Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model.

Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced.

[Evaluating radiotherapy patients' need for information: a study using a patient information booklet] . / Evaluation des besoins en information des patients suivis en radiothérapie: étude effectuée sur la base du livret de la radiothérapie.

The French Radiotherapy-Oncology Society (SFRO) and the National Trade of Radiotherapists-Oncologists (SNRO) elaborated and published a patient information booklet on radiotherapy, in 1999. This present study appraises the pertinence of the form and substance of this booklet one year after its release. Eight radiotherapy centers participated in this research which evaluated 162 patients at treatment initiation. The conclusions of this study demonstrated the importance of clearly informing patients of their disease, treatment, and the secondary effects of treatment. It is essential to emphasize that 97% of the patients declared that an information booklet is a real necessity, and that the one provided by the SFRO responds to the majority of their concerns. Obtaining technical and practical knowledge resulted in a reassurance about their treatment. The most revealing result is that 87% requested direct communication about their illness, and that cancer be named by this word and not other, evasive terms. Seventy-two percent of the patients requested more information about their cancer, different treatment options, and quality of life issues in an attempt to psychologically prepare themselves to face an illness for which they have little control. Patients refuse to be passive, and claim the right to become 'partners' of the medical teams, concerning their treatment and recovery.

Superposition of independent units of coordination during pointing movements involving the trunk with and without visual feedback.

Previous studies addressing the problem of the control of multiple degrees of freedom have examined the influence of trunk movement on pointing movements within the arm's reach. Such movements may be controlled by two functionally independent units of coordination (synergies): one involving only arm joints and producing the hand trajectory to the target (the transport synergy), and the other coordinating trunk and arm movements leaving the hand trajectory unchanged (the compensatory synergy). The question of whether or not this functional subdivision depends on visual feedback was addressed in the present study. We also tested whether or not the motor effects of different synergies are summated as independent components, a control strategy called "superposition." Finally, we investigated whether or not the relationship between different degrees of freedom within each synergy could be considered linear resulting in proportional changes in different joint angles. Seated subjects produced fast, uncorrected arm movements to an ipsi- or a contralateral target in the direction of +/-45 degrees to the sagittal midline of the trunk. Targets could be reached using the arm alone (control trials) or by combining the arm motion with a forward or backward trunk motion produced by hip flexion or extension (test trials), with and without visual feedback. The shape of the hand trajectory, its direction and tangential velocity, movement precision, joint angles and the sequence of the trunk and hand recruitment and de-recruitment were measured. In both visual conditions, the direction of the hand trajectory observed in control trials was generally preserved in test trials. In terms of sequencing, even in the absence of vision, the trunk movement was initiated before the onset of and outlasted the hand shift, indicating that the potential influence of the trunk on the hand movement was compensated by rotations in the elbow and shoulder joint. The analysis of other variables also implied that the effects of trunk recruitment on the hand trajectory were minor compared to those which could be observed if these effects were not compensated by appropriate changes in the arm joint angles. It was concluded that an arm-trunk compensatory synergy is present in pointing movements regardless of visual feedback. Principal component analysis showed that the relationship between elbow, shoulder and hip joint angles in individual arm and combined arm-trunk movements cannot be considered linear, implying that this relationship is adjusted according to the changing arm geometry. The changes in each arm joint angle (elbow, shoulder) elicited by a forward trunk bending in one block of trials were compared with those elicited by a backward bending in another block, whereas the hand moved to the same target in both blocks. These changes were opposite but of similar magnitude. As a result, for each moment of movement, the mean joint angle obtained by averaging across two directions of trunk motion was practically identical to that in control trials in which the trunk was motionless. It is concluded that the transport and arm-trunk compensatory synergies are combined as independent units, according to the principle of superposition. This principle may simplify the control of the coordination of a redundant number of degrees of freedom.

Recruitment and sequencing of different degrees of freedom during pointing movements involving the trunk in healthy and hemiparetic subjects.

