[Bilateral periostitis and arthritis: about a case of hypertrophic osteoarthropathy]. / Périostite bilatérale et polyarthrite : à propos d'un cas d'ostéoarthropathie hypertrophique pneumique.

We report the case of a 67-year-old female patient presenting swelling of the hands and feet and pain in both legs. Clinical examination and bone scintigraphy identify the triad "digital clubbing - arthritis - bilateral periostitis of the long bones", leading to a diagnosis of hypertrophic osteoarthropathy, a syndrome usually associated with pulmonary neoplasia. The thoracic CT-scan, followed by a biopsy, effectively diagnosed a right upper lobe adenocarcinoma. Surgical treatment of the neoplasia allowed the resolution of the clinical complaints and the pathological scintigraphic findings.

Nous rapportons le cas d'une patiente de 67 ans présentant des gonflements des mains et des pieds ainsi que des douleurs des deux jambes. L'examen clinique et la scintigraphie osseuse identifient la triade «hippocratisme digital - arthrites - périostite bilatérale des os longs¼, permettant de poser un diagnostic d'ostéoarthropathie hypertrophique, un syndrome habituellement associé à une néoplasie pulmonaire. Le scanner thoracique, suivi d'une biopsie, ont en effet diagnostiqué un adénocarcinome localisé au niveau du lobe supérieur droit. La prise en charge chirurgicale de la néoplasie a permis la résolution des plaintes cliniques et de l'aspect scintigraphique pathologique.

Reduced brain choline in homocystinuria due to remethylation defects.

OBJECTIVE: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects. METHODS: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine. RESULTS: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed. CONCLUSION: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

Monitoring the effects of mobile phone use on the brain by proton magnetic resonance spectroscopy.

PURPOSE: To determine whether extensive use of mobile phones affects brain metabolites detectable by proton magnetic resonance spectroscopy (1H MRS). MATERIALS AND METHODS: Twenty-one extensive mobile phone users (average use = 5.5 +/- 2.2 years at 2.4 +/- 1.1 hours/day) and 15 control subjects were recruited and submitted to a 1H MRS brain examination at 1.5 Tesla. Data were recorded in the most exposed right temporal and pontobulbar areas as well as in the contralateral left temporal area. The ratios of N-acetylaspartate (NAA), choline (Cho) and myo-inositol (mI) to creatine/phosphocreatine (Cr) were measured. RESULTS: No statistically significant changes in the NAA/Cr, Cho/Cr and mI/Cr ratios were measured between mobile phone users and control subjects and between the exposed and contralateral temporal areas. CONCLUSION: These results indicate that extensive exposition to mobile phone radiation does not cause MRS-detectable brain metabolic changes.

Influence of post-treatment delay on the evaluation of the response to focused ultrasound surgery of breast cancer by dynamic contrast enhanced MRI.

The assessment of the effectiveness of MRI-guided focused ultrasound surgery (MRIgFUS) of breast carcinomas can be performed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters which monitor the presence of residual tumour. The aim of this study was to evaluate the effect of the post-treatment delay on this assessment. DCE-MRI data were acquired immediately and 3-14 days after MRIgFUS treatment of 26 tumours (<7 days, n = 6; = or > ge;7 days, n = 20). The percentage of residual tumour was determined histologically on the resected mass and correlated with two DCE-MRI parameters: increase in signal intensity (ISI) and positive enhancement integral (PEI). No correlation could be found between DCE-MRI data acquired immediately after treatment and the percentage of residual tumour. Good correlation coefficients were found for data acquired several days after treatment (ISI, r = 0.749; PEI, r = 0.778). However, they were higher when the post-treatment time interval was 7 days or more (ISI, r = 0.962; PEI, r = 0.934). These results suggest that a post-treatment delay of 7 days is necessary for the accurate assessment of the presence of residual tumour by DCE-MRI parameters.

Brain metabolic differences as a function of hemisphere, writing hand preference, and gender.

