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Background A medicinal treatment optimisation (MTO) programme has been implemented since 2012 in a gerontological sector (GS) of our territory. Purpose Measure the degree of involvement of the Establishments for Elderly Dependent Persons (EEDP) in this programme. Material and methods A first audit evaluating each stage of the medication circuit (from prescription to drugs administration) was carried out between 2012 and 2014 in every EEDP of the GS (38 institutions). Then, individualised and specific improvement actions (IA) have been defined for each EEDP in a multidisciplinary way. Finally, since 2015, a second audit is carried out in each EEDP, with the same analysis criteria of the first audit. We presents here first comparison results (only from the EEDP that benefited from this second audit): on the one hand, we measured the rate of implementation of IA in every EEDP, and on the other we compared specific prescription indicators before and after implementation of these IA. Results These first results concern 47% of the EEDP of the GS (18/38). For these 18 EEDP, 250 IA were defined after the first audit, with an average of 13.9 IA per EEDP (min: 9, max: 22). After the second audit, we observed that 189 IA (75.6%) had been implemented partially or totally (average: 10.5IA/15 per EEDP). Concerning prescriptions’ indicators, the number of medications per prescription decreased from 7.5 on average per EHPAD after the first audit (min: 4.2, max: 14) to 5.5 after the second (min: 4, max: 8.1). A recent renal clearance (less than 1 year) was found in 63% of residents records after the first audit (min: 20%, max: 96%) and in 85% of residents records after the second (min: 63.3%, max: 100%). Conclusion The impact of our MTO programme appears to be positive, although these results have to be confirmed in other EEDP of the GS. One of the often-proposed IA for improving drug prescriptions in the elderly was the implementation of multidisciplinary proofreading sessions of prescriptions within the EEDP, with the participation of general practitioners. In the end, we observed a decrease of two drugs per prescription, and an increase of 20% in renal clearance measures.

Le but de ce travail est d’evaluer la prise en charge medicamenteuse du sujet âge au sein des etablissements sanitaires et medicosociaux de la filiere gerontologique, en vue de reduire la iatrogenie medicamenteuse evitable. L’audit clinique realise a permis d’evaluer d’une part la juste prescription par l’analyse de 980 ordonnances (incluant trois hopitaux et 28 EHPAD), et d’autre part les differentes etapes du circuit du medicament de 27 EHPAD de la filiere. Ainsi, des points forts et points faibles ont pu etre identifies, et des axes d’amelioration specifiques ont pu etre mis en place.

Afin d’optimiser la prise en charge medicamenteuse chez le sujet âge, des seances de relecture pluridisciplinaire d’ordonnances ont permis de proposer 435 optimisations therapeutiques pour 145 patients (arret, substitution ou introduction d’un traitement, respect du bon usage). Les medicaments inappropries doivent etre identifies. Le medecin traitant doit etre pleinement integre a la demarche, qui permet d’ameliorer la qualite, la securite et l’efficacite de la prise en charge globale du patient.

Introduction La duree d’antibiotherapie en cas de pneumonie de l’adulte peut etre reduite grâce a l’utilisation de la procalcitonine (PCT) ; aucune etude ne l’a cependant demontrer chez le sujet tres âge (> 80 ans), polymorbide ayant des delais de reponses therapeutique souvent plus difficiles a evaluer. Nous avons donc conduit un essai randomise multicentrique pour determiner si la PCT permettait une reduction de la duree antibiotique chez le sujet de plus de 80 ans. Materiels et methodes Essai randomise ouvert dans 6 centres hospitaliers francais. Les criteres d’inclusions etaient : > 80 ans, antibiotherapie debutee initialement pour une pneumonie depuis 0,25 ng/L) et un groupe Controle qui n’avait pas acces aux resultats des mesures de PCT le clinicien stoppant l’antibiotherapie selon les modalites classiques. Une mesures de PCT etait realisee tous les 2 jours, et a la sortie. Les donnees demographiques, cliniques, geriatriques, et de gravite (Pneumonia Severity Index (PSI), CURB 65) ont ete collectees. Le diagnostic etait confirme par radiographie thoracique ou tomodensitometrie thoracique. Le critere de jugement principal etait la duree d’antibiotherapie moyen dans les 2 groupes rapporte a l’evolution clinique a 45 jours. Resultats Cent dix-sept patients ont ete inclus et l’analyse finale a porte sur 107 pneumonies (57 dans le groupe temoin, 50 dans le groupe PCT), 10 inclusions a tord ont ete exclues. Les caracteristiques demographiques, cliniques et geriatrique ne differaient pas dans les 2 groupes ; la gravite initiale etait equivalente : 86 % avait CURB 65 ≥ 2 et 78 % un PSI ≥ IV dans le groupe PCT et respectivement 86 % et 84 % dans le groupe temoin. Les taux de PCT moyens ne differaient ni initialement ni dans leur evolution entre les 2 groupes. La duree d’antibiotherapie etait significativement plus courte dans le groupe PCT (8,4 ± 3,1 j) que dans le groupe temoin (10,7 ± 3,6 j) (p 85 %). L’algorithme a ete suivi dans 52 % des cas dans le groupe PCT. Lorsque l’algorithme etait suivi la reduction de l’antibiotherapie etait de 3 j (p Conclusion Un algorithme decisionnel base sur les niveaux de PCT dans la pneumonie hospitalisee du sujet de > 80 ans permet de reduire la duree antibiotique sans affecter le pronostic. La mesure de PCT qui semble la plus pertinente est au 6e jour. Des etudes ulterieures sont necessaires pour demontrer un impact individuel a long terme et un benefice collectif a cette reduction.

