Effect of brain and spinal cord injuries on motor imagery

Summary The timing of mentally executed movements was measured in ten patients with hemiplegia, tetraplegia and paraplegia. In hemiplegic patients a significant difference in mental duration times was found between the paralysed and the normal represented limb. The paralysed limb was mentally much slower than the healthy one. In contrast, movement times in tetraplegic and paraplegic patients did not differ from those in normal subjects. All patients reported a sensation of subjective effort accompanying the execution of the mental tasks. These observations are compatible with an outflow processing underlying motor imagery.     

Pulmonary and pleural localizations of Kaposi's sarcoma in AIDS

Intrathoracic Kaposi's sarcoma (KS) in AIDS is remarkable for its frequency and severity. It is responsible for 10% of "pneumonias" and almost 50% of pleurisies observed in these patients. The time elapsed between the discovery of the lesion and the patient's death does not exceed a few months on average. The initial manifestations of pulmonary KS are usually discreet and consist of cough and/or dyspnoea in patients with KS of the skin and mucosae. Fever is lacking or moderate. The most suggestive radiological findings are dense, nodular, tumour-like opacities and bilateral linear and/or micronodular opacities around the bronchi and vessels. The diagnosis rests on bronchial fibroscopy which shows red, non friable lesions which, to a trained endoscopist, are very characteristic. When these lesions are absent, thoracotomy may be necessary for diagnostic purposes. Treatment essentially consists of chemotherapy; zidovudine therapy and prophylaxis of pneumocystosis are indicated if the circulating CD 4 cell count falls below 200/mm3. When its symptoms are predominant, pleural KS is typically progressive, with normal or slightly elevated temperature, associated parenchymal lesions that are clearly visible on CT scans and copious, bilateral, blood-stained serous or chylous pleural fluid. When these signs are absent throacoscopy or thoracotomy may be necessary. Future advances in this field will be due not only to improvements in chemotherapy but also to a better understanding of the physiopathology of intrathoracic Kaposi's sarcoma.     

Endoscopic cordectomy. a proposal for a classification by the Working Committee, European Laryngological Society

The European Laryngological Society is proposing a classification of different laryngeal endoscopic cordectomies in order to ensure better definitions of postoperative results. We chose to keep the word “cordectomy” even for partial resections because it is the term most often used in the surgical literature. The classification comprises eight types of cordectomies: a subepithelial cordectomy (type I), which is resection of the epithelium; a subligamental cordectomy (type II), which is a resection of the epithelium, Reinke’s space and vocal ligament; transmuscular cordectomy (type III), which proceeds through the vocalis muscle; total cordectomy (type IV); extended cordectomy, which encompasses the contralateral vocal fold and the anterior commissure (type Va); extended cordectomy, which includes the arytenoid (type Vb); extended cordectomy, which encompasses the subglottis (type Vc); and extended cordectomy, which includes the ventricle (type Vd). Indications for performing those cordectomies may vary from surgeon to surgeon. The operations are classified according to the surgical approach used and the degree of resection in order to facilitate use of the classification in daily practice. Each surgical procedure ensures that a specimen is available for histopathological examination. Received: 29 December 1998 / Accepted: 2 July 1999     

Study of the Complex Between the Contrast Agent lobitridol (Xenetix®) and Elastase (PPE): A Model for Hydrophobic Site Protection in Drug-Protein Interactions

Purpose. The concept of Hydrophilic Sphere Stabilization, or Hydrophobic Shielding, has been postulated in the synthesis of biocompatible contrast agents in vascular imaging. To improve the safety of these polyiodinated agents, interactions with protein hydrophobic sites in biomacromolecules should be kept as low as possible. In order to evaluate the level of interactions with proteins, we have selected the serine proteinase Elastase, in presence of Iobitridol (Xenetix^®), as a model. Methods. The complex between Iobitridol and Pancreatic Porcine Elastase was investigated by X-ray diffraction techniques, on saturated monocrystals, using the synchrotron radiation at 0.98. Results. In contrast to Iohexol, which displays several interactions including one in the active site, Iobitridol is unable to interact directly with elastase. Only one partially occupied site is found in between two molecules of the crystal packing. Conclusions. The validation of the 'hydrophobic shielding' concept, which was at the origin of the design of the Iobitridol molecule, has been proven to be an essential feature in minimizing in vivo protein interactions.     

Mucoadhesion of Latexes. I. Analytical Methods and Kinetic Studies

A Fourier transform infrared spectroscopy/attenuated total reflection technique for direct quantification of adsorbed poly(styrene) latexes on rat intestinal mucosa was developed for deposited latex amounts up to 1.5 g/m². The method agreed well with another dosage assay of adsorbed particles by turbidimetry after denaturation of the mucus. Adsorption kinetics were made under static conditions at latex concentrations of 4 g/L in physiological saline. Ninety percent of equilibrium was reached after 10 min for a particle size of 230 nm, 20 min for a size of 320 nm, and 30 min for a size of 670 nm. The plateaus were between 0.6 and 0.9 g/m² (adsorbed mass per apparent surface of mucosa). The first phase of the kinetics was theoretically approached by a diffusion model in the suspension medium. Mucosa from rat jejunum and ileum could be considered as a homogeneous biological model for latex adsorption.     

K-complexes: are they signs of arousal or sleep protective?