A total of 35 university-educated normal men (24 right handwriters and 11 left handwriters) and 36 age- and education-matched women (25 right handwriters and 11 left handwriters) underwent a proton magnetic resonance spectroscopy examination in seven 8 cm(3) voxels including the right and left frontal lobe tips, the right and left mid-temporal lobes, the right and left thalami, and the hypothalamus. Dependent measures were N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine/phosphocreatine (Cr) metabolite peak area ratios relative to total H(2)O. As expected, thalamic grey matter contained higher NAA ratios than telencephalic voxels (containing white and grey matter) (p < .001). The thalamic Cr/ H(2)O ratio was higher on the right, but the opposite asymmetry was observed for the temporal lobe (p < .05). Women had a higher left frontal NAA/ H(2)O ratio than men, but men had a higher hypothalamic NAA/ H(2)O ratio than women. Right-handers had a higher temporal lobe NAA/H(2)O ratio than left-handers, particularly in the left hemisphere. In addition, several significant 2- and 3-way interactions between writing hand preference, gender, and hemisphere were observed, but only in the frontal lobe.

Long-term brain metabolic alterations in exogenous Cushing's syndrome as monitored by proton magnetic resonance spectroscopy.

The effects of exogenous Cushing's syndrome on the brain metabolism were investigated by proton magnetic resonance spectroscopy (MRS). Thirteen patients having been treated for 2 to 22 years with prednisone were recruited. On the average, none of the metabolites (NAA, Cr, Cho and mI) were significantly different from those of 40 normal subjects in any of the three regions studied: frontal area, thalamus and temporal area. However, the Cho/H(2)O ratios were found to decrease significantly in the thalamic area as a function of treatment period (-1.3%/year). In the frontal and temporal areas, decreases of the Cho/H(2)O ratios were measured with treatment period but they did not reach statistical significance. Effects on Cho levels can be related to those observed for patients with endogenous Cushing's syndrome and suggest an impairment at the membrane level. The Cho/H(2)O reductions were not found to be dose- or age-dependent. Other metabolite ratios did not vary with treatment period, dose or age.

Comparison of metabolite levels and water diffusion between cortical and subcortical strokes as monitored by MRI and MRS.

UNLABELLED: Labelle M, Khiat A, Durocher A, et al. Comparison of metabolite levels and water diffusion between cortical and subcortical strokes as monitored by MRI and MRS. Invest Radiol 2001;36:155-163. RATIONALE AND OBJECTIVES: Proton magnetic resonance spectroscopy (MRS) and functional imaging techniques are increasingly recognized as useful tools for the characterization of strokes. The aim of this study was to compare cortical and subcortical (lacunar) strokes by MRS and diffusion-weighted imaging (DWI) experiments as a function of time. METHODS: Single-voxel MRS, DWI, and perfusion-weighted imaging data were recorded on patients with cortical (n = 7) or subcortical (n = 7) strokes in the acute, subacute, and chronic periods. Magnetic resonance spectra were acquired in three regions: hyperintense DWI area, adjacent area with normal DWI intensity, and contralateral area. Neurological deficits were estimated by the National Institutes of Health Stroke Scale. RESULTS: Decreases in N-acetylaspartate, choline-containing compounds, and creatine/phosphocreatine signal intensity as well as the presence of lactate were observed at all times in the hyperintense DWI area of all lesions. Small decreases were measured in the subacute and chronic phases for the adjacent area of cortical strokes but not for the adjacent area of subcortical strokes. The existence of a surrounding affected area in subcortical strokes is deduced from a combination of MRS and DWI results, possibly corresponding to the ischemic penumbra. Differences were found between the two types of lesion, especially an increased time variability of apparent diffusion coefficients in subcortical strokes. CONCLUSIONS: Magnetic resonance spectroscopy provides evidence for the existence of affected tissue outside the hyperintense DWI regions in subcortical strokes. Cortical and subcortical strokes display different DWI and MRS characteristics.

Conformational analysis of endothelin-1 analogs with indolizidinone amino acids incorporated at the C-terminus.