Resume Propos En l’absence de recommandations precises sur la transfusion du sujet âge, nous avons realise une etude sur les pratiques transfusionnelles en geriatrie. Methodes Enquete descriptive transversale nationale realisee aupres de 14 services de geriatrie francais (12 CHU et deux CHG). Cinq dossiers de patients transfuses ont ete tires au sort par service (70 dossiers), afin d’analyser la typologie des patients, l’indication, les criteres et les modalites de transfusion, ainsi que l’adequation aux recommandations de l’Afssaps concernant les criteres de mauvaise tolerance et les seuils transfusionnels. Resultats Les dossiers de 70 patients ont ete analyses (âge moyen 86 ± sept ans, sex-ratio femme / homme 1,8 avec cinq ± deux pathologies et six ± trois traitements en moyenne). Les criteres de mauvaise tolerance etaient le plus souvent la confusion (23 %), la somnolence (22 %), l’insuffisance cardiaque (17 %) ou coronaire (16 %), et differaient des criteres rapportes par l’Afssaps dans la majorite des cas. Le seuil transfusionnel utilise en l’absence de signes de mauvaise tolerance (45 % des transfusions) differait de celui recommande par l’Afssaps dans 26 % des cas. Les evenements indesirables receveur etaient essentiellement representes par l’insuffisance cardiaque. Conclusion L’analyse des criteres de mauvaise tolerance de l’anemie ou des seuils transfusionnels utilises indique que les pratiques transfusionnelles en geriatrie ont des particularites. Des etudes sont necessaires pour valider la pertinence des pratiques decrites dans cette etude.

Total suspended particulate (TSP) samples have been collected at six stations in the C and B lines of the Buenos Aires underground system and, almost simultaneously, at six ground level sites outside and nearby the corresponding underground stations, in the Oct 2005/Oct 2006 period. All these samples were analyzed for mass and elemental Fe, Cu, and Zn concentrations by using the Particle Induced X-ray Emission (PIXE) technique. Mostly, TSP concentrations were found to be between 152 μg m−3 (25% percentile) and 270 μg m−3 (75% percentile) in the platform of the stations, while those in outside ambient air oscillated from 55 μg m−3 (25% percentile) to 137 μg m−3 (75% percentile). Moreover, experimental results indicate that TSP levels are comparable to those measured for other underground systems worldwide. Statistical results demonstrate that subway TSP levels are about 3 times larger on average than those for urban ambient air. The TSP levels inside stations and outdoors are poorly correlated, indicating that TSP levels in the metro system are mainly influenced by internal sources. Regarding metal concentrations, the most enriched element in TSP samples was Fe, the levels of which ranged from 36 (25% percentile) to 86 μg m−3 (75% percentile) in Line C stations, while in Line B ones they varied between 8 μg m−3 (25% percentile) and 46 μg m−3 (75% percentile). As a comparison, Fe concentrations in ambient air oscillated between 0.7 μg m−3 (25% percentile) and 1.2 μg m−3 (75% percentile). Other enriched elements include Cu and Zn. With regard to their sources, Fe and Cu have been related to processes taking place inside the subway system, while Zn has been associated with outdoor vehicular traffic. Additionally, concerns about possible health implications based on comparisons to various indoor air quality limits and available toxicological information are discussed.

Resume Nous rapportons une observation de periarterite noueuse (PAN) revelee par des hemorragies cerebrales par rupture d'anevrismes. Une patiente de 40 ans a presente a 12 jours d'intervalle deux hematomes intracerebraux, le second par rupture d'anevrismes. Le diagnostic de PAN a ete porte sur l'histologie de l'anevrisme montrant des lesions de vascularite, sur l'arteriographie evocatrice de PAN par ses localisations renales et spleniques, sur l'alteration de l'etat general, et sur la presence depuis plusieurs annees de nouures cutanees caracteristiques. L'evolution a ete globalement favorable sous corticotherapie et cyclophosphamide. Les accidents vasculaires hemorragiques cerebraux sont rares dans la PAN et exceptionnellement revelateurs de la maladie.

The age-related difference in fluoroquinolone-induced tendon toxicity was investigated. In vitro tendon cells from juvenile and young adult rabbits, respectively, were incubated with quinolone (nalidixic acid, NA) or fluoroquinolone (ofloxacin, OFX or pefloxacin, PEF) at 0.01 microM to 1 mM for 72 h. Redox status, glutathione (GSH), reactive oxygen species (ROS), and mitochondrial activity were assessed using intracellular fluorescent probes. Fluorescence signal was detected on living adherent tenocytes in microplates using cold-light cytofluorometry. Tendon toxicity differed significantly between the two cell groups and the difference was greatest with highest dose (1 mM). For 72 h, significant (p < 0.001) differences between immature and young adult primary tenocytes were observed for redox status decrease, GSH decrease, and ROS production increase. Mitochondrial activity remained unaltered in immature tenocytes. We confirm two groups of intrinsic tendon toxicity (OFX/NA vs. PEF) associated to oxidative stress (GSH decrease). Our in vitro experimental model confirms the clinical observations of age dependent tenotoxicity. First group (NA, OFX) showed greater intrinsic tenotoxicity for young adult than immature tenocytes, second group (PEF) was highly toxic for immature and young adult cells. The three quinolones do not altered mitochondrial activity in immature tenocytes whereas alteration was observed in young adult tenocytes.