SUMMARY  The number of K-complexes recorded at the central-temporal EEG derivation (C3-T3) during 5 min periods for both the ascending and descending phase of Stage 2 of NREM sleep for cycles 1,2… etc. were counted in 10 subjects for each of the following five groups: normal persons, patients with a primary generalized form of epilepsy, narcolepsy, insomnia and obstructive sleep apnoea. The differences in time spent in different stages of sleep were as expected for these types of patients. A 2-within, 1-between factors, repeated measure ANOVA was applied to the data on K-complexes. Overall, there was no significant difference between the number of K-complexes observed during the ascending and descending phases of the different sleep cycles. Patients with a sleep disorder had significantly less well-defined K-complexes than the normals and the patients with a primary form of generalized epilepsy: for insomnia ( P = 0.035), for apnoea ( P = 0.011) and for narcolepsy ( P = 0.001). There was a significant, but very low correlation coefficient between the number of K-complexes observed during Stage 2 of NREM sleep and the time spent during that stage for all groups combined (Rho 0.27, P = 0.002) and for the narcoleptic patients (Rho 0.44, P = 0.017). In all, the findings lend support to the hypothesis that a K-complex can be seen as a 'defensive response', or has a sleep protective function.     

The Effect of Modifying Dietary Calcium Intake Pattern on the Circadian Rhythm of Bone Resorption

In order to assess day-to-day variations of the circadian rhythm of biochemical bone resorption markers, urinary morning (6–8 a.m.) and evening (7–10 p.m.) samples from 35 individuals were monitored during 3 subsequent days. The bone-specific deoxypyridinoline (DPD) crosslinks of type I collagen followed a circadian rhythm in all individuals. In contrast, no such pattern was observed in the urinary hydroxyproline/creatinine and calcium/creatinine measurements. The DPD crosslink measurements showed a much larger difference between the morning and evening samples collected within 1 day compared with the variation between the samples collected in the morning or evening on subsequent days, indicating the importance of adequate timing of urine sampling for clinical trials aiming to monitor effects on bone resorption. The analysis of DPD crosslinks was then used to evaluate the effects of different patterns of dietary calcium intake on the circadian rhythm of bone resorption in osteoporotic patients. No significant effect on the circadian rhythm of the DPD crosslinks was found after concentrating the normal daily calcium intake to the evening (6–10 p.m.) during 8 days (n = 7). Ingestion of a dietary calcium supplement (600 mg) at 10 p.m. during 8 days (n = 7) resulted in an increased urinary calcium excretion in the morning, and a flattening of the circadian peak and nadir concentrations of urinary DPD/creatinine. The absolute levels of DPD/creatinine in the morning and evening urine samples, respectively, were not significantly altered compared with the control day. We conclude that dietary calcium supplementation in the evening only marginally affects the circadian rhythm of urinary DPD crosslinks in established osteoporosis patients. Received: 23 December 1996 / Accepted: 1 November 1998     

Vinflunine (20′,20′-difluoro- 3′,4′-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro

Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine®), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vincas, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids.     

Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs

Summary We have developed a pharmacokinetic/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a target cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells, of plasma from 11 acute myeloblastic leukemic patients treated with daunorubicin (DNR). Plasma, obtained before and serially for 24 h after DNR treatment, was assayed by HPLC for DNR and daunorubicinol (DNRol), its active metabolite. The corresponding observed PCA values (PCA_obs) against HL-60 cells were also measured with a flow-cytometric cell-survival assay that we had developed previously. The pharmacodynamics, i.e. PCA, were co-modeled (dual Hill equation with an interaction term to allow synergism or antagonism) with the pharmacokinetics. The intergration of the PCA profile provided the area under the observed PCA versus time curve (AUC_obs). For each patient, we also generated an interaction panel, by adding known amounts of DNR and DNRol to his or her pretreatment plasma. The corresponding cytotoxicities were measured, and then applied to the pharmacodynamic model. This provided a standard surface from which the PCA of each sample obtained after therapy was predicted (PCA_prd), on the basis of assayed concentrations of DNR and DNRol in that sample. For plasma samples obtained after treatment, the model simultaneously fit all three outputs, i.e. PCA and DNR/DNRol concentration, very well. We observed substantial interpatient variability in HL-60 growth rate in medium containing patient pretreatment plasma, in DNR activity in pretreatment plasma, and in the in vitro activity (PCA) of plasma obtained after DNR treatment. We also compared the AUC_prd to the AUC_obs for each patient, and we identified a subset of 4/11 acute myeloblastic leukemic patients who had developed much more PCA after DNR administration than could be explained by the measured concentrations of DNR and DNRol. This may be due to unidentified active metabolites or to factors produced in the plasma in response to the treatment. This pharmacokinetic/pharmacodynamic model is promising to describe pharmacodynamics and interactions of anticancer drugs in cancer patients.This work was presented, in part, at the 31st annual meeting of the American Society of Hematology, Atlanta, Ga., December 1989, and at the 91st Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Francisco, Calif., March 1990. Supported in part by grant RO-1-CA40 188 from the National Institutes of Health, National Cancer Institute, a grant from the Scientific Committee of NATO, Brussels, Belgium, and a grant from the Oeuvre Belge du Cancer, Brussels, Belgium     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.