In light of the fact that a beta-turn conformation at the C-terminus of endothelin-1 (ET-1) could be responsible for activity at the ET(B) receptor, the incorporation of (3S, 6S, 9S)-2-oxo-3-amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (IAA) should provide an elegant method to establish whether a formyl group on Trp21 plays a role in stabilizing a beta-turn. Eight linear ET-1 analogs, four formylated and four nonformylated, ET-1-(Leu17-Asp18-IAA-Trp21); ET-1-(Leu17-IAA-Ile20-Trp21); ET-1-(Leu17-Asp18-Pro19-Ile20-Trp21) and ET-1-(Leu17-Asp 8-Ile19-Pro20-Trp21) have been analyzed by high-resolution nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. Two-dimensional double quantum filtered correlation spectroscopy (DQFCOSY), total correlation spectroscopy (TOCSY) and nuclear Overhausen enhancement spectroscopy (NOESY) were resolved and analyzed for each molecule. Interspatial distance constraints were derived from the intensity of the NOESY connectivities, The formation of hydrogen bonding was monitored from the temperature-dependence of the NH chemical shifts. Molecular models calculated by means of distance geometry, simulated annealing and energy minimization, suggested a global elongated structure for the formylated analogs and a folded arrangement for the nonformylated derivatives, but no hydrogen bonding was detected at the C-terminus of ET-1 analogs.

Role of phospholipase A(2) on the variations of the choline signal intensity observed by 1H magnetic resonance spectroscopy in brain diseases.

Phospholipase A(2) catalyzes the hydrolysis of membrane glycerophospholipids leading to the production of metabolites observable by both 1H and 31P magnetic resonance spectroscopy. The signal of choline-containing compounds (Cho) observed by 1H magnetic resonance spectroscopy is constituted of metabolites of phosphatidylcholine, especially phosphocholine (PCho) and glycerophosphocholine (GPCho). The phosphomonoester (PME) and phosphodiester (PDE) signals observed by 31P magnetic resonance spectroscopy are, respectively, precursors and catabolites of phospholipids. A large number of brain diseases have been reported to cause variations in the intensity of the Cho, PME and PDE signals. Changes in the activity of phospholipase A(2) have been measured in many brain diseases. In this review, the relationships between the results of 1H and 31P magnetic resonance spectroscopy and the phospholipase A(2) assays are analyzed. In many brain diseases, the variation in the Cho signal intensity can be correlated with a stimulation or inhibition of the phospholipase A(2) activity.

Recovery of the brain choline level in treated Cushing's patients as monitored by proton magnetic resonance spectroscopy.

In a previous study from our group [A. Khiat, C. Bard, A. Lacroix, J. Rousseau, Y. Boulanger, Brain metabolic alterations in Cushing's syndrome as monitored by proton magnetic resonance spectroscopy, NMR Biomed. 12 (1999) 357-363], proton magnetic resonance spectroscopy (1H MRS) was used to evaluate changes in cerebral metabolites in patients with Cushing's syndrome as compared to normal subjects. Data recorded in the frontal, thalamic and temporal areas demonstrated statistically significant decreases of the Cho/Cr ratios in the frontal and thalamic areas but not in the temporal area for Cushing's syndrome patients. No statistically significant changes in the NAA/Cr ratios were measured in any of the areas studied. In this follow-up study, MRS data are reported for ten patients after correction of hypercortisolism which demonstrate a statistically significant recovery of the choline levels in the frontal and thalamic areas. No variation in the NAA, Cr and mI metabolite ratios relative to H(2)O could be measured. Results are interpreted as an inhibition of the phosphatidylcholine degrading phospholipases by glucocorticoids which disappears after correction of hypercortisolism.

Brain metabolic alterations in Cushing's syndrome as monitored by proton magnetic resonance spectroscopy.

Proton magnetic resonance spectroscopy ((1)H MRS) was used to evaluate changes in cerebral metabolites in 13 patients with Cushing's syndrome (including seven with pituitary corticotroph adenomas and six with primary adrenal disease) as compared to 40 normal subjects. Data were recorded in the frontal, thalamic and temporal areas; quantification of the MRS signals demonstrated a statistically significant decrease of the Cho/Cr ratio in the frontal and thalamic areas but not in the temporal area for patients with Cushing's syndrome. The largest decrease in Cho/Cr was measured in the thalamic area of patients with a Cushing's syndrome secondary to an adrenal disease. No statistically significant changes in the NAA/Cr ratio were measured in any of the areas studied. These results suggest that the quantification of choline levels could be helpful for monitoring the cerebral metabolite alterations in patients with hypercortisolism.

