanase-encoding genes, designated celCCC and celCCG. These two genes are flanked by two other partial open reading frames (ORF1 and celCCE) that probably encode two cellulases or related enzymes. The celCCC and celCCG genes appear to be present in a polycistronic transcriptional unit. Northern blot hybridisations with intragenic probes derived from celCCC and celCCG gave similar patterns. Two transcripts of about 5 and 6 kb were identified. The celCCC and celCCG ORFs extend over 1380 bp and 2175 bp, respectively. They are separated by only 87 nt. A typical signal sequence is present at the N terminus of the deduced polypeptides. The mature CelCCC and CelCCG proteins have M(r)s 47,201 and 76,101, respectively. Comparisons between their amino acid (aa) sequences and other known cellulase sequences revealed that: first, they both contain the repeated 24-aa sequence characteristic of clostridial beta-glycanases, secondly, the N-terminal catalytic domains of CelCCC and CelCCG can be classified into the D and E2 families, respectively, and thirdly, the largest CelCCG contains an additional internal domain which is very similar to that of the Bacillus-type cellulose-binding domain (CBD). The ORF1-C-terminal-encoded sequence also contains the clostridial 24-aa repeat. The CelCCE N-terminus consists of a typical signal sequence followed by a 168-aa domain homologous to the N-terminal repeated domain of Cellulomonas fimi CenC. This domain is connected to an incomplete catalytic domain of family E1 by a Pro-rich junction linker.


Subject(s)
Cellulase/genetics , Clostridium/genetics , Genes, Bacterial , Multigene Family , Amino Acid Sequence , Base Sequence , Clostridium/enzymology , DNA, Bacterial , Gene Expression Regulation, Bacterial , Gene Expression Regulation, Enzymologic , Molecular Sequence Data , Open Reading Frames , Plasmids , RNA, Messenger/genetics , Restriction Mapping
14.
FEBS Lett ; 373(1): 39-40, 1995 Oct 02.
Article in English | MEDLINE | ID: mdl-7589429

ABSTRACT

Interleukin-1 is a cytokine involved in the acute phase response against infection and injury. We obtained crystals of a complex of soluble, recombinant human interleukin-1 receptor and recombinant human interleukin-1 receptor antagonist, a naturally occurring antagonist. The crystals are suitable for X-ray analysis and diffract to 2.7 A resolution. Solvent content calculations indicate that the crystals contain one receptor and one antagonist molecule per asymmetric unit. Other receptor to antagonist ratios are highly unlikely. These results suggest that the interleukin-1 antagonist binds a single receptor molecule and does not cause receptor aggregation.


Subject(s)
Receptors, Interleukin-1/chemistry , Sialoglycoproteins/chemistry , Base Sequence , Cloning, Molecular , Crystallization , Crystallography, X-Ray , DNA Primers , Humans , Interleukin 1 Receptor Antagonist Protein , Ligands , Molecular Sequence Data , Polymerase Chain Reaction , Receptors, Interleukin-1/isolation & purification , Receptors, Interleukin-1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Sialoglycoproteins/isolation & purification , Sialoglycoproteins/metabolism , Tumor Cells, Cultured
15.
J Med Chem ; 33(8): 2157-62, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2197412

ABSTRACT

2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid (3) (aziridino-DAP) was identified as the product of spontaneous hydrolysis of alpha-(halomethyl)diaminopimelic acids (alpha-halomethyl-DAPs) 2a-c. Under physiological conditions, 3 is an extremely potent irreversible inhibitor of the bacterial enzyme diaminopimelic acid epimerase (DAP-epimerase; EC 5.1.1.7). This unusual mode of action of an alpha-halomethyl amino acid with a non-pyridoxal enzyme is investigated. Synthesis and characterization of 2a-c and 3, kinetics of spontaneous formation of 3 from alpha-halomethyl-DAPs, and kinetics of enzyme inhibition by both 3 and by alpha-halomethyl-DAPs are reported.


