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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.

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.

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.

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.

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.

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.

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.

Peripheral lymphocyte subsets were enumerated, using OKT monoclonal sera, in 56 diabetic (43 adults and 13 children) and 20 control subjects. Concomitantly, anti-islet humoral and cellular immunity was tested in vitro and serum thymulin level was measured. In the newly diagnosed patients ( (1) the magnitude of T-cell depletion and/or imbalance in diabetic subjects depended mainly on the duration of the disease, (2) anti-islet cellular immunity was the anomaly most frequently detectable, and (3) a decrease in serum thymulin level was infrequently detected.

To explore humoral immunity in insulin-dependent diabetic (IDDM) patients, we studied insulin release from isolated mouse islets stimulated by glucose + theophylline after incubation with the sera of these patients and complement. Eleven of 21 IDDM sera suppressed the stimulated insulin release while the arginine-stimulated glucagon release remained unchanged. Morphologic evidence and the trypan-blue exclusion test suggested that the suppression of insulin release was due to a cytotoxic effect of the sera. No beta-cell inhibition or morphologic damage was detectable in the presence of sera from 30 healthy subjects, 8 non-insulin-dependent diabetic patients, and 5 nondiabetic patients with autoimmune diseases. Beta-cell inhibition by IDDM sera was not observed when complement was omitted. After serum fractionation, the cytotoxic potency of IDDM sera was located in the immunoglobulin G fraction. Using human islets, insulin release was suppressed by 3 of 6 IDDM sera. Complement-dependent cytotoxicity was found in 1 of 5 recent-onset IDDM patients and 11 of 16 IDDM patients with autoimmune phenomena. It was associated in all cases with the presence of islet cell antibodies as detected by immunofluorescence, and with the presence of circulating lymphocytes which suppressed insulin release in vitro. Complement-fixing antibodies may contribute to the selective beta-cell damage in IDDM.

We previously showed that circulating lymphocytes from more than 90% of insulin-dependent diabetics, block extra insulin secretion induced by stimulatory media in mouse pancreatic cells in vitro, without altering the secretion of glucagon. The present work demonstrates that this phenomenon depends on lymphocytes having the OKT3 marker, i.e., thymodependent lymphocytes. However, OKT4+ T helper cells are not required for the above phenomenon as proved by experiments using monoclonal sera against the OKT4 marker. When diabetes is associated with other autoimmune diseases, the pancreatic lymphocyte cytotoxicity observed in vitro is inhibited by the addition of a normal lymphocyte population; this could indicate that a "suppressor" factor is lacking in these patients. Conversely, addition of normal lymphocytes does not prevent lymphocyte cytotoxicity in diabetics without associated autoimmune diseases. Such a difference confirms the present trend to make a distinction between these two categories of diabetes.

Cyclosporin 5-10 mg/kg daily was given for 2-8 months to twelve recently diagnosed type 1 diabetics from a mean of 49 +/- SE 14 days after the start of insulin therapy, which was regulated to give near-normal blood glucose and haemoglobin A1c values. Mean insulin dosage dropped from 46 +/- 5 U/day before cyclosporin treatment to 16 +/- 4 U/day by the 7th month. Four patients had a complete remission and the insulin needs of four more were cut by half. The remaining four did not have remissions. Initial basal and glucagon-stimulated C peptide concentrations were higher in those who went into remission than in those who did not; they rose during cyclosporin treatment in the former but not in the latter. OKT4+ lymphocyte functions were suppressed in all patients and OKT4/OKT8 ratios declined. Anti-beta-cell autoimmunity, as indicated by lymphocyte-induced inhibition of insulin release from mouse islet cells, declined in all patients who went into remission. No consistent trend was observed for anti-islet cell antibodies. In forty-four similar, but non-randomised, recently diagnosed diabetics treated with insulin alone, the incidence of remission was 6%.

Antilymphocyte sera, either allogeneic or xenogeneic, may retain the antigen used for the immunization of the animal producing the serum in the form of antigen-antibody complexes, at least when the animal is bled within the first two weeks following the last immunizing injection. Evidence for this has been obtained in vivo and in vitro (3). Thus, antilymphocyte injections may contain not only antibodies but the antigens used to prepare the serum as well, and active immunization to these antigens can result in the human or animal recipient. In the heart-allografted rat, pre-transplantation injection of immune complexes prepared from alloantisera prolongs graft survival. The filtrate from these complexes, presumably containing antigens, also prolongs graft survival when administered in conjunction with nonspecific immunosuppresive drugs after transplantation. These results, however, do not allow determination of whether the effect is active or passive, or perhaps both, nor what is the action of the complexes themselves.

A significant inhibition of insulin response was found after incubation of islet cells with blood lymphocytes from 18 out 20 insulin-dependent diabetics. No inhibition was found in 22 control subjects.

The insulin response of isolated islet cells to glucose and theophylline in vitro was studied after incubation with lymphocytes. The test was employed to explore cell-mediated immunity in diabetics. A significant inhibition of insulin response to glucose and theophylline as compared to insulin release in a "basal" medium was found after incubation with blood lymphocytes from 21 out of 23 insulin-dependent diabetics (mean secretion index 18 +/- 18 versus 118 + 8 (SEM) % in control subjects). Most of the patients studied had associated autoimmune diseases: all of these displayed inhibition of insulin release. In six cases, the diabetes had a recent onset with no associated autoimmune disease: four of them displayed the same inhibition. No inhibition was found in the 26 control subjects and in seven non-insulin-dependent diabetics (mean secretion index 134 +/- 17 versus 145 +/- 23 (SEM) % in four control subjects). Lymphocytes inhibiting islet cell response were not cytotoxic against mouse fibroblasts. Twenty-two insulin-dependent diabetics showed islet cell antibodies to human and/or mouse pancreatic islets. However, an inhibition of insulin release was found with no detectable islet cell antibodies in one case, and the converse in two cases. Lymphocyte cytotoxicity to islet cells could play a role in the natural history of insulin-dependent diabetes.

Mice peritoneal macrophages obtained after i.p. injection of a medium containing thioglycollate (Institut Pasteur, Paris) have increased levels of beta glucuronidase and acid phosphatase, when compared with macrophages obtained without previous thioglycollate injection. The maximum increase is observed between 7 and 10 days after injection and reaches up to 3 to 4 times the normal activity. When using separately the various components of the medium, the same phenomenon may be observed but never to the same degree. The injection of thioglycollate also produces: a) an increase in total number of peritoneal cells, and b) an increase in the percentage of macrophages among these cells. Kinetic studies suggest that thioglycollate injection first induces an increase in the number of peritoneal macrophages and subsequently macrophage modifications resulting in lysosomal enzyme increase.

Macrophage-rich adherent peritoneal cells from mice sensitized by two i.p. injections of allogeneic cells at days -- 12 and --2, were found non-specifically cytotoxic against (a) tumoral target cells, as evaluated by the chromium release test, and (b) normal target cells, as evaluated by a functional test based on the insulin secretion response to glucose stimulation of isolated pancreatic islet cells. This non-specific cytotoxicity was identical to that of macrophages "activated" by an in vitro incubation with supernatants of MLC between allograft donor and recipient as reported elsewhere. Moreover this cytotoxicity was not abolished by anti-theta serum treatment of adherent peritoneal cells before contact with target cells. It is concluded that an in vivo macrophage activation was obtained in our experiment. Using this same model, we found that the survival time of skin grafts from male C57BL/6 to female C57BL/6 mice was shortened if the graft was performed at the time when the recipient macrophages were found non-specifically cytotoxic (two days after the second allogeneic cell injection). The role of macrophage cytotoxicity in this accelerated allograft rejection is suggested by (a) the lack of any detectable cross-histocompatibility antigens between the immunizing cells and the skin graft, and (b) the absence of any alteration of the graft survival if the second immunizing injection two days prior to grafting is omitted (in that case only lymphocytes are found specifically cytotoxic against the strain of injected cells, while the non-specific cytotoxicity of macrophages is lacking).

Anti-β-cell–specific cell-mediated immunity was studied over a 12-mo period in 65 recently diagnosed diabetic patients randomly receiving either cyclosporin or placebo. Anti-β–cell cellular immunity was assessed by an in vitro test based on the inhibition of insulin release from cultured rat islet cells by patients' mononuclear cells. This β-cell–suppressive effect disappeared in cyclosporin A–treated patients within 1 mo and did not reappear during 12 mo of follow-up. Conversely, the suppressive effect persisted unchanged in placebo-treated patients during 12 mo of follow-up. These changes were predictive neither of cyclosporin A–induced remission nor of relapses. Results of the insulin-release inhibition test were not correlated to islet cell autoantibodies or HLA phenotype.

Hyperglycaemia in the afternoon is often not prevented by increasing the intermediate insulin dose in C-peptide deficient Type 1 diabetic patients, particularly children, treated with two injections of mixtures of short- and intermediate-acting insulins. To provide a better understanding of this, 19 Type 1 diabetic patients were studied using the euglycaemic clamp technique, after SC injection of either soluble, isophane (NPH) or lente insulin, or mixtures of these preparations. SC injection of 0.6 U kg-1 insulin, as either intermediate-acting (isophane (NPH) or lente) insulin alone or as a mixture of 50% soluble + 50% intermediate-acting insulins, indicates that, for the same total dose of SC insulin, a shift from soluble to intermediate-acting insulin results in a major loss of activity during the first 6 h after injection, with no compensatory increase over the next 6 h. The morning hypoglycaemic activity depends on different mechanisms with isophane (NPH) or lente insulin; the effects of soluble and isophane (NHP) insulin are superimposed, while with lente insulin, the peak of soluble insulin is blunted. For the afternoon, even large doses of isophane (NPH) or lente insulin do not meet the peak of insulin requirements following lunch.

It has been suggested that the immune system may be responsible for the destruction of insulin secreting cells in some types of diabetes. In order to test this hypothesis, we studied the consequences of immune-mediated reactions on the function of pancreatic islet cells in vitro. A model was set up in vitro where mouse pancreatic islet cells are exposed to human lymphocytes or sera + complement then stimulated for the release of insulin or glucagon. A selective inhibition of insulin secretion, but not of glucagon secretion, was observed in the presence of lymphocytes from 37 out of 40 insulin-dependent diabetic (IDD) patients and in the presence of sera (+ complement) from 22 out of 40. Lymphocytes were found inhibitory in almost all patients in both groups, with and without associated autoimmune diseases. In contrast, inhibitory sera were observed almost only in patients with associated autoimmune diseases or recent onset diabetes. The selective inhibition of insulin secretion, but not of glucagon secretion, suggests that lymphocytes or sera may be involved in a destructive process of insulin secreting cells in vivo. This cell-mediated effect depends on direct T lymphocyte cytotoxicity, rather than antibody-dependent cell cytotoxicity, as suggested by the lack of any effect of aggregated immunoglobulins on the reaction. In contrast, when C57BL/6 mice were immunized by mastocytoma cells from a DBA2 strain, their lymphocytes and sera blocked both secretions of insulin and glucagon when incubated in vitro with DBA2 islet cells. This non-selective inhibition may be due to anti-H2 immunity, rather than immunity directed against insulin secreting cells.

CBA Mice were immunized by two intraperitoneal injections of 30 X 10(6) DBA/2 or C57BL/6 spleen cells at days--12 and--2. Peritoneal cell population was obtained at day zero by washing the peritoneal cavity of Mice. Adherent cells were then separated using a 2 hrs. incubation in "Falcon" plates followed by washing. This macrophage-rich peritoneal cell population was found nonspecifically cytotoxic against 51Cr labeled tumoral target cells: P815 X DBA/2 mastocytoma cells, EL4 X C57BL/L lymphoma cells and spontaneous lymphoma AKR cells (same H--2k as CBA). This adherent peritoneal cell cytoxicity was demonstrated after 24 hrs. incubation with the target cells. It was found in nonspecific combination as well as when using target cells syngeneic to the donor. These findings suggest that adherent peritoneal cell cytotoxicity could be at least partly due to macrophages and result from factor (s) released by sensitized lymphocytes in vivo in the same way as has been previously demonstrated in vitro.

Alzheimer’s disease is characterised by a loss of cognitive function and behavioural problems as set out in the term “Behavioural and Psychological Symptoms of Dementia”. These behavioural symptoms have heavy consequences for the patients and their families. A greater understanding of behavioural symptoms risk factors would allow better detection of those patients, a better understanding of crisis situations and better management of these patients. Some retrospective studies or simple observations suggested that personality could play a role in the occurrence of behavioural symptoms. Finally, performance in social cognition like facial recognition and perspective taking could be linked to certain personality traits and the subsequent risks of behavioural symptoms. We propose to clarify this through a prospective, multicentre, multidisciplinary study. Main Objective: - To assess the effect of personality and life events on the risk of developing behavioural symptoms. Secondary Objectives: - To evaluate, at the time of inclusion, the connection between personality and performance in social cognition tests; - To evaluate the correlation between performance in social cognition at inclusion and the risks of occurrence of behavioural symptoms; - To evaluate the correlation between regional cerebral atrophy, using brain Magnetic Resonance Imaging at baseline, and the risk of behavioural symptoms. Study type and Population: Prospective multicentre cohort study with 252 patients with Alzheimer’s disease at prodromal or mild dementia stage. The inclusion period will be of 18 months and the patients will be followed during 18 months. The initial evaluation will include: a clinical and neuropsychological examination, collection of behavioural symptoms data (Neuropsychiatric-Inventory scale) and their risk factors, a personality study using both a dimensional (personality traits) and categorical approach, an inventory of life events, social cognition tests and an Magnetic Resonance Imaging. Patients will be followed every 6 months (clinical examination and collection of behavioural symptoms data and risk factors) during 18 months. This study aims at better identifying the patients with Alzheimer’s disease at high risk of developing behavioural symptoms, to anticipate, detect and quickly treat these disorders and so, prevent serious consequences for the patient and his caregivers. ClincalTrials.gov: NCT01297140