Automatic detection of skate strokes in short-track speed skating using one single IMU: validation of a new method.

Greater impulse is a key performance indicator of success in short track speed skating. The main objective of this study was to develop a method to measure skating strokes using a single IMU. Eight elite or world-class speed skaters had one IMU placed against their skin on the lower back, and a camera setup was positioned to capture the test. A maximal speed trial was then executed by each participant, and the data were analysed to estimate agreement between the camera and IMU estimates of skate stroke events. Inter-evaluator reliability was assessed on a dataset of 22 athletes performing speed trials as well. The algorithm detected 100% of the strokes identified on the video capture system with a root mean square error of 0.06s. Bland-Altman analysis showed a bias of 0.03s between the two methods, which corresponds to the frame rate of the camera. The inter-evaluator reliability yielded an intra-class correlation of 1.00 (ICC3,1) from a dataset of 7089 strokes. This study provides an example of on-ice evaluation of speed skating strokes using a single IMU. This equipment is less expensive than that employed by previous authors and can be implemented in training situations with low invasiveness.

Cost-effectiveness modeling of intrathecal baclofen therapy versus other interventions for disabling spasticity.

OBJECTIVE: To assess by simulation the cost-effectiveness of intrathecal baclofen (ITB) therapy compared with conventional medical treatments for patients with disabling spasticity and functional dependence caused by any neurological disease. METHODS: Two models were created to simulate therapeutic strategies for managing severe spasticity, one with and one without the use of ITB, to assess various treatment sequences over 2 years based on current medical practices in France. Successful treatment at each evaluation was defined as a combination of: (1) the increased patient and caregiver satisfaction as assessed by goal attainment scaling (GAS), and (2) a decrease of at least 1 point on the Ashworth score. Probabilistic sensitivity analyses were performed using 5000 Monte-Carlo simulations taking into account specific distribution curves for direct costs and effectiveness parameters in each treatment option. RESULTS: The model simulations suggest that including ITB as a first option strategy in the management of function of severely impaired patients with disabling spasticity results in a higher success rate (78.7% vs 59.3%; P < .001). In addition, the ITB therapy model revealed a lower cost (pound 59,391 vs pound 88,272; P < .001) and an overall more favorable cost-effectiveness ratio (pound 75,204/success vs pound 148,822/success; P < .001), compared with conventional medical management without ITB. CONCLUSION: Within the assumptions of our modeling, ITB therapy evaluated by a combination of treatment success criteria at 6-month intervals over a 2-year period may be a cost-effective strategy compared to conventional medical management alone.

Managing type 2 diabetes in France: the ECODIA survey.

In order to describe the profile and medical management of type 2 diabetes patients in France, a descriptive cross-sectional survey was conducted in 1999 among a national random sample of 311 general practitioners and 51 specialists. A practitioner questionnaire was designed to collect information on a representative sample of 4,119 patients presenting with type 2 diabetes. Data collected included demographic and clinical information and a full description of diabetes management over a 6-month retrospective period. Over 50% of the patients were more than 67 years old; 54% were male. Diabetes had been diagnosed 8.9 years earlier on average, most frequently (73%) during a visit not related to diabetes' symptoms or complications. 42% of patients had a BMI > or =30 kg/m(2), 46% were hypertensive (BP > 140-80 mmHg), 53% had a LDL-Cholesterol over 1.3 g/l. Overall, 33% of patients had at least one diabetic complication. 60% of patients had had at least one HbA1c dosage in the last 6 months. Among them, 31% had a HbA1c level over 8% and 35% between 6. 5% and 8%. 85% of patients were treated with oral anti-diabetic drugs, 9.5% with diet and exercise only and 5% with insulin. Sulfonylureas were the most commonly prescribed anti-diabetic agent, either alone or in combination. This survey confirms that the management of patients with type 2 diabetes is still often inappropriate in France despite recent progress. Improved disease management and monitoring is required in France as in other developed countries.

Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4.