Previous studies have shown that in neurologically normal subjects the addition of trunk motion during a reaching task does not affect the trajectory of the arm endpoint. Typically, the trunk begins to move before the onset and continues to move after the offset of the arm endpoint displacement. This observation shows that the potential contribution of the trunk to the motion of the arm endpoint toward a target is neutralized by appropriate compensatory movements of the shoulder and elbow. We tested the hypothesis that cortical and subcortical brain lesions may disrupt the timing of trunk and arm endpoint motion in hemiparetic subjects. Eight hemiparetic and six age-matched healthy subjects were seated on a stool with the right (dominant) arm in front of them on a table. The tip of the index finger (the arm endpoint) was initially at a distance of 20 cm from the midline of the chest. Wrist, elbow, and upper body positions as well as the coordinates of the arm endpoint were recorded with a three-dimensional motion analysis system (Optotrak) by infrared light-emitting diodes placed on the tip of the finger, the styloid process of the ulna, the lateral epicondyle of the humerus, the acromion processes bilaterally, and the sternal notch. In response to a preparatory signal, subjects lifted their arm 1-2 cm above the table and in response to a "go" signal moved their endpoint as fast as possible from a near to a far target located at a distance of 35 cm and at a 45 degrees angle to the right or left of the sagittal midline of the trunk. After a pause (200-500 ms) they moved the endpoint back to the near target. Pointing movements were made without trunk motion (control trials) or with a sagittal motion of the trunk produced by means of a hip flexion or extension (test trials). In one set of test trials, subjects were required to move the trunk forward while moving the arm to the target ("in-phase movements"). In the other set, subjects were required to move the trunk backward when the arm moved to the far target ("out-of-phase movements"). Compared with healthy subjects, movements in hemiparetic subjects were segmented, slower, and characterized by a greater variability and by deflection of the trajectory from a straight line. In addition, there was a moderate increase in the errors in movement direction and extent. These deficits were similar in magnitude whether or not the trunk was involved. Although hemiparetic subjects were able to compensate the influence of the trunk motion on the movement of the arm endpoint, they accomplished this by making more segmented movements than healthy subjects. In addition, they were unable to stabilize the sequence of trunk and arm endpoint movements in a set of trials. It is concluded that recruitment and sequencing of different degrees of freedom may be impaired in this population of patients. This inability may partly be responsible for other deficits observed in hemiparetic subjects, including an increase in movement segmentation and duration. The lack of stereotypic movement sequencing may imply that these subjects had deficits in learning associated with short-term memory.

Compensatory arm-trunk coordination in pointing movements is preserved in the absence of visual feedback.

This study examined the influence of trunk recruitment on the kinematic characteristics of pointing movements. The distribution of final positions of the hand, the extent and direction of the hand trajectory was basically preserved when trunk movement was combined with arm pointing. These effects were observed during pointing not only with but also without vision. The results imply that two functionally independent units of coordination are used in pointing regardless of visual feedback-one producing arm movement to the target (the reaching synergy) and the other coordinating trunk and arm movements diminishing the influence of the trunk on the arm endpoint trajectory (the compensatory synergy).

Intensive dance practice. Repercussions on growth and puberty.

To determine the effect of intensive sports training on growth and puberty, we studied a group of 97 young female dancers longitudinally for 5 years. We studied the changes in their heights, weights, and pubertal developments and compared these findings with those of a control group. We found that 15 (16%) dancers who started dance training had noticeably decreased growth velocity during the prepuberty stage after the beginning of ballet practice compared with the control group. This group had the same average training time compared with the other dancers, but these dancers were the slimmest and had the most inadequate nutritional intake. Puberty in dancers was delayed compared with the controls. We found that moderately intensive dance practice can lead to eating disorders and weight control early in childhood, with consequences that are poorly known. Weight and height statistics of children who practice individual sports involving body aesthetics must be monitored to detect early anomalies.

Moment arms and lengths of human upper limb muscles as functions of joint angles.

