Biomedical subjects
Publications and source records attributed to D Morvan.
Explore the source record for details and available documents.
N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response.
This study was designed in order to evaluate the feasibility of establishing an animal model of human uveal melanoma. IPC227, a cell line established from the biopsy of a patient with a spindle cell ciliary body melanoma, was transplanted into the anterior chamber of the eye in immunosuppressed New Zealand rabbits. In a second step, a tumour fragment from the anterior chamber was implanted transclerally into the posterior choroid. Complete ophthalmological examinations were then performed on the animals. Characteristic growth patterns were noted depending on the location of implantation. In the anterior chamber, diffuse, flat, heavily pigmented tumours appeared 8 days after the injection of the cell suspension that covered the iris and the angle by day 25, with a success rate of 100%. Nodular, lightly pigmented tumours were obtained 6-7 weeks after subchoroidal implantation, with a 25% success rate. Clinical examination, including fundus photography, ultrasound and magnetic resonance imaging, demonstrated the same characteristics as those of human uveal melanoma, confirming the value of this model for the evaluation of new therapeutic and diagnostic methods in the management of uveal melanoma.
A phase imaging technique is proposed to map out and quantify gradient nonlinearities of small-sized insertable gradient coils, assuming the whole-body system gradients are highly linear in the domain of interest. The theory is developed and simple equations are derived to allow quantification. It is applied to a 4-loop 18-cm diameter cylindrical gradient coil of optimal design. Experimental gradient nonlinearity maps are obtained for different fields of view. Gradient non-linearities are quantified locally and in regions of interest, showing close agreement with model data.
Medical imaging is now giving access not only to anatomy but also to functions of organs in the human body. Functional imaging may yield a direct appreciation of the function of a given organ, as is the case when measuring ejection fraction of heart with SPECT. Alternately the approach is indirect. This is the case of cerebral functional imaging, either with PET or NMR, where the perfusion increase induced by neuronal activity is detected. Recent developments of NMR, combining imaging and spectroscopy, allow now to detect modification of physiological parameters induced by muscular activity. Indirect detection of muscle activity is very rich in information alternately requiring invasive techniques. Water shifts resulting from intense exercise are detected either from muscle volume increase or water signal modifications, using simple NMR sequences. Then it is easy to identify which muscle is involved in a given protocol. These water shifts, studied in various muscles and several types of exercise protocols, reflect the perfusion increase induced by exercise, and the contribution of metabolic products such as lactate. In some patients with metabolic myopathies a decreased adaptation of perfusion has been detected. Perfusion measurements, previously performed by using venous occlusion plethysmography or radioactive tracers, now benefit from recently developed MR techniques. Oxygenation of muscle may be measured either by spectroscopy of myoglobin, allowing a time resolution of 1 second, or by spectroscopic imaging allowing a spatial resolution of 1-2 cm in a few minutes. Muscle temperature may be non invasively monitored by diffusion-weighted MR. Direct detection of muscle activity is useful only in those muscles that cannot be directly observed. Ultrafast MR imaging may be used to study vocal cords or oculomotor muscles. More interesting is the measurement of contractility, either in myocardium or skeletal muscle, allowed by MR with spin-tagging. Another contribution of MR to muscle studies is the possibility to quantify muscle cross section and muscle volume, in order to normalize strength or metabolism measurements. Sequences using T1 or T2 differences between muscular and adipose tissue allow to quantify the true muscular volume in patients with neuromuscular disorders. Protocols combining several of these parameters by interleaved NMR measurements of perfusion, phosphorylated metabolites, lactate, myoglobin, now open the way to many comprehensive non-invasive pathophysiological studies.