We have developed an automated surveillance system based on passive infra-red sensors. Eight sensors were installed in a hospital room. A computer automatically captured data from the sensors every night from 21:00 until 06:00 the following morning. The sensors were polled twice per second and when a sensor was activated by movement, the event and time were recorded in a data file. At the end of the surveillance period the program analysed the data and generated a report showing the activities taking place in the room and their times. Four elderly patients were observed for a total of 97 nights. A total of 1637 possible sequences of movements by the patient and the hospital staff were detected. The computer was able to identify 1450 sequences (89%) correctly, in comparison with manual analysis. Only 10 movements (0.6%) were undetected by the system; all were very short sequences (five or six activations of the sensors). The system was generally capable of detecting and classifying all major movements in the room.

Purpose Atrial fibrillation and venous thromboembolism are particularly frequent in the elderly. Whether or not prescribe oral anticoagulant treatment in the elderly is therefore a common question for the physician. Despite the benefits of anticoagulation demonstrated in clinical trials, oral anticoagulant therapy is underused in the elderly. Current knowledge and key points Indications for oral anticoagulation are discussed specifically in the elderly with a literature review. Only the length of anticoagulation treatment after a venous thromboembolism remained a purpose of discussion regarding the severity of the pathology. The frequency of systemic thromboembolism in nonvalvular atrial fibrillation is increasing with age. Oral anticoagulation reduces this risk. This benefice is to compare with the increasing rate of major bleeding complications in the elderly and in patient who had stroke, hyper-tension, diabetes mellitus or gastrointestinal bleeding. The objective of this article is to focus on the mode to measure oral anticoagulant benefice/risk ratio in the elderly and to propose several ways to minimize the risk for bleeding. Future prospects and projects The potential drug side effect severity of oral anticoagulation must lead to find the "reasonable" clinical indications in term of benefice/risk ratio and what measures should be take to increase the safety of oral anticoagulation in the elderly. The comprehensive geriatric evaluation should be considered as a decision-aid tool in long-term oral anticoagulation in the frail elderly. Anticoagulation clinics, informatics'-prescription coupled with dose-adaptation decision-aid adapted to the elderly should be helpful in this research of quality. Finally, prescribers education supports must insist on the early course of therapy that is at higher risk of bleeding.

Resume Propos. – La chirurgie de decompression des nevrites lepreuses n’est pratiquee que dans des centres de reference de lutte contre la lepre, souvent eloignes des lieux de residence des patients qui ne peuvent y acceder. L’objectif de ce travail est d’evaluer la faisabilite de cette chirurgie dans des conditions sanitaires precaires. Methodes. – Un chirurgien general forme a cette technique a ete recrute par l’hopital Bom-Pastor situe dans une region isolee d’Amazonie bresilienne, distante de 400 km du centre de reference. Les patients operes entre mai 1996 et decembre 1997 ont ete inclus dans cette etude retrospective. Resultats. – Quarante-cinq decompressions ont ete effectuees, au cours de 17 interventions, chez 13 patients dont 12 atteints de lepres multibacillaires. La chirurgie etait realisee apres un delai median de un an suivant le diagnostic de lepre et de trois mois et demi suivant le diagnostic de nevrite. Elle etait pratiquee 14 fois sur 17 pour des nevrites hyperalgiques recentes resistantes aux corticoides ou recidivantes dans le mois suivant l’arret de la corticotherapie et trois fois pour des nevrites anciennes avec deficit moteur et deformation. La chirurgie de decompression a permis une disparition des douleurs dans tous les cas de nevrites recentes sauf chez un patient presentant une reaction de type 2 severe, corticodependante. Une amelioration fonctionnelle a ete observee chez un des trois patients presentant des nevrites anciennes avec deficit moteur. Les complications chirurgicales ont ete une infection de cicatrice d’evolution favorable et une cheloide. Deux nevrites ont recidive deux et dix mois apres la chirurgie. Conclusions. – Dans une region isolee ou la lepre est endemique, la possibilite de realiser une chirurgie de decompression represente un progres reel dans la prise en charge des nevrites lepreuses.

Resume Introduction. – L’empyeme pleural primitif ou secondaire a une pneumopathie infectieuse reste a l’origine d’une surmortalite et d’hospitalisations prolongees. L’âge moyen de survenue d’un empyeme pleural est habituellement de 55 ans chez l’adulte et demeure rarement diagnostique chez le sujet tres âge (85 ans et plus). Nous rapportons ici deux observations d’empyeme pleural survenu chez deux patients tres âges illustrant la diversite des presentations cliniques. Exegese. – Les facteurs de risque d’empyeme pleural sont lies aux etats d’immunodepression habituellement decrits pour les syndromes septiques. Les germes responsables sont les cocci Gram positifs, les germes anaerobies et de facon moins frequente les bacilles Gram negatifs. Il existe toutefois une proportion elevee d’infections polymicrobiennes. L’histoire clinique peut cependant etre heterogene sans element favorable a l’origine infectieuse de l’epanchement pleural. La rapidite de la prise en charge therapeutique associant antibiotherapie et drainage pleural est un des facteurs pronostics les plus importants. Conclusion. – En raison de la diversite la presentation clinique des empyemes chez le sujet âge et du benefice de leurs traitements precoces, tout epanchement pleural non connu doit etre investigue.

