Identification of subgroups among fibromyalgia patients.

This paper presents some hypotheses concerning the identification of homogeneous subgroups among fibromyalgia (FM) patients in order to improve the management of the disease. It also reviews the available literature about this subject. Three methods for subgrouping are discussed according to clinical features, biomarkers, and gait analysis. Clinical subgrouping based on cluster analysis has been used for the identification of homogeneous subgroups of patients and, more recently, homogeneous clinical features. So far, longitudinal studies using clinical subgroups to direct treatment and predict outcome are still required. Biomarkers in FM, which is a neurobiological disease, are of promising interest, nevertheless currently, none of them can be used to subgroup FM patients. Due to the fact that cortical and subcortical mechanisms of gait control share some cognitive functions which are involved in FM, gait markers have been proposed to evaluate and to subgroup FM patients, in clinical settings. Three out of 4 core FM symptoms are linked to gait markers. Kinesia measured by means of cranio-caudal power is correlated to pain, and could be proposed to assess pain behavior (kinesiophobia). Stride frequency, which is linked to physical component, allows the identification of a hyperkinetic subgroup. Moreover, SF has been correlated to fatigue during the 6 minute walking test. Stride regularity, which expresses the unsteadiness of gait, is correlated to cognitive dysfunction in FM. Decreased stride regularity allows the recognition of a homogeneous subgroup characterized by an increased anxiety and depression, and decreased cognitive functions. These results need further studies to be validated and so used in the daily clinical practice.

Effect of fatigue on stride pattern continuously measured by an accelerometric gait recorder in middle distance runners.

AIM: The purpose of this study was to analyze the continuous changes in stride patterns of athletes running at speed elicited VO(2max). METHODS: Six male sub-elite middle-distance runners carried out a constant track running test to exhaustion (time to exhaustion: 409+/-71 s) at their maximal aerobic speed (17.4+/-1.1 km.h(-1)). The body accelerations were measured with a triaxial accelerometer fixed at the low back. A set of variables was computed from the accelerometer output: stride frequency, stride symmetry and regularity, signal energies and impulses in each axis and the integral of the total acceleration vector. An ANOVA with repeated measures was performed to test the changes of these variables during the three times: the onset point, midway point and end point of exercise. RESULTS: The following changes were observed: the regularity index which describes the similarity of crania-caudal movements over successive strides, decreased significantly between the start and the end of the test (309.9 to 274.5; P<0.05). During the same time, the media-lateral impulse (4.69%BW.s to 5.71%BW.s; P<0.001; BW: body weight) and signal energy (1.40 G(2).s to 2.06 G(2).s; P<0.001; G=9.81 m.s(-2)) increased significantly. CONCLUSIONS: The changes in medio-lateral axis (increase of energy expenditure which is not useful for propulsion) and in the regularity index (modifications in the temporal-spatial periodicity of the running cycle) could be considered as early alterations of running pattern when the athletes got fatigued.

[Analysis of gait disorders in Parkinson's disease assessed with an accelerometer]. / Analyse des troubles de la marche par une méthode accélérométrique dans la maladie de Parkinson.

The objective of this study was to analyse stabilized gait disorders in newly diagnozed Parkinson patients using an accelerometric device, which had been previously validated for human locomotion analysis (Auvinet et al., 1999), and to compare Parkinson's gait variables with those obtained in a matched normal population (same gender, age, height and weight). The patient group included 22 subjects (women: 9, men: 13; age: 69+/-9 y; height: 164+/-9 cm; weight: 71+/-15 kg) with motor score from 4 to 59 (mean: 23.5+/-3.0). Gait analysis system included two accelerometers held over the middle of the low back by means of a semi-elastic belt, cranio-caudal and side to side accelerations were recorded at a frequency of 50 Hz. Subjects were asked to walk at their own speed along a straight 40 meter long corridor. A 20 second period of stabilized walking was used to calculate stride frequency, step symmetry, stride regularity and cranio-caudal activity (related to hypokinesia). The walking speed was measured with an electronic stop watch. Parkinson's gait was characterized by a reduction of walking velocity (p<0.0001) which was explained by reduction of stride frequency (p<0.001) and step length (p<0.001), but mainly we noticed a reduction of walking regularity (p<0.0001) and of the cranio-caudal activity (p<0.0001). These two last variables were strongly correlated to the motor score ((r=-0.59 (p<0.01); r=-0.65 (p<0.003), respectively)). In conclusion regularity and cranio-caudal activity appeared as the most interesting variables to characterize stabilized Parkinson's gait.