Conformational analysis of biologically active truncated linear analogs of endothelin-1 using NMR and molecular modeling.

Some linear truncated analogs of endothelin-1 display potent agonistic activity at the ET(B) receptor, especially when the side chain of Trp21 is N-formylated. Then, the three-dimensional arrangements of six structurally reduced linear analogs, three formylated and three nonformylated, have been investigated by high resolution NMR spectroscopy and molecular modeling, in order to pinpoint the conformational features related to the biological activity. Two-dimensional double-quantum-filtered correlation spectroscopy (DQFCOSY), total correlation spectroscopy (TOCSY) and nuclear Overhauser enhancement spectroscopy (NOESY) were recorded and analyzed for each molecule. Interspatial distance constraints were derived from the intensity of the NOESY connectivities. The formation of hydrogen bonding was monitored from the temperature dependence of the NH chemical shifts. Molecular models calculated by means of distance geometry, simulated annealing and energy minimization, using the NMR constraints, strongly suggested a global elongated structure for the formylated analogs exhibiting biological activity, and a folded arrangement for the unformylated derivatives. Homology comparisons allowed the identification of a beta-turn-like folding of the C-terminal segment Asp18-Trp21 as a probable key-factor for activity.

Identification of the motilide pharmacophores using quantitative structure activity relationships.

Erythromycin A and some derivatives have been shown to act as agonists at the motilin receptor site (motilides) and a structural similarity between these molecules and the N-terminal fragment of motilin has been proposed. Conformational analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been used to determine the homology between a series of erythromycin A derivatives and motilin 1-10. A total of 18 compounds has been studied to correlate the gastrointestinal motor stimulating (GMS) activity with the structure-related parameters determined by 3D-QSAR. Two models with good predictive power of the GMS activity are presented, leading to the prediction of motilin 1-10 activity. The models are consistent with the majority of the data available. The most significant parameters for GMS activity are a favorable dispersion interaction from the quaternary ammonium group of the desosamine ring. In motilin 1-10, the aromatic side chains of Phe1 and Tyr7 seem to play the same role as the quaternary ammonium group in models 1 and 2, respectively. Some hydroxyl groups of erythromycin A derivatives and hydrophobic groups of the Val2 and lle4 side chains of motilin also contribute to the GMS activity. The experimental GMS activities measured are in good agreement with the predicted values, with correlation coefficient values of 0.98 and 0.94 in models 1 and 2, respectively.

Three-dimensional structure of the Y1 receptor agonist [Leu31, Pro34]NPY as determined by NMR and molecular modeling.

The solution structure of the Y1 receptor agonist, porcine [Leu31, Pro34]NPY, has been investigated by two-dimensional NMR and molecular modeling. A complete assignment of the NMR resonances was achieved and 201 inter-residue nuclear Overhauser enhancement spectroscopy (NOESY) connectivities could be identified, comprising several connectivities between the N- and C-terminal segments. A molecular model was calculated by distance geometry, simulated annealing and conjugate gradients energy minimization using the NOE constraints. The results indicate that, like NPY and other peptides of the family, [Leu31, Pro34]NPY adopts a folded hairpin structure with the terminal segments in close proximity. Analysis of the secondary chemical shifts for the CH(alpha)'s and of the temperature dependence of the NH chemical shifts combined with the NOE constraints indicates a tendency toward helix structure for the segment 18-30 and the presence of turn structure for the C-terminal segment (residues 31-36). Native NPY and [Leu31, Pro34]NPY have most of their structures in common but differ slightly in their C-terminal portion. Based on the structures of NPY and of its specific agonists, [Leu31, Pro34]NPY and NPY 13-36, conclusions can be drawn about the structural requirements for binding to the Y1 and Y2 receptor subtypes.

Solution structure of neuropeptide tyrosine 13-36, a Y2 receptor agonist, as determined by NMR.