Digoxin-specific Fab are recognized to be effective in the treatment of acute cardiac glycoside poisoning but no pharmacokinetic studies have been performed in human volunteers. We thus propose an allometric approach among three mammalian species to predict Fab pharmacokinetic parameters in humans. Plasma disposition of digoxin-specific Fab was studied at a 20 mg/kg i.v. dose in mice, rats, and rabbits. Fab plasma concentration was determined by a sensitive and specific radioimmunoassay. Allometric equations showed that the pharmacokinetic parameters (distribution volumes (Vc (ml) = 0.084 W0.96; Vdss (ml) = 0.24 W0.96; Vd beta (ml) = 0.55 W0.96, r2 = 1), total body clearance (Cltot (ml/hr) = 0.61 W0.67, r2 = 0.999), and terminal half-life (t 1/2 beta (hr) = 0.63 W0.29) correlated with body weight. The Fab plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot and t 1/2 beta were calculated as 10.75 liter, 24.64 liter, 17.9 ml/min, and 16 hr, respectively, for a human subject of 70 kg body weight. These values are in accordance with those previously described in digoxin-Fab-treated patients (body weight = 61 +/- 3 kg, Vd beta = 24.9 +/- 3. 7 liter; Cltot = 20.8 +/- 2.1 ml/min; t 1/2 beta = 14.3 +/- 1.8 hr). Results indicate that the primary Fab pharmacokinetic parameters can be reasonably estimated in man using pharmacokinetic data from three animal species.

Using published data, we have investigated the relationship of the association constant (Ka) of 265 MAbs for haptens with molecular weights ranging from 111 to 1202 Da. The study indicates that: (1) differences of a factor 10(3)-10(5) are frequently found between the lowest and the highest value of Ka for the same hapten; (2) the relationship between log Ka and the hapten molecular weight of either the native drug or the molecular entity used for the Ka determination is described by a hyperbolic function; (3) beyond a critical molecular weight of approximately 300-325 Da, the log Ka reaches a plateau at a maximal value near 10(-12) M-1.

We applied the PIXE (Particle‐Induced X‐ray Emission) technique to samples of atmospheric aerosols collected in filters in the Auger South Observatory, Malargue, Argentina, with instrument Andersen Graseby 240. We analyzed the concentration PM2.5, PM2.5–10 and PM10 by gravimetric analysis and the elemental composition of fine (size

One of the main difficulties with primary rat brain endothelial cell (RBEC) cultures is obtaining pure cultures. The variation in purity limits the achievement of in vitro models of the rat blood-brain barrier. As P-glycoprotein expression is known to be much higher in RBECs than in any contaminating cells, we have tested the effect of five P-glycoprotein substrates (vincristine, vinblastine, colchicine, puromycin and doxorubicin) on RBEC cultures, assuming that RBECs would resist the treatment with these toxic compounds whereas contaminating cells would not. Treatment with either 4 microg/mL puromycin for the first 2 days of culture or 3 microg/mL puromycin for the first 3 days showed the best results without causing toxicity to the cells. Transendothelial electrical resistance was significantly increased in cell monolayers treated with puromycin compared with untreated cell monolayers. When cocultured with astrocytes in the presence of cAMP, the puromycin-treated RBEC monolayer showed a highly reduced permeability to sodium fluorescein (down to 0.75 x 10(-6) cm/s) and a high electrical resistance (up to 500 Omega x cm(2)). In conclusion, this method of RBEC purification will allow the production of in vitro models of the rat blood-brain barrier for cellular and molecular biology studies as well as pharmacological investigations.

Antivitamin K treatments (AVK) are related to increased morbidity and mortality, notably in elderly patients. The International Normalized Ratio (INR) should be well controlled and its stabilisation within the therapeutic range help to prevent the haemorrhagic complications.A one-year prospective survey on all the cases of excess AVK was conducted in hospitalised patients aged over 70.During the study period, 225 hospitalised patients treated with AVK (mean age 84 years) were identified: 62% received warfarin, 19% fluindione, 8% acenocoumarol and 11% received several successive AVK. During this period, 1.904 INR measurements were recorded: 97 (5.1%) wereor =5.0 and 12 (0.63%) wereor =9.0. In all, 59 patients (23.1%) exhibited one or several episodes of excess AVK (INRor =5.0) and 57 exhibited a target INR of 2.5. Three patients died of accidental haemorrhage--two of them due to intra-cerebral bleeding--among the 59 patients with excess AVK. In three cases, the INR was greater than 7.0 at the time of the accident.In half of the cases of excess, the episode occurred during the month following initiation of treatment with AVK. In nearly two thirds of cases, a change had been made in drug therapy in the 10 days preceding the excess, with the prescription of a drug enhancing the effect of the AVK: anti-infection agents (antibiotics and anti-fungals) and amiodarone were the drugs most frequently involved. Oral or intravenous vitamin K1 was administered in only 19% of cases.In very old patients treated with oral anticoagulants, certain risk factors must be identified: the initiation period of treatment, the occurrence of an intercurrent disease and the subsequent change in the drug therapy. INR monitoring should be intensified in order to detect any excess and, if detected, ensure the optimal management of the patient.

Atrial fibrillation and venous thromboembolism are particularly frequent in the elderly. Whether or not prescribe oral anticoagulant treatment in the elderly is therefore a common question for the physician. Despite the benefits of anticoagulation demonstrated in clinical trials, oral anticoagulant therapy is underused in the elderly.Indications for oral anticoagulation are discussed specifically in the elderly with a literature review. Only the length of anticoagulation treatment after a venous thromboembolism remained a purpose of discussion regarding the severity of the pathology. The frequency of systemic thromboembolism in nonvalvular atrial fibrillation is increasing with age. Oral anticoagulation reduces this risk. This benefice is to compare with the increasing rate of major bleeding complications in the elderly and in patient who had stroke, hyper-tension, diabetes mellitus or gastrointestinal bleeding. The objective of this article is to focus on the mode to measure oral anticoagulant benefice/risk ratio in the elderly and to propose several ways to minimize the risk for bleeding.The potential drug side effect severity of oral anticoagulation must lead to find the "reasonable" clinical indications in term of benefice/risk ratio and what measures should be take to increase the safety of oral anticoagulation in the elderly. The comprehensive geriatric evaluation should be considered as a decision-aid tool in long-term oral anticoagulation in the frail elderly. Anticoagulation clinics, informatics'-prescription coupled with dose-adaptation decision-aid adapted to the elderly should be helpful in this research of quality. Finally, prescribers education supports must insist on the early course of therapy that is at higher risk of bleeding.

Primitive thoracic empyema or empyema secondary to pneumonia represents a significant medical problem necessitating prolonged hospitalizations and increasing the rates of morbidity and mortality. Average patient age is 55 years and remains rare in very old patients (85). We report here two observations in very old patients, pointing out the diversity of the clinical presentation.Empyema thoracis is classically associated with underlying diseases. It is often polymicrobial but Gram-positive bacteria and anaerobes are more frequent than Gram-negative bacteria. The clinical presentation may be aspecific without any parameters in favor of infectious disease: the rapidity of pleural drainage and antibiotic therapy are the main prognostic factors.Because of the diversity of clinical presentation in the elderly population, and because of the efficiency of rapid treatment, geriatric physicians should perform an examination of pleural fluid when pleural effusion is unknown.

Only leprosy resource centres undertake surgery for neuritis. Patients' accessibility to this surgical procedure is poor because these centres are often far from their homes. The aim of our work is to study the feasibility of neuritis surgery in the field.A surgeon trained in this surgery was recruited by Bom-Pastor hospital in Brazilian Amazonia, which is located 400 km away from the leprosy resource centre. Patients operated from May 1996 to December 1997 were enrolled in this retrospective study.A total of 45 operations were carried out during 17 procedures on 13 patients, among which 12 were multibacillary cases. The decompression surgery was performed with a median delay of 1 year after leprosy diagnosis and 3.5 months after the neuritis diagnosis. Among 17 operations, 14 were performed for painful neuritis of recent onset unsuccessfully treated with corticoids or recurring during the month after corticoids were withdrawn. The other three operations were performed for long-standing neuritis with paralysis and deformity. Pain was relieved in all the cases of recent neuritis, except for one patient who suffered from a serious steroid-dependant erythema nodosum leprosum. An improvement of motor function was observed in one out of three patients with long-standing neuritis. Adverse effects were few: a scar infection with a rapid recovery and a keloid scar. Two neurites recurred 2 and 10 months after the surgery.In an endemic leprosy region, field access to surgery for neuritis appears to prove real progress in the management of leprosy neuritis.

To optimize drug therapy in the elderly, multidisciplinary proofreading of prescriptions sessions allowed to provide 435 therapeutic optimizations for 145 patients (stop, substitution or introduction of treatment, respect of proper use). Inappropriate drugs must be identified. The general practitioner must be fully integrated into the process, which improves the quality, the safety and effectiveness of the patient overall care.

We have developed a method for remote wound assessment in the elderly. Wound images were taken with a digital camera at a resolution of 640×480 pixels. JPEG compression was then used to produce images of about 100 kByte. Selected clinical data were transmitted by email, together with standardized digital images of wounds. The remote physician then read the clinical data and viewed the digital images on a 38 cm colour display monitor, at a resolution of 800×600 pixels, in 16-bit colour, using standard software. Three elderly inpatients with pressure sores or leg ulcers had both bedside and remote examinations, by different physicians. The diagnosis and therapeutic recommendations proposed after each of the two examinations were compared qualitatively. There was reasonable agreement between the two physicians in the assessment of wound size, anatomical classification, wound bed and status of infection. However, the lack of palpation represented a major limitation to remote wound assessment, despite the use of probes to delineate the depth of any opening in the wound bed.

Increasing optical power and electrical-to-optical conversion efficiency enable visible light-emitting diodes to advance into new applications and wider markets. InGaAlP/GaAs and InGaN/sapphire material systems cover the whole visible spectrum of saturated colors used for display, signage, and automotive use. A combination of blue InGaN LEDs with phosphor delivers a 'white' spectrum adequate for most lighting needs. Demand for high optical power requires larger chips suitable for high-current operation. Current crowding effects and their negative consequences for chip performance and reliability limit the performance of high-power chips based on both material systems. Despite the differences between InGaAlP/GaAs and InGaN/sapphire chip structures, a number of common design concepts leading to higher external efficiency and total luminous output have been proposed, including large chips operating at high drive currents. This paper highlights fundamental current spreading and reliability issues related to the chip size and operating current density, outlines a framework for quantitative analysis, proposes and compares a number of novel high-power chip designs.© (2000) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

To investigate the clinical, neuropsychological and imaging manifestations of Sjögren's syndrome (SS), a chronic auto-immune disease with peripheral and central nervous system (CNS) involvement.Fourteen female patients suffering from confirmed SS underwent within 2 weeks: neurological examination, immunological staging, brain MRI, brain 99m Tc-HMPAO SPECT, psychological evaluation and in-depth neuropsychological testing.All patients showed neuropsychological abnormalities. The cognitive symptoms were of the same type in all patients, mostly frontal lobe syndrome and memory problems. The neuropsychological involvement was not associated with other kinds of CNS involvement or MRI abnormalities, but accurately reflected HMPAO imaging results.The results of this study indicate that cognitive evaluation is the most sensitive clinical test to diagnose CNS involvement in patients with SS, and that CNS involvement in SS seems to be more frequent when systematically assessed by neuropsychological tests.