Biliary, plasma, and urinary disposition of paclitaxel and paclitaxel metabolites were determined simultaneously in a patient with percutaneous biliary drain. The complete chemical structures of the major metabolites were established by mass spectrometry and NMR spectroscopy. A nonlinear elimination model was indicated by the fact that the rate of biliary excretion of paclitaxel rose as plasma concentrations fell. Dihydroxypaclitaxel was the predominant biliary metabolite, in contrast to the barely detectable levels in two previous patients. This derivative results from hydroxylation at the C6 position of the taxane ring and at the phenyl C3'-position on the C13 side chain mediated by cytochrome P450 2C8 and 3A4, respectively. In line with this mechanism, the two other main metabolites corresponded to 6alpha-hydroxypaclitaxel and to the paclitaxel derivative hydroxylated in the para-position on the phenyl ring at the C3'-position of the C13. A high CYP3A4 activity in the patient is consistent with the repeated administration of methylprednisolone for 14 days before paclitaxel treatment, a compound known to induce the CYP3A isoform, and with the increased ratio of 6beta-hydroxycortisol/cortisol in urine, an index of CYP3A activity. These findings emphasize the influence of pretreatment with corticoids on the disposition of paclitaxel.

In vivo electrically mediated protein and gene transfer in murine melanoma.

We show that efficient permeabilization of murine melanoma can be obtained in vivo by applying electric pulses. More than 80% of the cell population is affected as shown by the penetration of propidium iodide. A protein, beta-galactosidase, can be transferred and expressed into the cells by incorporating either the protein or a plasmid carrying the reporter gene with respective efficiencies of 20% and 4%. This is obtained by a direct injection of either the protein or the plasmid in the tumor, followed by the application of electric pulses with surface electrodes in contact with the skin. This approach is simple and safe to use, reproducible, and specific; moreover, it is potentially applicable to a wide variety of tissues, cell types, and animals.

Combined NMR and molecular modeling study of an iduronic acid-containing trisaccharide related to antithrombotic heparin fragments.

An iduronic acid-containing trisaccharide, methyl-O-(4-O-methyl-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1-->4)-O- (2-O-sulfo-alpha-L-idopyranosyluronic acid)-(1-->4)-O-2,6-di-O-sulfo-alpha-D-glucopyranoside, related to antithrombotic heparin fragments has been subjected to a combined NMR and molecular modeling investigation. The conformational behavior of the two constituting disaccharide segments was investigated using a systematic grid search approach with the MM3 force field along with the proper parameters for the sulfate ester group. The exploration of the potential energy surfaces of the trisaccharide was performed through the use of the CICADA methods interfaced with the MM3 force field. In all cases, the 2-O-sulfo-alpha-L-iduronate moiety was given the three favored ring conformations (1)C4, (4)C1, and (2)S0. Conformations were clustered into families, four of which are likely to exhibit significant occupancy in solution. The different low-energy conformational families display different orientations at the glycosidic linkages and/or different ring shapes for the iduronate ring. The (2)S0 conformation is the major one for the 2-O-sulfo-alpha-L-iduronate but is still in equilibrium with the (1)C4 ring shape. The occurrence of such a conformational equilibrium in solution was probed via high-resolution NMR spectroscopy through measurements of coupling constants and NOE build-up. These results are in keeping with the observation that 2-O-sulfated pentasaccharides display a similar affinity for antithrombin III as their 2-N-sulfated counterparts.

Transgenic mice expressing the Sh ble bleomycin resistance gene are protected against bleomycin-induced pulmonary fibrosis.

Despite the high efficiency of bleomycin (BLM) as a chemotherapeutic agent against various carcinomas, the potentially lethal and chronic fibrotic response of the lung is a major dose-limiting side effect. Here, we explore the possibility of a direct inhibition of lung tissue injury by in vivo expression of the actinomycetes BLM resistance protein Sh ble. Transgenic mice expressing the Sh ble gene under the control of a composite viral promoter were produced after introduction of the transgene into D3 ES cells. The protein was detected at high level in lungs, spleen, and kidney. We then assessed its ability to modulate the BLM-induced fibrotic response in the transgenic mice in comparison with C57BL/6 and 129/Sv parental mice. Cumulative doses of 300, 400, or 500 mg/kg BLM were administered either by i.p. or s.c. repeated injections in the different strains. Transgenic mice were shown to be clearly less sensitive to BLM toxicity, as assessed by lung histology. The pulmonary hydroxyproline content in the treated transgenic mice was close to its baseline level, whereas it was up to 50% higher than the control level in C57BL/6 and 129/Sv parental mice. These observations are consistent with the hypothesis that a resistance gene specifically expressed in lungs may prevent the BLM-induced inflammation.

Solution conformations of pectin polysaccharides: determination of chain characteristics by small angle neutron scattering, viscometry, and molecular modeling.