BACKGROUND: Patients with chronic heart failure (CHF) often complain of prolonged dyspnea after exercise. The determinants of oxygen consumption after exercise in these patients are unknown. We hypothesized that the kinetics of oxygen consumption recovery after graded exercise was prolonged in parallel with the recovery of muscle energy stores, was not affected by the exercise level, and could be used to assess the circulatory response to exercise. METHODS AND RESULTS: Seventy-two patients with CHF in Weber's class A (n = 28), B (n = 21), and C/D (n = 23) and 13 healthy subjects performed maximal upright bicycle exercise with breath-by-breath respiratory gas analysis. Kinetics of recovery of ventilation (VE), oxygen consumption (VO2), and CO2 production (VCO2) after exercise were characterized by T1/2, the time to reach 50% of the peak value. T1/2 VO2 (seconds) increased with the severity of CHF (97 +/- 17 for CHF A [P < .05 versus CHF B, P < .05 versus CHF C/D], 119 +/- 22 for CHF B [P < .05 versus control subjects, P < .05 versus CHF A, and P < .05 versus CHF C/D], 155 +/- 55 for CHF C/D [P < .05 versus control subjects, P < .05 versus CHF A, and P < .05 versus CHF B] compared with 77 +/- 17 for control subjects). T1/2 VCO2 and T1/2 VE also increased similarly with the worsening of CHF. T1/2 VO2 was correlated negatively with peak VO2 (r = .65) and was reproducible (r = .96). To study the relation between T1/2 VO2 and the duration of exercise, 10 healthy subjects and 22 patients underwent a second graded test at 75% and/or 50% of peak workload. T1/2 VO2 was minimally shortened, at only 50% of peak workload (P = .02). Finally, 19 patients underwent 31P nuclear magnetic resonance spectroscopy of the anterior compartment of the leg during exercise; the half-time of recovery of the ratio of inorganic phosphate to creatine phosphate (T1/2 Pi/PCr), reflecting the level of involvement of oxidative metabolism in the restoration of energetic metabolites after exercise, was linearly correlated with the half-time of VO2 recovery (r = .70, P < .01). CONCLUSIONS: Postexercise T1/2 VO2 increases when CHF worsens, perhaps in part a result of slower kinetics of recovery of muscle energy stores. The time course of oxygen consumption recovery may represent a simple new criterion for measuring the impairment of the circulatory response to exercise in CHF, even submaximal exercise.
To investigate whether diffusion-related compartmentalization could be observed in skeletal muscle and whether this compartmentalization was affected by exercising, attenuation curves of signal against diffusion weighting were obtained in skeletal muscle of nine healthy volunteers at rest and after an exercise. Fifteen points were obtained for each diffusion curve with diffusion weightings ranging between approximately 0 and 560 x 10(6) s/m2. Data were fitted a biexponential model using three parameters to yield two apparent diffusion coefficients, a long one, ADCL, and a short one, ADCS, together with the fractional volume, fL, associated with the long one. At rest, values of parameters ADCL, ADCS, and fL were 46 x 10(-9) +/- 37 x 10(-9) m2/s, 1.74 x 10(-9) +/- 0.11 x 10(-9) m2/s, and 3.6 +/- 1.3%, respectively. After exercise, these values were 89 x 10(-9) +/- 37 x 10(-9) m2/s (p < .001 vs. rest), 1.94 x 10(-9) +/- 0.13 x 10(-9) m2/s (p < .001), and 5.2 +/- 1.3% (p < .05), respectively. These variations demonstrate significant changes in attenuation curves between rest and postexercise in skeletal muscle and may support an interpretation of the long and the short components in terms of a microvascular and an extra-microvascular compartments.
The aim of this study was to compare proton T2 and apparent diffusion coefficient (ADC) variations induced by exercise in skeletal muscle, to provide some more information on the source of their variations. T2 and ADC were measured in the forearm flexor digitorum muscles in 12 healthy volunteers at rest and after an exercise, using a sequence allowing simultaneous measurements of both parameters. At rest, T2 was 30.6 +/- 1.8 ms (mean +/- 1 SD) and ADC was 1.82 +/- 0.11 x 10(-9) m2/s. With exercise, T2 varied by +2.8 +/- 12% (p < .001 vs. rest) and ADC varied by +12 +/- 3% (p < .001). The recovery of T2 after exercise was faster than that of ADC, with half-times of 7 +/- 2 min and of 15 +/- 8 min (p < .01), respectively. It is concluded that both T2 and ADC with exercise are probably different, T2 mostly reflecting changes in water content and ADC reflecting temperature variations.
The thermal dependence of the translational diffusion coefficient and of the regional blood volume was investigated in vivo by using a special MR pulsed gradient technique with reduced sensitivity to bulk tissue motion. Measurements were done at 0.5 T, using a small gradient insert. The diffusion coefficient of muscle water was calibrated against thermocouple-measured temperature in vitro, both with the muscle fibers parallel and perpendicular to the diffusion gradient. The maximum muscle temperature variation obtained by percutaneous conduction was -8.8 +/- 1.6 degrees C under cooling and +3.7 +/- 1.6 degrees C under heating, from basal state. Simultaneously the fractional regional blood volume decreased by a factor of 3.5 under cooling and increased by a factor of 2.7 under heating. Due to the interdependence of microcirculation and tissue temperature, this technique may be used to follow heat production or deposition in living tissue (muscle exercise, electromagnetic irradiation, etc.).