The aim of this study was to investigate the pharmacokinetics and the accumulation and stationarity of thiocolchicoside after repeated intramuscular administration.The pharmacokinetics of thiocolchicoside were studied in 6 healthy male volunteers after one single dose and repeated intramuscular doses of 4 mg twice a day for seven days. Plasma and urine samples were assayed for thiocolchicoside levels by a radioimmunoassay (RIA) using a cross-reacting colchicine-specific polyclonal antibody. The pharmacokinetic parameters between the first and the last days were compared using Student's t-test.Thiocolchicoside pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the repeated-dose regimen, the terminal half-life was not significantly different (2.7 (0.3) h) from that predicted from a single-dose (2.8 (0.2) h). The accumulation ratio, based on the repeated-dose/single-dose ratio of AUCtau was approximately 1.25. A decrease of CLT/f was found between day 1 (24.1 (5.2) l/h) and day 7 (19.9 (3.4) l/h), suggesting that moderate time-related alterations occur in the pharmacokinetics of thiocolchicoside, which may be due to a change in its CL(NR) (CL(R) was constant) or to the extent of bioavailability, explained by enterohepatic recirculation.Serum thiocolchicoside concentrations accumulated to steady-state when the drug was given twice a day for seven days and the pharmacokinetics were modified. But no adjustments of dose or dosing interval were necessary because the accumulation did not lead to marked change in the plasma levels.

F(ab')2 fragments are sometimes preferred to whole IgG for therapeutic or diagnostic uses. Preclinical pharmaceutical development studies are necessary before their use in humans. Here we propose an allometric approach among three mammalian species to predict F(ab')2 pharmacokinetic parameters in humans. Plasma disposition of horse antivenom F(ab')2 fragments labeled with iodine 125 was studied at a dose of 10 mg/kg i.v. in mice, rats, and rabbits. Using the allometric method, we demonstrate that the pharmacokinetic parameters that correlated with body weight were distribution volume (Vdc (ml) = 0.125 W0.87; Vdss (ml) = 0.251 W0.87; Vd beta (ml) = 0.290 W0.87, r2 = 1), total clearance (Cltot (ml/h) = 0.049 W0.53, r2 = 0.99), and terminal half-life (t1/2 beta (h) = 4.35 W0.33). The F(ab')2 plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot, and t1/2 beta were calculated as 4.12 liter, 4.78 liter, 19.07 ml/h, and 7.2 days, respectively, for a human subject of 70 kg body wt. Predicted human pharmacokinetic parameters were comparable for volume of distribution with the value reported by Hnatowich et al. (Cancer Res. 47, 6111-6117, 1987): 3.5 liter. However, the clearance was six-fold lower than values given by Hnatowich et al. (130 ml/h) and Ho et al.

The mechanisms by which antivenom neutralizes the venom are still poorly understood. In the present work, we studied the effects of antivenom, constituted with either F(ab')2 or Fab, on the processes of absorption and elimination of Vipera aspis venom in experimentally envenomed rabbits. We first concluded from this study that during the few hours after intramuscular injection, the venom rapidly disappeared from the site of injection but did not immediately reach the vascular system, suggesting that it is partly absorbed via the lymphatic circulation. Concerning the elimination process of the venom in the presence of antivenom, we observed that the elimination of F(ab')2/venom complexes is slower than that of free venom in the absence of antivenom but faster than that of free F(ab')2, suggesting that F(ab')2/venom complexes are eliminated by phagocytosis. The Fab/venom complexes, on the other hand, are eliminated more slowly than free Fab. These complexes are not eliminated through the renal route in agreement with their high molecular weight. In addition, we observed that the treatment of envenomed rabbits with antivenom made of Fab, but not F(ab')2, is responsible for an oliguria that could be responsible for clinical problems.

The effects of dietary (n-6)/(n-3) polyunsaturated fatty acid balance on fatty acid composition, ouabain inhibition, and Na(+) dependence of Na(+), K(+)-ATPase isoenzymes of whole brain membranes were studied in 60-day-old rats fed over two generations a diet either devoid of alpha-linolenic acid [18:3(n-3)] (sunflower oil diet) or rich in 18:3(n-3) (soybean oil diet). In the brain membranes, the sunflower oil diet led to a dramatic decrease in docosahexaenoic acid [22:6(n-3)] membrane content. The activities of Na(+), K(+)-ATPase isoenzymes were discriminated on the basis of their differential affinities for ouabain and their sensitivity to sodium concentration. The ouabain titration curve of Na(+), K(+)-ATPase activity displayed three inhibitory processes with markedly different affinity [i.e., low (alpha1), high (alpha2), and very high (alpha3)] for brain membranes of rats fed the sunflower oil diet, whereas the brain membranes of rats fed the soybean oil diet exhibited only two inhibitory processes, low (alpha1) and high (alpha2' = alpha2 + alpha3). Regardless of the diet, on the basis of the Na(+) dependence of Na(+), K(+)-ATPase activity, three isoenzymes were found: alpha1 form displaying an affinity 1.5- to 2-fold higher that of than alpha2 and 3-fold higher that of alpha3. In rats fed the sunflower oil diet, alpha2 isoenzyme exhibited higher affinity for sodium (Ka = 8.8 mmol/L) than that of rats fed the soybean oil diet (Ka = 11.7 mmol/L). These results suggest that the membrane lipid environment modulates the functional properties of Na(+), K(+)-ATPase isoenzymes of high ouabain affinity (alpha2).