Modeling of musculoskeletal structures requires accurate data on anatomical parameters such as muscle lengths (MLs), moment arms (MAs) and those describing the upper limb position. Using a geometrical model of planar arm movements with three degrees of freedom, we present, in an analytical form, the available information on the relationship between MAs and MLs and joint angles for thirteen human upper limb muscles. The degrees of freedom included are shoulder flexion/extension, elbow flexion/extension, and either wrist flexion/extension (the forearm in supination) or radial/ulnar deviation (the forearm in mid-pronation). Previously published MA/angle curves were approximated by polynomials. ML/angle curves were obtained by combining the constant values of MLs (defined by the distance between the origin and insertion points for a specific upper limb position) with a variable part obtained by multiplying the MA (joint radius) and the joint angle. The MAs of the prime wrist movers in radial/ulnar deviation were linear functions of the joint angle (R2 > or = 0.9954), while quadratic polynomials accurately described their MAs during wrist flexion/extensions. The relationship between MAs and the elbow angle was described by 2nd, 3rd or 5th-order polynomials (R2 > or = 0.9904), with a lesser quality of fit for the anconeus (R2 = 0.9349). In the full range of angular displacements, the length of wrist, elbow and shoulder muscles can change by 8.5, 55 and 200%, respectively.

[Precocious puberty and polycystic ovarian syndrome: apropos of 13 cases]. / Puberté précoce et syndrome des ovaires polykystiques: à propos de 13 observations.

BACKGROUND: Precocious puberty and polycystic ovarian syndrome are two different entities which appear at different stages of ovarian development. Their association is uncommon. POPULATION: Thirteen girls presented idiopathic central precocious puberty with sexual development before the age of 8 years; menstruations were seen at the age of 9.5 years in one patient. Nine of them were given medroxyprogesterone or cyproterone acetate and two patients LHRH analog. Menarche occurred at a mean age of 11.8 +/- 1.5 years. After a mean free interval of 22 months, these thirteen patients developed hirsutism with irregular menstruations (eight patients) and weight gain (seven patients). The diagnosis of polycystic ovarian syndrome was confirmed by increased plasma testosterone (mean 91.1 +/- 14 ng/dl) and LH levels during LHRH test and by ultrasonography or coelioscopy. The treatment included cyproterone acetate plus 17 beta oestradiol; it was discontinued in eleven cases after 2 years of treatment. Plasma testosterone levels were normal 6 months later in association with regular menstruations. But three patients presented clinical and hormonal recurrence one year later, requiring repeated treatment. CONCLUSION: This association seems to be related to the same gonadotropin dysfunction. It is necessary to regularly follow patients treated for precocious puberty.

[How to manage a symptomatic ovarian follicular cyst in a female child?]. / Que faire devant un kyste folliculaire ovarien symptomatique chez la petite fille?

BACKGROUND: --Ovarian cysts are common in childhood but most are non functioning. Treatment of those follicular cysts that develop in young children may be difficult. CASE REPORTS: Case no. 1.--A 1 1/2 month-old baby was admitted because of an acute abdominal syndrome. Ultrasonography showed a pelvic, heterogeneous mass without calcifications. Laparotomy showed right ovarian torsion with necrosis of a cyst requiring ovariectomy. At that time, there was an isolated increase in FSH after LHRH stimulation. A transitory premature thelarche without pubertal type response to LHRH was seen at the age of 3 months. Clinical and ultrasonographic controls remain normal with a follow-up of 1 year. Case no. 2.--A 4 yr 10 m-old girl was admitted because of an acute abdominal syndrome. Ovariectomy was necessary because laparotomy showed right ovarian torsion with necrosis of a cyst. Recurrent abdominal pain, 4 months later, was associated with an enlarged left ovary without sexual precocity. Gonadotropin were slightly increased after LHRH stimulation and the patient was given LHRH agonist that suppressed endogenous LHRH within 3 months. Clinical and ultrasonographic controls remain normal 1 year after cessation of treatment. Case no. 3.--A 19 month-old girl was admitted because of a genital hemorrhage with recent development of secondary sexual characteristics. Skeletal age was 2 yrs. Ultrasonography showed an enlarged uterus and a left ovarian cyst, heterogenous with calcifications. Plasma levels of estradiol were increased but gonadotropin were normal. Ovariectomy was performed, followed by disappearance of secondary sexual characteristics. However, the patient was given LHRH agonist at the age of 2 yr 7 mo because of recurrent pubertal activity. CONCLUSIONS: --These cases underline the difficulty in treating follicular cysts in young girls. The possibility of cyst recurrence with manifestations of pubertal activity after ovariectomy lead to discuss indication of LHRH agonists for an undetermined duration.

Viscoelastic properties of the human lumbodorsal fascia.

The purpose of this study is to provide better understanding of the mechanical response of the lumbodorsal fascia to dynamic and static traction loadings. Since the fascia shows a viscoelastic behaviour, tests in which time is a variable were used, namely hysteresis and stress relaxation. Load-strain and load-time curves obtained from the hysteresis and stress-relaxation tests point out three different phenomena. First, an increase in stiffness is noticed when ligaments are successively stretched, i.e. strains produced by successive and identical loads decrease. Second, if a sufficient resting period is allowed between loadings, stiffening is reversed and strains tend to recover initial values. The third phenomenon, observed in stress-relaxation tests as time progresses, is ligament contraction in stretched and isometrically held samples. This third phenomenon may be explained by the possibility that muscle fibres capable of contracting spontaneously could be present in lumbodorsal fascia ligaments.

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1-29)-NH2 in children with GH deficiency.

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 +/- 1.3 micrograms/l) aged 8-10.3 years (mean, 2.7 +/- 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1-29)-NH2 infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 +/- 0.1 to 3.5 +/- 0.7 micrograms/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9 +/- 0.9 micrograms/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 micrograms/l during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1-29)-NH2 were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.

[Digestive and nutritional manifestations of Netherton's syndrome]. / Manifestations digestives et nutritionnelles du syndrome de Netherton.

Netherton's syndrome is a group of skin diseases where the cutaneous lesions may be associated with chronic digestive symptoms. We have observed five cases over a 10 year period, of which three in the same family. Management of nutritional and digestive problems was of major importance for vital prognosis. The literature data concerning the digestive involvement in Netherton's syndrome and the different associations between skin diseases and gastro-intestinal signs have been reviewed. The presence of villous atrophy in three of the five children suggests that a jejunal biopsy should be carried out in each case of Netherton's syndrome. Nutritional artificial support appears primordial at the initial stage of the illness, in order to maintain normal growth. Allergenic protein-free diet should not be systematic but discussed for each case and depend on the allergic and digestive laboratory results.

High voltage orbital radiotherapy and surgical orbital decompression in the management of Graves' ophthalmopathy.

We report on 2 groups of patients with Graves' ophthalmopathy. A group of 21 patients was treated by high voltage (18 MV) orbital radiotherapy combined with mean doses of corticoids. The results were good or excellent in 12 patients (mean score 6.62 before and 4.0 after, soft tissues greater than proptosis greater than extraocular muscle involvement), without any complications from irradiation. Patients undergoing surgery initially presented less severe symptoms, even 7 patients treated after corticoid and/or radiotherapy failure. The results were satisfactory in all patients (mean score 5.1 before and 2.4 after, proptosis greater than soft tissues greater than extraocular muscle involvement). Both methods showed results within 3 months, and they can be combined.

Immunoreactive fibroblast growth factor (FGF) in rat tissues: molecular weight forms and the effects of hypophysectomy.

Rat tissues were extracted at neutral pH with dilute (0.15 M) ammonium sulfate and examined for presence of fibroblast growth factor immunoreactivity (ir-FGF). Ir-FGF was found in substantial amounts in all the tissues but higher amounts were found in liver and kidney. Gel filtration column chromatography showed the presence of three molecular weight peaks of ir-FGF, one associated with the void volume (the major form in kidney extract), another with an apparent molecular weight of 150-180,000 Da (the major form in serum) and a third one of 70,000 Da (the major form in the other tissues examined: pituitary, brain, liver, spleen and thymus). No immunoreactivity coeluted with authentic FGF purified from bovine pituitary glands, suggesting that FGF is present in neutral extracts in association with binding molecules and/or precursors. Hypophysectomy had no major effect on ir-FGF in the tissues, but increased its amount in serum. The results establish a wide distribution of FGF in several embryologically, morphologically and developmentally distinct tissues and indicate that the pituitary is not the major source of FGF immunoreactivity, although it can be involved in the regulation of plasma levels.