The three-dimensional structure of neuropeptide tyrosine (NPY) 13-36, a specific Y2 receptor agonist, has been investigated by two-dimensional 1H-NMR spectroscopy in solution. Analysis of the double-quantum-filtered correlation spectroscopy (DQFCOSY), total correlation spectroscopy (TOCSY) and nuclear Overhauser enhancement spectroscopy (NOESY) spectra provided a complete assignment of the proton signals. The interproton connectivities observed in the NOESY spectra comprised 166 intraresidue and 95 interresidue distance ranges which were used as constraints for molecular modeling by distance geometry, simulated annealing and energy minimization. The optimal structures are characterized by a helical C-terminal fragment Leu30-Tyr36 and a wide loop from Leu17 to Ser22. The structure of NPY 13-36 is analogous to the structure of NPY under the same solvent conditions. Comparison with other reported Y2 agonists suggests that the helical Leu30-Tyr36 fragment is the most critical for activity.

Solution structure of the HIV protease inhibitor acetyl-pepstatin as determined by NMR and molecular modeling.

The structure of acetyl-pepstatin has been investigated in solution by two-dimensional NMR spectroscopy and molecular modeling. The analysis of DQFCOSY, TOCSY and NOESY spectra lead to a full assignment of the -NMR signals both in DMSO-d6 and in TFE-d3:H2O 1:1. Interproton distances, dihedral angles and exchanger regimes of NH or OH protons were derived from ROESY connectivities, coupling constants and temperature dependences of the chemical shifts, respectively. Molecular modeling using the NMR distance and dihedral angle constraints obtained in DMSO-d6 yielded a model showing a well-defined structure for the N-terminal segment Ac-1 to Sta-4, but a flexible structure for the C-terminal segment. The structure was less defined in TFE-d3:H2O 1:1 and 13C T1 measurements are indicative of higher mobility. Comparison of the NMR-determined solution structure of acetyl-pepstatin with its crystal structure when bound to HIV-1 protease shows that the conformation is more extended in the complex as a result of intermolecular interactions.

Tissue-specific regulation of fat cell lipolysis by NPY in 6-OHDA-treated rats.

The effects of neuropeptide Y (NPY), peptide YY (PYY), [Leu31, Pro34]NPY, and NPY (13-36) on adipocyte lipolysis have been studied in subcutaneous (inguinal) and visceral (parametrial) rat adipose tissues. A 48-h fasting period and chemical sympathectomy were used to evaluate the regulation of Y1 and Y2 pathways in rat adipocytes. NPY, PYY, and [Leu31, Pro34]NPY significantly inhibited fat cell lipolysis by about 25% in both tissues (p < or = 0.05). This inhibition was achieved mainly through the Y1 pathway. No significant response to NPY (13-36) was observed, suggesting a lack of involvement of the Y2 pathway in the antilipolytic effect of NPY and PYY. The 48-h fasting period led to the loss of the Y1 inhibitory effect previously observed in control rats. On the other hand, the chemical sympathectomy induced a 35% increase of fat cell lipolysis (p < or = 0.05). The latter involved the Y2 pathway as stimulated by NPY (13-36), and was observed in the parametrial tissue exclusively. These results suggest that: a) rat Y receptors reported to exhibit Gi responses can also express Gs-like responses, and b) visceral and subcutaneous adipose tissues exhibit specific regulation of fat cell lipolysis.

Post-stroke inpatient rehabilitation. I. Predicting length of stay.

This study was undertaken to identify factors predicting stroke inpatient rehabilitation length of stay in an acute inpatient rehabilitation program, including occupational therapy, physical therapy, and speech therapy. A cohort of 152 patients suffering from stroke (76 women and 76 men) voluntarily participated in this study. They were recruited from a general hospital in which they had received physical rehabilitation. The functional status of patients was observed by a physiotherapist, using the Functional Independence Measure(SM). The functional status was observed on patient admission to rehabilitation and at 1 wk from admission. Post-stroke biologic characteristics, including physical, neuropsychological, and clinical characteristics, as well as sociodemographic characteristics were also collected. A path analysis, using successive multiple linear regressions, was adopted to predict length of stay in rehabilitation. Significant predictors of length of stay were age, functional status at 1 wk post-rehabilitation admission, perceptual status, and balance status. These predictors accounted for 43.6% of the total variance in the rehabilitation length of stay. Indirect predictors of length of stay were identified as the following: functional status at admission, rehabilitation program, motor status, communication problems, and medical complications. Functional, biologic, and sociodemographic characteristics should be considered simultaneously in the prediction of length of stay as well as for the better understanding of the stroke rehabilitation process.