The solution behavior of pectin polysaccharides has been investigated by small angle neutron scattering (SANS), viscosimetric, and molecular modeling studies. The samples used in the experimental study were obtained from apple and citrus and had degrees of methylation ranging from 28 to 73%, with a rhamnose content lying between 0.6 and 2.2%. Persistence lengths, derived from intrinsic viscosity measurements, ranged from 59 to 126 A, whereas those derived by SANS were between 45 and 75 A. These values correspond to 10-17 monomer units. The modeling simulations were performed for both homogalacturonan itself and homogalacturonan carrying various degrees of rhamnose inserts (rhamnogalacturonan). This required the evaluation of the accessible conformational space for the eight disaccharides that represent the constituent repeating segments of the homogalacturonan and rhamnogalacturonan polysaccharides. For each dimer, complete conformational analysis was accomplished using the flexible residue method of the MM3 molecular mechanics procedure and the results used to access the configurational statistics of representative pectic polysaccharide chains. For homogalacturonan, an extended chain conformation having a persistence length of 135 A (corresponding to 30 monomers) was predicted. The inclusion of varying amounts of rhamnose units (5-25%) in the model in strict alternating sequence with galacturonate residues (equivalent to the rhamnogalacturonan "hairy region" chains) only slightly reduced the calculated persistence length. The extended overall chain conformation remained relatively unchanged as a consequence of the self-cancellation of the kinking effects of successive paired rhamnose units.

A molecular builder for carbohydrates: application to polysaccharides and complex carbohydrates.

A new procedure (POLYS) for producing three-dimensional structures of polysaccharides and complex carbohydrates is described. This employs a builder concept combining a database of monosaccharide structures with a database containing information on populations of independent neighboring glycosidic linkages in disaccharide fragments. The computer program is written in C, and it can cope with both the complexity and the diversity of carbohydrates and the unique topological features arising from multiple branching. A simple ASCII syntax was developed for describing the primary structures in accordance with IUPAC nomenclature. The translation of the primary structure is made through the combined use of a lexical analyzer and a command interpreter. In this way the program can be considered as a compiler of primary structures of carbohydrates. However, it also generates secondary and tertiary structures in the form of Cartesian coordinates in formats used by most molecular mechanics programs and packages. In our laboratory POLYS was exhaustively tested on standard homopolysaccharide systems such as cellulose and mannan and found to work very well. We now report the ease of use and the efficiency of the molecular builder in applications to more complex carbohydrate systems. These include the structural exploration of a pentaantennary oligosaccharide having 135 residues, the complex family of pectic polysaccharides including the organization and distribution of side chains (arabinan, arabinogalactan, and galactan) on the rhamnogalacturonan backbone.

Computer modelling of sulfated carbohydrates: applications to carrageenans.

In this study, X-ray crystallographic data of sulfated monosaccharides have been used to derive appropriate parameters for sulfate groups in the Tripos force field, previously parameterized for carbohydrates. A database of nine sulfated monosaccharides occurring as building blocks of sulfated polysaccharides such as carrageenans and sulfated glycosaminoglycans has been built. These tools have then been used to evaluate the conformational energies of the repeating units of the kappa-, iota- and lambda-carrageenan polymers, taking into account the rotation around the sulfate groups. In a third step, helical conformations of carrageenans have been explored and the results compared with the experimental data obtained by X-ray fibre diffraction. Stable, single, right-handed helices, with geometric and helical parameters in close correspondence with the best models derived from X-ray diffraction data, have been generated. Finally, the configurational statistics of random-coil carrageenan chains have been investigated and compared with experimental data currently available on these polymers. A highly flexible character is predicted for kappa- and iota-carrageenans, with lambda-carrageenan showing slightly more extension.

Synthesis, antitumor evaluation and SAR of new 1H-pyrrolo [3,2-c] quinoline-6,9-diones and 11H-indolo [3,2-c] quinoline-1,4-diones.