Antivenomous immunotherapy is still used empirically. To improve the efficacy and safety of immunotherapy, we studied the effects of administering antivenom antibodies (F(ab')2) on the pharmacokinetics of the Vipera aspis venom in rabbits. Free venom levels were measured by enzyme-linked immunosorbent assay and total concentrations were quantified by measuring the radioactivity of trichloroacetic acid-precipitable radioiodinated venom. The intravenous infusion of 125 mg of antivenom 7 h after intramuscular injection with 700 microg x kg(-1) of V. aspis venom produced a redistribution of the venom antigens from the extravascular to the vascular space. Moreover, anti-venom antibodies were able to neutralize the totality of venom antigens in the vascular space, because no free plasma venom was detectable by enzyme-linked immunosorbent assay within 15 min after antivenom injection. Similar effects were obtained after injection of 25 mg of antivenom; however, the venom was only partially neutralized with lower doses (5 and 2.5 mg). We further established that intravenous injection is the most efficient route for antivenom administration, and we examined the effects of early and late immunotherapy. Finally, the efficacy of Fab antibodies was compared with that of F(ab')2; the plasma redistribution and the immunoneutralization of the venom were lower than those induced after injection of the same dose of F(ab')2. The difference between the effects of F(ab')2 and Fab could be explained by the differential pharmacokinetics of the two fragments.

Three isoenzymes of digitalis receptors (alpha 1, alpha 2, alpha 3) in the brain and only one in the kidney (alpha 1) can be distinguished by their ouabain affinities and their responsiveness to sodium. Since we have reported modulations for these digitalis receptors by their fatty acid membrane environment, anaesthesics could bind on and modulate either directly these receptors or indirectly by disturbing membrane lipids. The aim of this study was to evaluate this anaesthetic action on apparent ouabain affinities and sodium dependence of cerebral and renal Na+, K(+)-ATPase isoenzymes activities. Rat brain and kidney membrane fractions with pentobarbital-induced anaesthetized state were compared to an unanaesthetized state for their (1) fatty acid composition of total membrane phospholipids, (2) responsiveness to ouabain and (3) Na+ dependence of digitalis receptors. An anaesthesia period of 10 minutes induced (1) a fatty acid modification of brain membranes and (2) a significant sensibilization to ouabain for the alpha 2 and alpha 3 isoforms of digitalis receptors (alpha 2, IC50; 8.2 +/- 0.5 x 10(-7) mol/l vs 4.5 +/- 0.2 x 10(-7) mol/l; alpha 3, IC50; 6.0 +/- 0.3 x 10(-8) mol/l vs 2.5 +/- 0.1 x 10(-8). In contrast, the ouabain affinity of the alpha 1 subunit expressed in kidney and brain membranes was unaltered. No anaesthetic effect was observed on the Na+ dependence of the alpha 1 isoenzyme in the brain (4 mmol/l) and the kidney (8 mmol/l). Pentobarbital induced a desensibilization for alpha 2-receptors (8.3 +/- 0.5 vs 16.0 +/- 1.4 mmol/l Na+) and a sensibilization for alpha 3-receptors (14.4 +/- 0.8 vs 10 +/- 1.3 mmol/l Na+). These altered properties could be related to a selective modification of the fatty acid composition and/or to the presence of a specific binding site for pentobarbital on these two neuronal digitalis receptors.

To analyze behavioral adaptation of hemiplegic patients performing a complex manual task without time constraint. It was postulated that ipsilateral motor disturbance could not be observed after a hemispheric stroke.Two manual tasks were used: (1) a new one, "Pig-Tail," required the patients to run a 3-cm-diameter copper ring in a wooden handle along a wavy copper wire without any time constraint; (2) the second task was the Nine-Hole Peg Test (NHPT).A hospital department of rehabilitation.A consecutive sample of 36 patients, who had all suffered an ischemic stroke in the middle cerebral artery territory, 18 with left hemisphere damage (LHD) and 18 with right (RHD), and who had similar ages (mean 54 +/- 13), stroke severity, time since stroke (mean 60 days), and functional independence according to the FIM.Main data were number of faults, time in seconds, and difference of time for two trials. Analysis compared the results with the same hand for patients and 86 healthy subjects.Patients scores for NHPT were worse than controls, whatever the side of the lesion (p.05). For Pig-Tail, the number of faults by patients was greater than by controls (p.05); time was higher for LHD, but not significantly, and was similar to controls for RHD. All patients and controls speeded up between the two trials. Although the RHD were clumsy, they were always faster than LHD patients.There are ipsilateral motor disturbances in a complex manual task after hemispheric stoke, even without a speed constraint, and regardless of the hemisphere damaged. Further studies are needed to examine speed control that seemed impaired by right hemisphere damage and could explain clumsiness in these patients.