Subject(s)
Amino Acid Isomerases , Amino Acids, Diamino , Aziridines/pharmacology , Diaminopimelic Acid , Isomerases/antagonists & inhibitors , Racemases and Epimerases/antagonists & inhibitors , Chemical Phenomena , Chemistry , Diaminopimelic Acid/analogs & derivatives , Escherichia coli/enzymology , Hydrolysis , Kinetics , Thermodynamics
16.
J Med Chem ; 21(1): 50-5, 1978 Jan.
Article in English | MEDLINE | ID: mdl-619149

ABSTRACT

Fourteen structural analogues of ornithine were synthesized and evaluated as inhibitors of preparations of the enzyme L-ornithine carboxylase (ODC) (E.C. 4.1.1.17) obtained from rat liver, rat hepatoma cells in culture, or bull prostate. The synthesis of these compounds was achieved either via a Bucherer type reaction or via alkylation of carbanions derived from ethyl acetamidocyanoacetate, methyl isocyanoacetate, benzyl alpha-isocyanopropionate, methylbenzaldimine alanate, and the azlactone derivative of ornithuric acid. (+)-alpha-Methylornithine, which was assigned the L configuration on the basis of rotational criteria, was found to be the most potent reversible inhibitor of ODC among the synthesized compounds. From the degree of inhibition of ODC activity in the presence of the various ornithine analogues, it has been possible to delineate some of the structural features of the substrate L-ornithine which are required for binding to the mammalian ODC active site.


Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Ornithine Decarboxylase Inhibitors , Ornithine/analogs & derivatives , Animals , Binding Sites , Cattle , In Vitro Techniques , Liver/enzymology , Male , Neoplasms, Experimental/enzymology , Ornithine/chemical synthesis , Ornithine/pharmacology , Ornithine Decarboxylase/isolation & purification , Ornithine Decarboxylase/metabolism , Prostate/enzymology , Rats , Structure-Activity Relationship
17.
J Med Chem ; 41(14): 2461-80, 1998 Jul 02.
Article in English | MEDLINE | ID: mdl-9651152

ABSTRACT

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.


Subject(s)
Drug Design , Ketones , Leukocyte Elastase/antagonists & inhibitors , Neutrophils/enzymology , Oligopeptides , Serine Proteinase Inhibitors , Administration, Oral , Animals , Azetidines/chemistry , Binding Sites , Cricetinae , Crystallography, X-Ray , Fluorocarbons/chemistry , Fluorocarbons/metabolism , Fluorocarbons/pharmacology , Hemorrhage/chemically induced , Hemorrhage/enzymology , Hemorrhage/prevention & control , Humans , Isoquinolines/chemistry , Ketones/chemical synthesis , Ketones/chemistry , Ketones/metabolism , Ketones/pharmacology , Leukocyte Elastase/metabolism , Lung Diseases/chemically induced , Lung Diseases/enzymology , Lung Diseases/prevention & control , Models, Molecular , Molecular Conformation , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Pancreatic Elastase/antagonists & inhibitors , Pancreatic Elastase/metabolism , Proline/analogs & derivatives , Proline/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Swine
18.
J Nucl Med ; 37(10): 1731-4, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8862320

ABSTRACT

UNLABELLED: The purpose of this study was to directly compare the sensitivity and specificity of SPECT and pinhole imaging for the detection of acute pyelonephritis using histology as the standard of reference. METHODS: Bilateral vesicoureteral reflux of infected urine was induced in 16 piglets (32 kidneys) by unroofing the intravesical ureter and subsequently instilling a broth culture of E. coli into the bladder. DMSA scans were obtained by both pinhole and SPECT techniques at 24 hr (4 piglets), 48 hr (5 piglets), 72 hr (4 piglets) and 10 days (3 piglets) after instillation of bacteria into the bladder. Kidneys were harvested immediately after scintigraphy for histopathologic examination. Results of the SPECT images, pinhole images and histologic findings were interpreted independently in a blinded fashion. The images of each kidney were classified as positive or negative for pyelonephritis regardless of the severity and number of lesions. To evaluate accuracy of SPECT and pinhole imaging for the detection of individual lesions, each kidney was arbitrarily divided into three zones (upper, middle and lower). Image findings were then compared with the pathology results for the presence or absence of pyelonephritis in each zone. RESULTS: Histopathology revealed pyelonephritis in 24 of 32 kidneys (58 of 96 zones). The sensitivity of the DMSA scan for detection of affected kidneys was 92% for SPECT and 83% for pinhole; overall accuracy was 88% for both. The sensitivity of SPECT for the detection of affected renal zones was slightly better than pinhole imaging (91% compared with 86%), but its specificity was lower (82% compared with 95%) resulting in a similar accuracy. Excluding four piglets where scans were obtained within 24 hr after instillation of bacteria into the bladder, the sensitivity of SPECT and pinhole for the detection of affected kidneys were 95% and 90%, respectively. Their overall accuracy were 96% and 92%. In this subgroup, the sensitivity, specificity and accuracy of SPECT for the detection of involved zones were 96%, 95% and 96%, respectively. The corresponding values for pinhole imaging were 90%, 95% and 92%, respectively. CONCLUSION: Although the sensitivity of SPECT for the detection of acute pyelonephritis is slightly better than pinhole DMSA scan, the overall accuracy of these two imaging techniques is essentially the same.


Subject(s)
Kidney Cortex/diagnostic imaging , Organotechnetium Compounds , Pyelonephritis/diagnostic imaging , Succimer , Tomography, Emission-Computed, Single-Photon , Acute Disease , Animals , Kidney/pathology , Male , Pyelonephritis/pathology , Sensitivity and Specificity , Swine
19.
Chest ; 100(1): 44-50, 1991 Jul.
Article in English | MEDLINE | ID: mdl-2060390

ABSTRACT

Clinically apparent myocardial disease is infrequent in sarcoidosis. However, autopsy data show myocardial involvement in up to 30 percent of patients. Unexplained exertional symptomatology is a common complaint in patients with sarcoidosis. In this study, we investigated whether abnormal cardiac function might limit exercise performance in patients with sarcoidosis without overt cardiac involvement. We studied exercise responses in 35 patients with sarcoidosis and compared them with 28 untrained controls. Seventy-seven percent of the patients were symptomatic. Pulmonary function test results were lower in the group with sarcoidosis than normal controls, but they were within normal range. Only one patient had evidence of ventilatory limitation to exercise. Sixteen (46 percent) patients had abnormally increased heart rates (HRs) at rest prior to exercise testing and/or with exercise. Rapid HRs were confirmed during daily activities by continuous ambulatory electrocardiographic (ECG) monitoring. Left ventricular ejection fraction (LVEF) was measured to determine if systolic dysfunction could account for abnormal HR responses. Of patients with abnormally increased HRs, five had LVEFs less than 50 percent, and eight had normal LVEFs, of whom 75 percent had tachycardia at rest. Retrospective comparison of HR responses and LVEF between patients who did or did not receive corticosteroids revealed no significant differences between groups. We conclude that abnormal HR responses in patients without evident cardiac sarcoidosis are common and exertional symptoms in this population are often associated with chronotropic abnormalities. The exact mechanisms underlying the chronotropic abnormalities are unclear, but they likely include ventricular systolic dysfunction, sinus node dysfunction from granulomatous infiltration, or combinations of the two.


Subject(s)
Heart Diseases/diagnosis , Sarcoidosis/complications , Adult , Electrocardiography , Electrocardiography, Ambulatory , Exercise Test , Female , Gated Blood-Pool Imaging , Heart Diseases/diagnostic imaging , Heart Diseases/etiology , Heart Rate , Humans , Lung/diagnostic imaging , Male , Radiography , Respiratory Mechanics , Sarcoidosis/diagnostic imaging , Sarcoidosis/physiopathology , Stroke Volume
20.
J Neurosci Methods ; 76(2): 135-41, 1997 Oct 03.
Article in English | MEDLINE | ID: mdl-9350964

ABSTRACT

Diaphragmatic strength can be measured by transdiaphragmatic pressure during phrenic nerve stimulation. In order to avoid phrenic nerve dissection, a transjugular approach of the phrenic nerve can be performed. The objective of this study was to verify the identity of perinervous and transvenous techniques of phrenic nerve stimulation to assess diaphragmatic force. In intact (n = 9) or right phrenicotomized (n = 12) rabbits, we compared esophageal pressure (Peso) induced by supramaximal perinervous stimulation of the phrenic nerve with that obtained by transvenous stimulation of the phrenic nerve. Electromyography (EMG) of the thoracic muscles was studied in four animals. We found no difference between Peso induced by perinervous (PNS) and transvenous (TVS) unilateral or bilateral phrenic nerve stimulation. During unilateral stimulation, no EMG activity was recorded in the non stimulated diaphragm, or in the middle part of the esophagus, or in ipsi- and contralateral accessory inspiratory muscles. We conclude that in rabbits, unilateral or bilateral TVS of the phrenic nerve is functionally equivalent to PNS, whatever the side of stimulation; Peso is not altered by esophageal contraction in TVS. Transvenous stimulation can replace perinervous stimulation in experimental studies, when cervical access is difficult.


Subject(s)
Diaphragm/physiology , Phrenic Nerve/physiology , Animals , Electric Stimulation , Electromyography , Muscle Contraction/physiology , Rabbits , Veins
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