Echocardiographic assessment of the interventricular delay of activation and correlation to the QRS width in dilated cardiomyopathy.

The aim of the study was to define criteria for left ventricular pacing in dilated cardiomyopathy (DCM) using an echocardiographic evaluation of interventricular electromechanical delay (IMD) and a correlation of IMD to QRS duration. Standard 12-lead ECG and echocardiography with pulsed Doppler tissue imaging (DTI) were recorded in 35 DCM patients (mean age 58 +/- 11 years) with QRS duration from narrow (80 ms) to broad (222 ms) patterns. The timefor left ventricular activation was evaluated from the onset of QRS to the onset of aortic flow (Q-Ao) by standard pulsed Doppler (SP) or to the onset of mitral annulus systolic wave (Q-Mit) (DTI). The time for right ventricular activation was determinedfrom the onset of QRS to the onset of pulmonary flow (Q-Pulm) (SP) or to the onset of tricuspid annulus systolic wave (Q-Tri) (DTI). (Q-Ao)-(Q-Pulm) and (Q-Mit)-(Q-Tri) determined IMD for each method, respectively. QRS width and IMD showed correlation coefficients of r = 0.86 ([Q-Ao]-[Q-Pulm]) and r = 0.82 ([Q-Mit]-[Q-Tri]) (P < or = 0.001 ). Mean IMD of 77 +/- 15 ms (SP) and 88 +/- 26 ms (DTI) were noted for QRS width above 150 ms. Left ventricle delayed activation was positively correlated to QRS widening with both methods, (r = 0.90, [Q-Ao]), (r = 0.83, [Q-Mit]) (P < or = 0.001). In conclusion, QRS duration is a good marker of an interventricular mechanical asynchrony. According to IMD correction, left ventricular pacing may be mainly proposed to symptomatic DCM patients with QRS duration > 150 ms.

[Phase II trial evaluating the effect of megestrol acetate-prednisolone combination in the treatment of anorexia during the palliative-care phase of lung cancer]. / Essai de phase II évaluant l'effet d'une association acétate de mégestrol et prednisolone dans le traitement de l'anorexie au cours du cancer bronchique en phase palliative.

OBJECTIVES: Anorexia is one of the most frequent complaints in patients who have reached the palliative-care phase of lung cancer. Megestrol acetate (or medroxyprogesterone acetate) and corticosteroids have been used with success, but the effect of their combination remains unknown. We conducted a phase II trial to assess the impact of combination therapy. PATIENTS AND METHODS: Patients with lung cancer given palliative care and who developed anorexia with or without weight loss were given 320 mg/d megestrol acetate in 2 doses and 40 mg/d prednisolone in one dose in the morning for 1 month. The principal outcome criterion was anorexia assessed on a visual analog scale prior to treatment and then at day 15 and day 30. Variation in daily calorie intake and weight were also recorded. We used an Armitage sequential plan to determine the number of inclusions necessary and the preference method (closed schema) to evaluate the principal outcome criterion. RESULTS: Inclusions were stopped after the eighth patient (giving p<0.05) as we observed a significant improvement in patient appetite. Daily calorie intake improved significantly (p<0.0001), by 39.18% the first 15 days and 16.57% more the next 15 days. Body weight improved significantly by 5.4% in one month (p=0.5). No treatment-related complication occurred during the study period or during the six consecutive months. CONCLUSIONS: The megestrol acetate-prednisolone combination was found to improve anorexia in patients with lung cancer in the palliative-care phase and allowed a significant improvement in calorie intake and body weight.

Accelerometric gait analysis for use in hospital outpatients.