Uptake of [3H]colchicine (2.5 ng/ml) by human lymphocytes in culture was slow in the length of time to reach steady state (48 hr) and was limited in the maximal intracellular colchicine amount (1-2% of total extracellular colchicine). Efflux of intracellular colchicine was investigated 40 hr after colchicine cell exposure by using either washing of the extracellular medium or adding different colchicine-specific Fab fragments:colchicine dose molar ratios of 0.5, 1 and 5. Except for the 0.5 dose molar ratio, the kinetics of [3H]colchicine efflux from lymphocytes induced by extracellular specific Fab fragments were similar to those obtained by washing and were characterized by a first-order decline with half-lives ranging from 15.5 to 16.4 hr. These half-lives were in the same range as those characterizing the dissociation of colchicine from the intracellular tubulin receptor. Our data demonstrate that a tightly bound intracellular toxin may be extracted by antibody with high affinity for the toxin present in the extracellular space at a rate depending on the rate of dissociation of the toxin from its receptor.

Lithium disposition in plasma, red blood cells (RBC) and urine was studied in acute self-poisoned patients upon chronic lithium therapy (n = 4) and in chronic intoxicated patients receiving oral lithium (n = 10). Following acute intoxication upon chronic lithium therapy, lithium pharmacokinetics did not differ from previous reports. Terminal plasma half-life ranged from 19.0-29.0 h and RBC/plasma ratio was 0.32 +/- 0.11. The distribution volume of the terminal phase, Vz, was estimated at 0.84 +/- 0.32 l/kg and renal clearance was 0.38 +/- 0.11 ml/mn/kg. After chronic intoxication lithium pharmacokinetics differed from those of the acute patients. Terminal plasma half-life ranged from 36.5-79.4 h and zero-order decline appeared in 8 of the 10 patients. The RBC/plasma ratio was 0.87 +/- 0.22 on admission. Vz was estimated at 0.71 +/- 0.27 l/kg and renal clearance was 0.16 +/- 0.07 ml/mn/kg. These modifications in lithium elimination kinetics could be related to the decrease in the glomerular filtration rate with age or renal dysfunction in this group of patients.

Rabbit renal proximal tubule suspensions have proved a convenient model for nephrotoxicity studies, particularly for direct nephrotoxins such as Cephaloridin (Olivier et al., 1992). In order to evaluate the ability of this model to metabolize certain drugs to nephrotoxic compounds, we used another B-lactam antibiotic, Imipenem, known to be nephrotoxic through renal metabolism via hydrolysis by dehydropeptidase I (DHP) (Birnbaum et al., 1985). The use of Cilastatin, an inhibitor of this enzyme, should confirm this metabolic pathway.

Relationships between pharmacokinetics (PK) and pharmacodynamics (PD) are now widely investigated for many drugs with the aim of improving the amount and the rate of drug delivery so as to control the duration and intensity of the pharmacological effect (Levy 1966; Holford 1981). Such relationships have not yet been investigated for toxic effects of drugs as occurs after acute self-poisoning. The establishment of relationships between kinetics of drugs at toxic doses (Toxicokinetics) and those of their pharmacological effects (Toxicodynamics) can be of interest in clinical toxicology. The aim would be to predict the occurrence and the intensity of toxic effects as a function of the ingested dose and the first plasma concentrations on admission of the patient to improve management. In this paper, we describe the different techniques of kinetic-effect modelling actually available, their applications in the case of acute digitalis poisoning and the limits of such techniques in clinical toxicology.

Plasma and follicular fluid (FF) hormone assays for follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestradiol (E2), progesterone (P), delta-4-androstenedione (A4) and testosterone (T) were performed on the day of oocyte retrieval in two groups of normo-ovulatory women enrolled in an in-vitro fertilization (IVF) programme: 24 were treated using the decapeptyl agonists DTRP6, of luteinizing hormone-releasing hormone (LHRH) in the long protocol associated with human menopausal gonadotrophin (HMG) (49 FF) and 14 were stimulated with HMG alone (33 FF). In both FF and plasma the mean concentration of P was greater, and the E2/P ratios as well as the LH levels were lower in the agonist-treated group. In this group the follicular concentration of P was greater and the E2/P ratio lower when pregnancy occurred following IVF. The hormonal modifications may be due to greater functional maturity of the granulosa cells.

The NOD mouse is studied as an animal model of human insulin-dependent diabetes mellitus (IDDM). To evaluate the role of IFN gamma in the pathogenesis of the disease, we have studied the effect of anti-IFN gamma mAb on the expression of insulitis and clinical diabetes. Treatment of mice with anti-IFN gamma mAb prevented the induction of early IDDM by cyclophosphamide as well as the adoptive transfer of diabetes by spleen cells from diabetic NOD mice. The protection against induction of diabetes by cyclophosphamide was observed in animals treated with the anti-IFN gamma mAb within 24 h following the first cyclophosphamide injection but not in animals in which mAb treatment was started 7 days later. Transfer of disease was prevented both in adult irradiated and in newborn recipients. The absence of clinical signs in these mice was corroborated by a significant reduction of both the extent and severity of insulitis. Over-expression of Ia antigen on endothelial cells lining the islets was also considerably reduced in mice treated with mAb. These data strongly suggest a role for IFN gamma during the autoimmune process leading to beta cell destruction in diabetes and prompt further investigation of the use of such antibodies in the immunoprevention of IDDM.

Paclitaxel is a new antimitotic derived from yew-tree, used for the treatment of ovarian and breast cancers. The local toxicity of paclitaxel is still poorly known. We report one of the first observations of accidental subcutaneous extravastion of paclitaxel. Local epidermic necrosis was observed and evolution was good with local treatment only. Treatments of such extravasation are discussed.