1. The left ventricular myocardial mass is a measurement that is easy to obtain by echocardiography. It is currently used for the definition of left ventricular hypertrophy, but cut-off values are often critical, since they depend on covariates of left ventricular myocardial mass such as sex, age, body surface area, physical training, blood pressure, etc. As it is very difficult in any laboratory to obtain a sufficient number of normal subjects for the establishment of left ventricular myocardial mass experimental distributions, we propose a non-linear model for the calculation of echocardiographic left ventricular myocardial mass distribution in normal subjects, from personal and literature data. left ventricular myocardial mass probability density function was computed from the following two assumptions: the joint distribution of the internal and external left ventricular diameters is assumed to be bivariate normal, and the relation between left ventricular myocardial mass and ventricular diameters is given by the formula of Devereux & Reicheck (Devereux, R. B. & Reicheck, N. Circulation 1977; 55, 613-8). 2. The Gaussian assumption was tested by using skewness tests. The model was further developed for the myocardial mass index distribution. The calculated probability density functions were compared with experimental data and showed very good agreement. Furthermore, they were used to define cut-off values of left ventricular hypertrophy at selected false-positive ratios. Finally, since left ventricular myocardial mass may vary under normal conditions with co-variates, the model may provide co-variate-matched cut-off values for any, even small, series of non-diseased control subjects.
Heart involvement is frequent in Friedreich's ataxia (FA), the most prevalent of the spino-cerebellar degenerative diseases, which is inherited with an autosomal recessive pattern. However, the pathophysiological link between cardiac and neurological disorders is not yet clearly established. We compared a group of 10 patients with FA to a control group (C) of 16 normal subjects, using Doppler-echocardiography. To see whether cardiac involvement was specific to FA, the data of patients with FA were also compared to those of patients with autosomal dominant olivo-ponto-cerebellar atrophia (OPCA), another spino-cerebellar degenerative disease. There was an increase in left ventricular mass index in FA (154 +/- 9 g.m-2 vs 99 +/- 7 g. m-2 in C, P < 0.001), systolic function was normal, the ejection fraction (EF) slope and E/A ratio were decreased (85 +/- 9 mm.s-1 vs 130 +/- 7 mm.s-1 in C, P < 0.001 and 1.5 +/- 0.1 vs 1.7 +/- 0.1 in C, P < 0.01, respectively), while the isovolumic relaxation period was increased (96 +/- 3 ms vs 92 +/- 2 ms in C, P < 0.01). Deceleration time and time-velocity integrals of A wave to total mitral flow were not modified. In OPCA only the E/A ratio was decreased (1.5 +/- 0.1 vs 1.7 +/- 0.1 in C, P < 0.05). These data show the presence of cardiomyopathy in FA with left ventricular hypertrophy and suggest the presence of diastolic function abnormalities. The cardiomyopathy seems specifically associated with FA and not to spino-cerebellar degenerative disease in general.
To investigate temperature increases in tissues during magnetic resonance (MR) imaging or spectroscopy, the authors measured temperature changes in vitro and in vivo (leg of a volunteer) in a condition simulating hydrogen-1 decoupling in MR spectroscopy. Noninvasive measurements were obtained by using the temperature dependence of the translational diffusion coefficient of water. Temperature was measured at 0.5 T (86 MHz) by using a stimulated-echo sequence that included intense gradient pulses and a procedure reducing sensitivity to bulk tissue motion. Calibration curves of the diffusion coefficient against thermocouple-measured temperature were obtained for a gelatin phantom and bovine muscle. Temperature changes were 5.3 degrees C +/- 0.5 at 2.5 cm from the coil in gelatin and 7.7 degrees C +/- 0.5 at 0.7 cm in bovine muscle. The temperature changed by 4.9 degrees C +/- 1.9 at 2.2 cm from the coil in the calf muscle of a volunteer. The H-1 decoupling protocol can be adapted (modifications in transmission power, duty cycle) to reduce heating effects to below safety recommendations.