New 1H-pyrrolo [3,2-c] quinoline-6,9-diones, 11H-indolo [3,2-c] quinoline-1,4-diones and 7,8,9,10-tetrahydro-11H-indolo [3,2-c] quinoline-1,4-diones, either unsubstituted or methylated, have been synthesized and evaluated for antitumor activity. They were compared to previously described quinones which bear either a methoxy group or an aziridinyl substituent on the quinone nucleus in order to establish structure-activity relationships and to obtain compounds as active as aziridinylquinones, but with less toxicity. A new synthetic route was developed using dimethoxy derivatives as key compounds that reacted with ceric ammonium nitrate (CAN) to give quinones by oxidation demethylation. The biological results obtained in vitro indicated that: (i) new quinones display cytotoxicity higher than that of the methoxyquinones; (ii) unsubstituted compounds are the most active; (iii) methylation of the pyrrole NH has no influence on unsubstituted quinones, but affords inactive derivatives when the quinone nucleus is methylated; (iv) compared to the aziridinyl-quinones, some compounds are equally active or more active. Despite the cytotoxicity exerted in vitro, we could not find evidence for any antitumor activity of quinones against in vivo P388 murine leukemia.

DNA excision-repair synthesis is enhanced in a murine leukemia L1210 cell line resistant to cisplatin.

Among various molecular mechanisms of cell resistance to antitumor agents such as cisplatin, it has recently been suggested that enhanced DNA-repair activity might be involved in the resistant phenotype of cell lines. Mouse leukemia-cisplatin-resistant cell lines L1210/10 (adapted in vitro) and L1210/DDP (adapted in vivo) have been reported to exhibit an increase DNA-repair activity, as determined by host-cell reactivation after transformation with damaged plasmids. In this paper, excision-repair activity was monitored by an in-vitro assay allowing quantification of DNA-repair synthesis in cell extracts from resistant and sensitive parental cells (L1210/10 versus L1210/0 and L1210/DDP versus L1210/S). Experimental conditions for optimal repair-synthesis activity were found to be different from these reported with human cell-line extracts. L1210/S sensitive cell line, grown in vivo by a weekly intraperitoneal graft in mice, displayed a repair activity about fourfold lower than the same cell line maintained in vitro or than L1210/0 cell grown in vitro. The repair activity was found similar in a L1210/10 and L1210/0 cell lines, but it was enhanced in L1210/DDP resistant cell line when compared with its parental line.

Solution conformation of a pectin fragment disaccharide using molecular modelling and nuclear magnetic resonance.

In the present study, the conformational behaviour of methylated pectic disaccharide 4-O-alpha-D-galactopyranurosyl 1-O-methyl-alpha-D-galactopyranuronic 6,6'-dimethyl diester 1 has been completely characterized through combined n.m.r. and molecular modelling studies. The 1H-1H n.O.e. across the glycosidic bond was measured by both steady-state and transient 1D and 2D experiments. In parallel, the complete conformational analysis of the disaccharide has been achieved with the MM3 molecular mechanics method. The conformation of the pyranose ring is confirmed by the excellent agreement between the experimental and calculated intracyclic scalar coupling constants. The iso-energy contours displayed on the 'relaxed' map indicate an important flexibility about the glycosidic linkage. There is no significant influence of the methoxyl group on the conformational behaviour of the disaccharide. The theoretical n.m.r. data were calculated taking into account all the accessible conformations and using the averaging methods appropriate for slow internal motions. 3JC-H coupling constants were calculated using an equation suitable for C-O-C-H segments. The agreement between experimental and theoretical data is excellent. Within the potential energy surface calculated for the disaccharide, several conformers can be identified. When these conformations are extrapolated to a regular polymer structure, they generate pectins with right- and left-handed chirality along with a two-fold helix. These different types of helical structure are the result of small changes in conformation, without any drastic variation of the fibre repeat.

In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S 9788 in P388/VCR leukemia model.

S 9788, a new triazinoaminopiperidine derivative, was found to be a potent reversant of vincristine resistance in the in vivo murine leukemic P388/VCR model. In two treatment regimens (Q4D days 1, 5 and 9 and QD days 1-9), S 9788 enhanced the antitumor activity of vincristine in a dose-dependent manner, resulting in a complete circumvention of drug resistance for well-tolerated doses of S 9788. S 9788 was also effective in enhancing therapeutic effects of vincristine in the treatment of sensitive P388-bearing mice. These results strongly suggest that S 9788 may be a potential candidate for circumvention of multidrug resistance (MDR) in clinical practice.

Preclinical antitumor activity of a new Vinca alkaloid derivative, S 12363.