OBJECTIVES: To provide clinicians with a quantitative human gait analysis tool suitable for routine use. METHODS: We evaluated the reproducibility, sensitivity, and specificity of gait analysis based on measurements of acceleration at a point near the center of gravity of the body. Two accelerometers held over the middle of the low back by a semi-elastic belt were used to record craniocaudal and side-to-side accelerations at a frequency of 50 Hz. Subjects were asked to walk at their normal speed to the end of a straight 40 meter-long hospital corridor and back. A 20-second period of stabilized walking was used to calculate cycle frequency, stride symmetry, and stride regularity. Symmetry and regularity were each derived from an auto-correlation coefficient; to convert their distribution from nonnormal to normal, Fisher's Z transformation was applied to the auto-coefficients for these two variables. Intraobserver reproducibility was evaluated by asking the same observer to test 16 controls on three separate occasions at two-day intervals and interobserver reproducibility by asking four different observers to each test four controls (Latin square). Specificity and sensitivity were determined by testing 139 controls and 63 patients. The 139 controls (70 women and 69 men) were divided into five age groups (third through seventh decades of life). The 63 patients had a noninflammatory musculoskeletal condition predominating on one side. ROC curves were used to determine the best cutoffs for separating normal from abnormal values. RESULTS: Neither intra- nor interobserver variability was significant (P > 0.05). Cycle frequency was significantly higher in female than in male controls (1.05 +/- 0.06 versus 0.98 +/- 0.05 cycles/s; P < 0.001). Neither symmetry nor regularity were influenced by gender in the controls; both variables were also unaffected by age, although nonsignificant decreases were found in the 61 to 70-year age group, which included only nine subjects. In the ROC curve analysis, the area under the curve was high for all three variables (frequency, 0.81 +/- 0.04; symmetry, 0.85 +/- 0.03; and regularity, 0.88 +/- 0.03), establishing that there was a good compromise between sensitivity and specificity. CONCLUSION: Our gait analysis method offers satisfactory reproducibility and is sufficiently sensitive and specific to be used by clinicians in the quantitative evaluation of gait abnormalities.

[Importance of urinary methylhistamine measurements during allergy provocation tests]. / Intérêt du dosage de la méthylhistamine urinaire au cours des tests de provocation en allergie.

Methylhistamine, histamine's metabolite, was measured in urine by radio-immuno-assay in 79 provocation test. Six of them were positive with clinical symptoms. All of the six were associated with a significant increase of urinary methylhistamine (UMH). Therefore, there is a good correlation between positive provocation tests and increase of UMH level. In these cases, the severity of clinical symptoms is related to the increase of U.M.H.

Effects of some chelating agents on bismuth absorption in the rat.

Bismuth encephalopathies appeared in the mid-seventies in France and concerned about 1,000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/l. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years ago.

The distribution of elements in the tissues of Watanabe Heritable Hyperlipidemic Rabbits.

A deficiency or an excess of some elements in the diet is reported to modify the concentration of cholesterol in plasma, and, conversely, a reduction of cholesterol in the diet decreases zinc in plasma. We have studied the distribution of elements Na, K, Ca, Mg, Fe, Cu, Zn, S, P, and Mn in the tissues, plasma, heart, aorta, lung, liver, spleen, kidney, thymus, and brain of New Zealand White rabbits (NZW) and of Watanabe Heritable Hyperlipidemic rabbits (WHHL). The WHHL rabbits had a massive hypercholesterolemia (7.45 +/- 1.2 g/L) induced by a lack of liver low density lipoprotein receptors. The concentrations of elements in the tissues of the control NZW rabbits were very similar to those found in the normal rat. In WHHL, compared to NZW, besides the very important increase of total phosphorus in plasma explained by the augmentation of phospholipids, there was an increase of plasma copper (+44%) and zinc (+36%). The other noticeable changes were an increase of iron in heart (+19%), sulfur, and zinc in liver (+15% and +18%). The other changes observed in WHHL rabbits were, besides the increase of ceruloplasmin, the increase of vit E (+468%) and MDA (+62%). In conclusion, despite a massive increase of lipids in plasma, there was no major disturbance of element distribution in WHHL rabbits.

Pharmacokinetics of desferrioxamine and of its iron and aluminum chelates in patients on peritoneal dialysis.

We have studied the pharmacokinetics of desferrioxamine (DFA), ferrioxamine (FeA) and aluminoxamine (AlA) in patients with chronic renal failure on continuous ambulatory peritoneal dialysis (CAPD) after 10 mg/kg (15.24 mumol/kg) body weight desferrioxamine (DESFERAL) administration by intramuscular and intraperitoneal routes. The results show an easy exchange of DFA between the plasma and the peritoneal fluid regulated by the relative concentrations of DFA in the two compartments. When the equilibrium is reached, the concentration of DFA are approximately the same in the plasma and the peritoneal fluid.

Pharmacokinetics of desferrioxamine and of its iron and aluminium chelates in patients on haemodialysis.

We have used a new analytical micromethod to study the pharmacokinetics of desferrioxamine and its aluminium chelates in patients with chronic renal failure on haemodialysis. Desferrioxamine (Desferal, CIBA, Basle) was given by 1-h infusion just after the haemodialysis at 20, 40, 80 mg/kg body wt. and during the first and the last hour of the haemodialysis at 40 mg/kg. The concentrations of desferrioxamine during infusions showed a linear increase with increasing doses. The maximum concentrations and the AUC obtained when desferrioxamine was infused during the haemodialysis were not statistically different but slightly lower than those obtained in post dialysis administration. This result indicates that the loss of desferrioxamine by transfer in the dialysate is quite moderate within 1 h. During the interdialysis period, there was a decrease of plasma desferrioxamine concentrations with a mean half-life of 18.7 +/- 5.2 h and an increase in plasma concentrations of aluminium desferrioxamine chelate. In vitro studies show that a lengthy contact between desferrioxamine and plasma is necessary for complete chelation of A1 already present in plasma. During the following dialysis session, there was an important decrease of desferrioxamine and of its iron and aluminium chelates in blood plasma representing their transfer to the dialysis fluid.

Pharmacokinetics and renal elimination of desferrioxamine and ferrioxamine in healthy subjects and patients with haemochromatosis.

1 Desferrioxamine mesylate (DM) (10 mg kg-1 = 15.24 mumol kg-1) was given by intramuscular injection to five healthy subjects and to six patients with haemochromatosis, after informed consent. 2 Desferrioxamine (DFA), ferrioxamine (FeA), aluminoxamine (AlA), aluminium (Al) and iron (Fe) were measured in plasma, before and 10, 20, 30, 60 min and 2, 4, 6, 8, 12 h after DM injection and in urine collected over a 6 h period the day before and the day of administration. 3 The predominant form in plasma from control subjects was DFA whereas FeA predominated in plasma from patients. In controls, rapid and slow phases of decline in plasma DFA concentrations were found, with half-lives of 1.0 h and 6.1 h, respectively. In the patients, only a single phase of decline was observed, with a half-life of 5.6 h. Total clearances of DFA were 296 ml h-1 kg-1 in controls and 239 ml h-1 kg-1 in patients. 4 The amount of FeA eliminated in urine during 6 h was significantly lower in controls (8.0 +/- 4.6 mumol) than in patients (129.2 +/- 40.0 mumol), with respective renal clearances estimated over 6 h of 516 ml h-1 kg-1 and 1,716 ml h-1 kg-1. DFA elimination was similar in both groups and its renal clearance estimated over 6 h was 91 ml h-1 kg-1 in controls and 85 ml h-1 kg-1 in patients. 5 Since there was no overlap in the 1 h DFA/FeA plasma ratio between controls and patients, this might be useful as an index of iron overload.

Blood plasma fluoride in haemodialysed patients.

Blood plasma fluoride was determined in 15 chronic haemodialysed patients (60.2 +/- 7.2 yr old) before and after a 4-h dialysis using dialysates with very low fluoride level, and in two control groups, the first of 20 healthy younger subjects (45.9 +/- 3.4 yr old), the second of 8 healthy older subjects (69.1 +/- 6.8 y old). Before haemodialysis the fluoride concentration (1.31 +/- 0.31 mumol/l; 24.8 +/- 5.9 micrograms/l), was higher than in both control groups (0.35 +/- 0.16 mumol/l; 6.6 +/- 3.1 micrograms/l and 0.44 +/- 0.16 mumol/l 8.4 +/- 3.0 micrograms/l, respectively). During dialysis, the mean fluoride concentration fell to 0.94 +/- 0.26 mumol/l, remaining however, significantly higher than in control subjects. The use of fluoride-free dialysates seems to partially compensate the effect of renal impairment since plasma fluoride is only moderately increased in these patients.