Heart disease frequently occurs in advanced acromegaly. In order to investigate cardiac mass and function in acromegaly in the absence of obvious cardiac disease, we performed Doppler echocardiography in 15 asymptomatic acromegalic patients (six of them had systemic hypertension). The data were compared with those of a group of 10 age-matched controls. Left ventricular mass index (LVMI) was increased in acromegaly (110 +/- 32 vs 32 +/- 12 g m-2, P = 0.02), but shortening fraction and systolic time intervals did not differ. Mitral EF slope was decreased (80 +/- 21 vs 101 +/- 30 mms-1, P less than 0.02), while the duration of the isovolumic relaxation period (IRP) was increased (92 +/- 13 vs 69 +/- 16 ms, P less than 0.01). Hypertensive acromegalic patients (n = 6) had a higher LVMI than normotensive acromegalic patients (n = 9) (133 +/- 27 vs 94 +/- 24 g m-2, P = 0.02) and this was confirmed by a meta-analysis of data in the literature: the prevalence of hypertrophy was 76% in the presence of hypertension vs 50% in its absence, P less than 0.002. IRP was prolonged in normotensive acromegalic patients vs normal controls (90 +/- 11 vs 69 +/- 16 ms, P less than 0.01). In conclusion, subclinical cardiac abnormalities occur frequently in acromegaly in the absence of obvious heart disease, and hypertrophy is observed in asymptomatic hypertensive acromegaly. Moreover, diastolic abnormalities are found in asymptomatic acromegaly and could be caused by several heart-related factors.
Discriminant factor analysis (DFA) enables one to distinguish among diagnostic groups using diagnostic variables. It provides discriminant functions that are linear combinations of the diagnostic variables and that optimally separate diagnostic groups. It was used to enhance the accuracy of 31P NMR data in the diagnosis of myopathies. DFA allowed a good separation of normal subjects, congenital neuromuscular disorders with type I fiber predominance, and McArdle's diseases. It elicited an unexpected homogeneity of idiopathic rhabdomyolyses, the metabolic origin of which is unknown, and suggested that the abnormality could involve the mitochondrial oxidative metabolism in some of them. In mitochondrial myopathies, an expected heterogeneity is shown by DFA. It may allow an automatic diagnosis of some myopathies from 31P NMR data or guide biochemists by comparing biochemical features of a new patient to those of previously established groups.
Cardiac disease is common in acromegaly. Several mechanisms have been implicated: hypertension, coronary artery disease, valvular heart disease, endocrinopathies including "acromegalic cardiomyopathy". Fifteen consecutive patients with acromegaly, aged 48 +/- 13 years and treated for 4 +/- 5 years, underwent Doppler echocardiography. The patients had no cardiovascular symptoms: 6 had hypertension for 10 +/- 7 years and were compared with a group of 10 control subjects of the same age (48 +/- 17 years). The myocardial mass index (MMI) was higher in acromegaly (110 +/- 32 vs 82 +/- 12 g/m2, p = 0.02), left ventricular enddiastolic dimensions where comparable (48 +/- 7 vs 48 +/- 5 mm, NS) fractional shortening was slightly greater (0.37 +/- 0.04 vs 0.34 +/- 0.04, p = 0.07) as was velocity of shortening (NS) and the ratio of systolic time intervals (NS). The mitral EF slope was decreased (80 +/- 21 vs 101 +/- 30 ms; p less than 0.02); the ratio of the amplitudes of the E and A waves was a little decreased and the isovolumic relaxation phase was increased (92 +/- 13 vs 69 +/- 16 ms; p less than 0.01). Hypertensives (N = 6) had higher MMI (133 +/- 27 vs 94 +/- 24 g/m2, p = 0.02). Normotensive patients had larger isovolumic relaxation periods than control subjects (90 +/- 11 vs 69 +/- 16 ms, p less than 0.05). These results show that in the infraclinical phase, the heart in acromegaly is hypertrophied, not dilated. Hypertension plays a significant role in the development of this hypertrophy. Left ventricular systolic function is normal but diastolic function is impaired.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Muscle data from phosphorus-31 magnetic resonance (MR) spectroscopy and hydrogen-1 MR imaging and popliteal artery data from duplex Doppler ultrasound were compared during an exercise test of the anterior compartment of the leg, in nine healthy volunteers. Significant variations (mean +/- standard deviation) were observed at the end of exercise versus rest in intracellular pH (pHi) (6.32 +/- 0.02 vs 7.02 +/- 0.04, P < .001), T2 (38.2 msec +/- 2.3 vs 29.5 msec +/- 1.1, P < .001), and popliteal output (652 mL/min +/- 232 vs 149 mL/min +/- 65, P < .001). These variables showed the following significant correlations at the end of exercise: T2 and pHi (r = -.784, P < .01), T2 and popliteal output (r = .737, P < .03), and pHi and popliteal output (r = -.902, P < .001). However, during recovery, the T2 curve was significantly different from those of pHi and popliteal output. This suggests that even if circulatory conditions play a role in the maximum T2 variation during exercise, they do not directly explain T2 changes. Furthermore, the correlations involving pHi suggest the role of the metabolism of exercising muscle in transcapillary fluid movement.