Dephosphorylation of L-pyruvate kinase during rat liver hepatocyte isolation.

In isolated rat liver cells, the inhibition of L-pyruvate kinase (L-PK) by a cyclic AMP-dependent phosphorylation mechanism is involved in the hormonal control of glycolysis and gluconeogenesis. The aim of this study was to ascertain whether or not the in vivo phosphorylation state of the enzyme was maintained during the liver perfusion used to prepare isolated liver cells. When the L-PK phosphorylation state was studied indirectly in liver extracts by kinetic measurement, it was found that, during the perfusion, the S0.5 of phosphoenol pyruvate (PEP) for L-PK was decreased in a time-dependent manner from 1 +/- 0.08 to 0.64 +/- 0.1 mM (P less than 0.01) and 0.58 +/- 0.06 mM in liver cells. This shift was prevented only by the addition of glucagon to the perfusion medium. The extent of phosphorylation of L-PK was also estimated by incubation of the liver extract with [gamma-32P]ATP, protein kinase, and cyclic AMP, and measurement of 32Pi incorporated in L-PK by specific immunoprecipitation. In liver extracts removed at the beginning of the perfusion, 0.4 mol Pi/mol L-PK was incorporated and there was no stimulation by cyclic AMP. In contrast, in the liver extracts removed after 30 min of perfusion, cyclic AMP stimulated 32P incorporation two to threefold, and 1.6 mol Pi/mol L-PK was incorporated. These data suggest that L-PK was activated by a dephosphorylation mechanism during rat liver perfusion. This phenomenon could be involved in the classical inactivation of gluconeogenesis observed in the perfused rat liver model.

[Treatment of anxiety with bromazepam in clinical practice (author's transl)]. / Le traitement de l'anxiété par le bromazépam en médecine practicienne.

In this co-operative study 50 patients of both sexes, aged from 18 to 66 years and suffering from neurotic anxiety with functional symptoms were treated with bromazepam (Lexomil) alone for 28 days. With daily doses averaging 6 to 9 mg, good or excellent results were obtained in 78% of the cases, including 58% of somatic cures. Assessment of the anxiety, carried out on days 0, 14 and 28 with the Pull-Guelfi and Hamilton scales, showed optimal response on the 14 th day of treatment in ambulatory patients. Side-effects mostly consisted of sedation which regressed spontaneously or after dosage was reduced.

Participation of serotonin in thyrotropin release. II. Evidence for the action of serotonin on the phasic release of thyrotropin.

During a 12-h light 12-h dark schedule (lights off at 1900 h), male Sprague-Dawley rats show a circadian rhythm of plasma TSH with a zenith near midday. The participation of serotonin (5HT) in the phasic release of TSH was studied using both pharmacological and surgical-stereotaxical approaches. Animals treated with parachlorophenylalanine methyl ester (pCPA), an inhibitor of 5HT synthesis (one or two injections of 250 mg/kg each) showed a reduction or a disappearance of the diurnal peak of TSH, respectively. Additional treatment by 5-hydroxytryptophan, a precursor of 5HT, completely, restored the diurnal TSH peak. Treatment with 5,6-dihydroxytryptamine creatine sulfate, a neurotoxin which selectively destroys 5HT terminals, also induced alterations of the diurnal peak of TSH. There were no major modifications observed in the low nocturnal levels of TSH in rats treated with pCPA, 5-hydroxytryptophan, or 5,6-dihydroxytryptamine. The major serotoninergic innervation of the hypothalamus originates from the raphe dorsalis or centralis; destruction of these two nuclei caused a quasiabolition of the diurnal TSH peak (only a low amplitude TSH circadian rhythm persisted). Hypothalamic 5HT content was measured in the majority of these experiments; the greatest depletions (near 90%) were observed after two injections of pCPA or in rats bearing raphe lesions. We conclude that the diurnal peak of TSH, observed during the physiological circadian rhythm, is serotoninergic dependent.