[Plasma catecholamine concentrations during exercise in the untrained subject and in the sportsman]. / Concentration plasmatique de catécholamines à l'effort chez le sujet non entraîné et chez le sportif.

Plasma noradrenaline (NA) and adrenaline (A) concentrations were measured by high liquid pressure chromatography in five untrained subjects and in five well-trained rowers during an exercise test on bicycle ergometer. Blood samples were collected, via a venous catheter, at rest, after standing 5 minutes, at maximal work level and at 5, 10, 20 minutes of post-exercise. Plasma NA and A concentrations at rest and after 5 minutes of standing were similar in the two groups. At maximal work load (340 +/- 38 for rowers and 220 +/- 11 W for untrained subjects), for a same pulse rate (178.0 +/- 7.6 for rowers and 176.6 +/- 4.7 beats/minutes-1 for untrained subjects), NA and A concentrations were higher in athletes (NA: 5.57 +/- 1.32 microgram/l; A: 0.95 +/- 0.31 microgram/l) than in untrained subjects (NA: 2.13 +/- 0.80 microgram/l; A: 0.40 +/- 0,34 microgram/l). During recovery, no significant difference was observed between the two groups.

[Tissue binding of orally administered bismuth in the rat. Effect of the digestive microbial flora]. / Fixation sur les tissus du bismuth administré par voie orale chez le rat. Influence de la flore microbienne digestive.

Strains of E. coli and Str. faecalis, which do not darken in the presence of Bismuth in vitro, and which had been previously isolated from faeces of patients having presented bismuthic myoclonic encephalopathy, were implanted in the digestive tract of axenic rats. Then these monoxenic rats were treated orally for 15 days with bismuth subnitrate (0,24 millimoles = 50 mg/animal/day) and sacrificed on day 16. At this time, levels of bismuth in blood, brain, kidney and femur from these rats did not significantly differ from those obtained from axenic rats or monoxenic rats implanted with the homologous bacterial strains which darken in the presence of bismuth. Conversely, under the same conditions, levels of bismuth in kidney, muscle and femur were significantly lower in holoxenic rats than in axenic rats. Levels of bismuth in kidney and femur were also significantly lower in holoxenic rats than in monoxenic rats implanted with one of the four bacterial strains mentioned above.

Enhanced bismuth digestive absorption in rats by some sulfhydryl compounds: nmr study of complexes formed.

In a preliminary paper [Thérapie 34, 397 (1979), we showed that cysteine enhances bismuth digestive absorption in rats. In this paper, we have studied in rats the effects of various thiol compounds (mercaptopropionic acid, penicillamine, cysteine, homocysteine, 2-mercaptoethylamine, mercaptoethane) and nonthiol compounds (methionine, serine, alanine) orally administered on the absorption and elimination of bismuth also given orally. Bismuth was measured in blood and urine by electrothermal atomic absorption spectrophotometry. All of the thiol substances, and particularly cysteine, homocysteine, and mercaptopropionic acid, have considerably enhanced bismuth absorption and elimination; whereas, nonthiol substances have had no effect. Moreover, the acute toxicity of bismuth was enhanced when bismuth was given as a complex with cysteine (LD50 = 156 +/- 20 mg/kg). Studies by nmr spectroscopy of interactions between bismuth and these organic compounds have shown that bismuth induces an important chemical shift of the protons of the alpha carbon of the sulfhydrile group. Mainly, studies of C and N have confirmed this fact. The selectivity of such a complexation, in our pH conditions, may be tentatively explained on the ground of hard and soft acid and base (HSAB) theory. We have suggested that an increase in the concentration of thiol compounds in the gastrointestinal tract arising from food, or more probably from microorganism synthesis, could be an explanation for human encephalopathies.