S 12363 is a new Vinca alkaloid derivative obtained by appending an optically active alpha-aminophosphonate at the C23 position of O4-deacetyl vinblastine. S 12363 was evaluated for cytotoxic and antitumor activity against a spectrum of murine and human tumors. This compound was, respectively, on average, 72- and 36-fold more cytotoxic than were vincristine and vinblastine, when tested on a panel of 2 murine and 37 human tumor cell lines using the microculture tetrazolium assay. S 12363 exhibited significant antitumor activity against murine transplantable tumors (i.p. and s.c. P388 leukemia, i.p. L1210 leukemia, i.p. and i.v. B16 melanoma, i.p. M5076 sarcoma, and s.c. colon adenocarcinoma 38), while no activity was observed on s.c. Lewis lung carcinoma. S 12363, when administered i.p., showed moderate activity on human NCI-H460 lung and PANC-1 pancreas tumor xenografts in nude mice. However, when it was administered i.v., it exerted a significant activity against human HT-29 colon, NCI-H460 lung, NCI-H125 lung, PANC-1 pancreas, and A-431 vulvar tumor xenografts. S 12363 was also active in vivo against a P388 leukemia subline resistant to vincristine. On the in vivo panel of tumors used in this study, S 12363 was at least as active as reference compounds, while its optimal dosage was 10- to 40-fold lower than that of vinblastine, depending on the models studied. The effects of schedule and route of administration on the antitumor activity of S 12363 were studied in both i.p. inoculated P388 leukemia and B16 melanoma, in which the activity was improved by single and intermittent treatment (Days 1, 8, and 15) and i.p. route. S 12363, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 300-fold less cytotoxic and 1000-fold less potent in vivo than was S 12363. These results suggest that S 12363 could present a therapeutic advantage over its congeners and deserves further pharmacological evaluations.

Syntheses and in vitro evaluation of water-soluble "cationic metalloporphyrin-ellipticine" molecules having a high affinity for DNA.

The synthesis of hybrid "cationic metalloporphyrin-intercalator" molecules is reported. These molecules are based on 9-methoxyellipticine as intercalator and tris-(4-N-methylpyridiniumyl)metalloporphyrins having a 4-aminophenyl or a 4-hydroxyphenyl group for the attachment of the linker. The effect of the length of linker (7-13 bonds), the chemical nature of the linking group (with a carboxamido or an ether function), the position of amino group between the two parts of hybrid molecules, the number of intercalator moieties (ellipticinium) covalently attached to the metalloporphyrin, and the nature of the central metal atom (Mn, Fe, Zn) on the biological activity of these hybrid molecules were studied. In addition, these molecules have a high affinity for double-stranded DNA (affinity constant of hybrid molecule 9Mn,Me = 2.3 x 10(9) M-1 for poly[d(A-T)] and 2.8 x 10(8) M-1 for poly[d(G-C)] and are cytotoxic against murine leukemia cells L1210 in vitro (IC50 of 9Mn,Me = 0.8 microM). Their cytotoxicities are dependent on the nature of central atom. Iron derivatives are less active than manganese analogues and the corresponding zinc derivatives are nearly inactive despite their same affinity for nucleic acids. These highly water-soluble hybrid molecules could be considered as efficient bleomycin models based on a cationic metalloporphyrin.

Antineoplastic activity of didemnin congeners: nordidemnin and modified chain analogues.

Nordidemnin (2), a natural analogue of the marine cyclodepsipeptide didemnin B (1b), showed cytotoxic activity against L1210 leukemia and antineoplastic activity against P388 leukemia as well as B16 melanoma; nordidemnin (2) was as active as didemnin B (1b). The influence of synthetic modifications in the linear peptidic chain on in vitro and in vivo activity was also studied. Replacement of the terminal lactyl residue by mandelyl and 3-(p-hydroxyphenyl)propionyl residues in compounds 3 and 4, respectively, did not affect the cytotoxic activity against L1210 leukemia (ID50 of 1.1 nM and 1.2 nM, respectively) or the in vivo activity against P388 leukemia. Unlike these aromatic substituants, the lipophilic palmityl residue induced a dramatic loss in cytotoxic activity. The inverted chirality of the MeLeu joining residue in compound 6 caused a marked reduction in the in vitro activity.

Heterocyclic quinones. 17. A new in vivo active antineoplastic drug: 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione.

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile.

The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24-hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by mass spectrometry (fast atom bombardment and desorption chemical ionization) and 1H-NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3' of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol.