[Withdrawal of artificial nutrition and hydration in severe stroke: medical, legal and ethical considerations]. / Aspects médicaux, législatifs et éthiques de l'arrêt de la nutrition et de l'hydratation artificielles dans l'accident vasculaire cérébral grave.

In the majority of cases, severe stroke is accompanied by difficulty in swallowing and an altered state of consciousness requiring artificial nutrition and hydration. Because of their artificial nature, nutrition and hydration are considered by law as treatment rather basic care. Withdrawal of these treatments is dictated by the refusal of unreasonable obstinacy enshrined in law and is justified by the risk of severe disability and very poor quality of life. It is usually the last among other withholding and withdrawal decisions which have already been made during the long course of the disease. Reaching a collegial consensus on a controversial decision such as artificial nutrition and hydration withdrawal is a difficult and complex process. The reluctance for such decisions is mainly due to the symbolic value of food and hydration, to the fear of "dying badly" while suffering from hunger and thirst, and to the difficult distinction between this medical act and euthanasia. The only way to overcome such reluctance is to ensure flawless accompaniment, associating sedation and appropriate comfort care with a clear explanation (with relatives but also caregivers) of the rationale and implications of this type of decision. All teams dealing with this type of situation must have thoroughly thought through the medical, legal and ethical considerations involved in making this difficult decision.

Temporal lobe aggression in rats.

Although reports of aggressive behavior in temporal lobe epileptics are common, it has proven difficult in clinical settings to gain the experimental control necessary to systematically investigate temporal lobe aggression or even to provide unequivocal evidence of its existence. Increases in aggressive behavior were observed in rats with experimentally induced epileptic foci in temporal lobe structures but not in control rats or those with foci in the caudate.

Substandard medicines in resource-poor settings: a problem that can no longer be ignored.

The circulation of substandard medicines in the developing world is a serious clinical and public health concern. Problems include under or over concentration of ingredients, contamination, poor quality ingredients, poor stability and inadequate packaging. There are multiple causes. Drugs manufactured for export are not regulated to the same standard as those for domestic use, while regulatory agencies in the less-developed world are poorly equipped to assess and address the problem. A number of recent initiatives have been established to address the problem, most notably the WHO pre-qualification programme. However, much more action is required. Donors should encourage their partners to include more explicit quality requirements in their tender mechanisms, while purchasers should insist that producers and distributors supply drugs that comply with international quality standards. Governments in rich countries should not tolerate the export of substandard pharmaceutical products to poor countries, while developing country governments should improve their ability to detect substandard medicines.

Avascular necrosis of the femoral head in patients treated for leukaemia. Assessment of the need for a diagnostic protocol. / Necrosis avascular de cabeza femoral en pacientes tratados de leucemia. Evaluación de la necesidad de un protocolo diagnóstico.

OBJECTIVE: To evaluate the incidence of avascular necrosis of the hip in leukaemia patients treated in our hospital with high doses of corticosteroids in order to evaluate the necessity for an early detection protocol. MATERIAL AND METHODS: Observational-descriptive and retrospective study from 2005 to 2016 of 253 patients diagnosed with paediatric leukaemia. Patients with musculoskeletal pathology were identified and patients with avascular necrosis were analysed. RESULTS: A total of 26 patients (10%) had musculoskeletal symptoms. Three patients with avascular necrosis (1.2%) were analysed. One girl, 7 years old, was treated conservatively with traction - suspension and discharge. Two boys, an 11 and a 15.4 year-old,who developed graft-versus-host disease secondary to bone marrow transplantation, and whose treatment included high doses of corticosteroids, developed avascular necrosis of the hip. One was treated with bisphosphonates and forage and the other ended up with a total hip arthroplasty. DISCUSSION: The occurrence of musculoskeletal symptoms during the treatment of leukaemia is different according to the bibliographic series (0.43 -12.6%). Some authors observe an increased risk in female patients between the ages of 10 and 17. A retrospective study reveals that there is a delay of 3.9 months in the diagnosis of CAP since the onset of pain. Other authors relate NAV to loading joints, age and high doses of corticosteroids. CONCLUSION: Based on the low incidence of avascular necrosis of the hip in our 14-year-old population treated for leukaemia, the creation of diagnostic protocols seems not to be necessary. However, close monitoring of patients with potential risk factors recognized in the literature, is advisable.

Conditioned effects of kindling.

Mild periodic electrical stimulation to any one of many brain sites leads to the development and progressive intensification of elicited motor seizures. Since its discovery in 1969, this kindling phenomenon has been widely studied both as a model of epileptogenesis and as a form of neuroplasticity, and recently there has been increasing interest in kindling as a model of the interictal (i.e. between-seizures) changes in emotionality that accompany certain forms of epilepsy. Despite the extensive use of the kindling model, little consideration has been given to the role played by the cues regularly associated with the delivery of the kindling stimulations. However, we have recently demonstrated that cues associated with the standard kindling protocol (e.g. the stimulation environment) produce conditioned effects on both the motor seizures and interictal behavior of rats and that some kindling sites, such as the amygdala, produce conditioned interictal behaviors that are defensive in nature. The implications that these findings have for the study of interictal behavioral changes in particular and to kindling research in general are discussed.

Increased susceptibility to the epileptic effects of alcohol withdrawal following periodic electroconvulsive shocks.

There was a progressive intensification (kindling) of the motor seizure pattern when electroconvulsive shocks (ECSs) were administered to rats at 3-day intervals, but not when the inter-ECS interval was 1 hr. Similarly, the incidence of convulsive symptoms elicited by subsequent alcohol exposure and withdrawal was a function of the number of antecedent ECSs administered at 3-day, but not at 1-hr, intervals. Significant ECS-produced intensification of the alcohol withdrawal syndrome persisted for 3 weeks following ten periodic ECSs and occurred even when the motor seizures elicited by the antecedent ECSs were pharmacologically suppressed.

Intensification of the alcohol withdrawal syndrome following periodic electroconvulsive shocks.

Repeated electroconvulsive shocks (ECSs) administered once every 3 days to rats at either of two current intensities led to a progressive intensification of the motor seizure pattern. Moreover, the incidence of convulsive symptoms elicited by subsequent alcohol exposure and withdrawal was greatly increased by prior exposure to the repeated ECSs. These results illustrate a treatment--drug interaction which could have hazardous consequences for patients undergoing electroconvulsive therapy. Thus, until the appropriate tests can be conducted on human patients, drug intake following electroconvulsive therapy should be carefully regulated.

Changes in emotional behavior produced by long-term amygdala kindling in rats.

The effects of long-term amygdala kindling on emotional behavior were investigated. In Experiment 1, rats received 99 basolateral amygdala, central amygdala, or sham stimulations. The rats in both kindled groups displayed more resistance to capture from an open field and more open-arm activity on an elevated plus maze than did the sham control rats. In Experiment 2, rats received either 20, 60, or 100 amygdala stimulations or sham stimulations. Compared to the sham controls, the kindled rats explored less during the first 30s in a novel open field, avoided the central area of the open field, resisted being captured from the open field, and engaged in more open-arm activity on the elevated plus maze. The magnitude of these effects was greatest in the 100-stim rats and least in the 20-stim rats. Together, these results suggest that long-term amygdala kindling in rats is a useful model for studying the emotionality associated with temporal lobe epilepsy.

Persistence of the interictal emotionality produced by long-term amygdala kindling in rats.

Long-term amygdala kindling in rats results in large and reliable increases in emotional behaviour that model the interictal emotionality often observed in temporal lobe epileptics [Kalynchuk L. E. et al. (1997) Biol. Psychiat. 41, 438-451; Pinel J. P. J. et al. (1977) Science 197, 1088-1089]. These experiments investigated the persistence of these kindling-induced increases in emotional behaviour after the cessation of the kindling stimulations. In Experiment 1, rats received 99 amygdala or sham stimulations. Then, they were tested on three tests of emotionality (i.e. activity in an unfamiliar open field, resistance to capture from the open field, and activity in an elevated-plus maze) either one day, one week, or one month after the final stimulation. The rats tested one day after the last stimulation displayed substantial decreases in open-field activity, increases in resistance to capture and increases in open-arm activity on the elevated-plus maze; these effects decreased, but not to control levels, in the rats tested one month after the final stimulation. In Experiment 2, rats received 99 amygdala or sham stimulations, and their resistance to capture was assessed one day later. Then, after a 60-day stimulation-free period, the rats received another zero, one, 10, or 30 amygdala stimulations and their resistance to capture was reassessed one day later. The high levels of resistance to capture observed in the rats tested one day after the 99 stimulations declined significantly during the 60-day stimulation-free period, but it remained significantly above control levels. However, the administration of 30 additional stimulations reinstated asymptotic levels of resistance to capture. These results provide the first systematic evidence that kindling-induced increases in emotional behaviour persist at significant levels for at least two months following the termination of kindling stimulations. Thus, they suggest that the neural changes underlying the genesis of interictal emotionality may be closely related to those mediating epileptogenesis itself.

Rhinal cortex lesions and object recognition in rats.

Rats with bilateral lesions of lateral entorhinal cortex and perirhinal cortex were tested on a nonrecurring-items delayed nonmatching-to-sample (DNMS) task resembling the one that is commonly used to study object recognition in monkeys. The rats were tested at retention delays of 4 s, 15 s, 60 s, 120 s, and 600 s before and after surgery. After surgery, they displayed a delay-dependent deficit: They performed normally at the 4-s delay but were impaired at delays of 15 s or longer. The addition of bilateral amygdala lesions did not increase their DNMS deficits. The present finding of a severe DNMS deficit following rhinal cortex damage is consistent with the authors' previous finding that bilateral lesions of the hippocampus and amygdala cause only mild DNMS deficits in rats unless there is also damage to rhinal cortex (D.G. Mumby, E.R. Wood, & J.P.J. Pinel, 1992). These findings add to accumulating evidence that the rhinal cortex, but not the amygdala, plays a critical role in object recognition.

Characterization of the defensive nature of kindling-induced emotionality.

Long-term amygdala kindling produces substantial changes in emotional behavior in rats. The purpose of these experiments was to determine whether kindling-induced emotionality is fundamentally defensive or aggressive in nature. In Experiment 1, amygdala-kindled rats tested as intruders in a resident-intruder paradigm preferred an active defense strategy (i.e., defensive upright stance, jump attacks), whereas the sham-stimulated rats preferred a passive defense strategy (i.e., freezing). In Experiment 2, amygdala-kindled rats explored an unfamiliar open field significantly less than did the sham-stimulated rats, and they were significantly more resistant to capture from the unfamiliar open field than were the sham-stimulated rats. In contrast, there were no significant differences between the kindled and sham-stimulated rats in resistance to capture from their home cages. These results suggest that the emotionality produced by long-term amygdala kindling is fundamentally defensive in nature.

Impaired object recognition memory in rats following ischemia-induced damage to the hippocampus.

Transient cerebral ischemia can produce irreversible neuronal damage and permanent learning and memory impairments in humans. This study examined whether ischemia-induced brain damage in rats results in impairments on the delayed nonmatching-to-sample (DNMS) task, a nonspatial recognition task analogous to tests on which amnesic patients display impairments. Male Wistar rats received either sham surgery or 20-min forebrain ischemia induced by bilateral carotid occlusion and hypotension. Four weeks after surgery, ischemic rats were significantly impaired in both learning and performing the DNMS task at retention intervals up to 5 min. Extensive presurgical training did not reduce this impairment. Observable cell loss in ischemic rats was limited to CA1 pyramidal neurons and a subset of cells in the dentate gyrus. The results indicate that ischemic damage to the hippocampus in rats results in recognition memory deficits similar to those produced by ischemic damage in humans.

Effect of an ascending dose regimen on the development of tolerance to the anticonvulsant effect of diazepam.

The effect of an ascending dose regimen on the development of tolerance to diazepam's anticonvulsant effect was assessed. During the 22 trials of the tolerance development phase, amygdala-kindled rats received either a series of dosage injections ranging from high (10 mg/kg), to low (1.0 mg/kg), and ascending (1.0 mg/kg and increased by 0.2-mg/kg increments to 3.0 mg/kg) or saline injections. Diazepam was administered by ip injection once every 48 hr, and each injection was followed 1 hr later by a convulsive stimulation. The ascending dose rats displayed significantly more tolerance to the anticonvulsant effect of diazepam than did the high dose, low dose, or saline rats. By contrast, both the ascending and high dose rats displayed a significant withdrawal effect (i.e., increased duration of convulsions) after the cessation of diazepam injections. Results demonstrate that administration of ascending dosages can facilitate the development of tolerance to anticonvulsant drug effects and that tolerance and withdrawal are not necessarily inextricably related.

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats.

Three groups of amygdala-kindled rats received 10 bidaily treatment trials: On each trial, the drug-before group received a diazepam (2.5 mg/kg i.p.) injection 1 hr before a convulsive stimulation, the drug-after group received a diazepam injection 1 hr after a stimulation, and the vehicle control group received a vehicle injection either 1 hr before or 1 hr after a stimulation. After treatment, only the drug-before group displayed significantly longer forelimb clonus under the influence of diazepam (that is, they displayed contingent tolerance to diazepam's anticonvulsant effect) and significantly longer forelimb clonus while drug free. Following a 14-day retention period, the rats in the drug-before group retained significant levels of contingent tolerance but did not display significant increases when tested drug free. These data suggest that compensatory responses do not play a causal role in the expression of contingent tolerance.

Conditioning of ictal and interictal behaviors in rats by amygdala kindling: context as the conditional stimulus.

The authors showed that conditional effects of the stimulation environment modulate both the ictal and interictal behaviors of rats subjected to amygdala kindling. Rats received 53 stimulations to the left basolateral amygdala in 1 conditional stimulus (CS) context (CS+) and 53 sham stimulations (the stimulation lead was attached but no current was delivered) in another context (CS-), quasirandomly over 54 days. Three kinds of conditional effects were observed. First, after several stimulations, less ambulatory activity, more freezing, and less rearing reliably occurred in the CS+ context than in the CS-context. Second, after 45 stimulations, all of the rats chose the CS- context over the CS+ context in a conditioned place preference test. Third, when the rats were finally stimulated in the CS- context, their motor seizures were less severe: Latencies were longer, motor seizures were shorter, convulsive patterns were of a lower class, and there were fewer falls.

Pyrithiamine-induced thiamine deficiency impairs object recognition in rats.

Pyrithiamine-induced thiamine deficiency (PTD) in rats is used to model the etiology, diencephalic neuropathology, and memory deficits of Korsakoff's amnesia. We assessed the performance of rats exposed to PTD on a test of object recognition--nonrecurring-items delayed nonmatching-to-sample (DNMS). PTD produced thalamic lesions similar to those of Korsakoff's amnesics and similar to those previously observed in PTD rats. PTD rats required more trials to master DNMS at a 4-s retention delay than did controls, and after they had done so, they performed more poorly than controls at delays of 15, 30, 60, and 120 s. DNMS deficits were also observed in PTD rats that received training prior to PTD treatment. These findings support the validity of the PTD rat model of Korsakoff's disease by demonstrating that PTD rats display object-recognition deficits that are similar to those reported in Korsakoff amnesics.

Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats.

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.

Ischemia-induced object-recognition deficits in rats are attenuated by hippocampal ablation before or soon after ischemia.

The literature on the role of the hippocampus in object-recognition contains a paradox: Transient forebrain ischemia (ISC) produces hippocampal damage and severe deficits on the delayed nonmatching-to-sample (DNMS) task, yet hippocampal ablation (ABL) produces milder deficits. Experiment 1 confirmed that pretrained rats display severe DNMS deficits following ISC, but not ABL. Ischemia produced loss of CA1 neurons, but no obvious extrahippocampal damage. In Experiments 2 and 3, ISC rats from Experiment 1 received ABL, and ABL rats received ISC; neither treatment affected DNMS performance. In Experiment 4, rats that received ISC followed 1 hr later by ABL displayed only mild deficits. It is hypothesized that ISC-induced DNMS deficits are due to extrahippocampal damage produced by pathogenic processes that involve the hippocampus.

Object-recognition and spatial learning and memory in rats prenatally exposed to ethanol.

Prenatal ethanol exposure can produce cognitive and behavioral impairments. In the present study, rats from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) treatment conditions were tested on the object-recognition delayed-nonmatching-to-sample (DNMS) task with nonrecurring items and on the spatial-navigation Morris water maze task. In Experiment 1, there were no significant differences among groups in object-recognition learning and memory, distractibility, or response perseveration on the DNMS task. In Experiment 2, the same rats were tested in the water maze; E rats took significantly longer to learn the task than did the PF or C rats. These data suggest that the mechanisms underlying spatial cognitive abilities are more vulnerable to the teratogenic effects of prenatal ethanol exposure than those underlying object-recognition abilities.

Pirenperone does not attenuate morphine analgesia in spinal rats.

The selective serotonin type-2 (S2) receptor blocker pirenperone (0.24 mg/kg, SC) attenuates morphine-produced tail-flick antinociception in intact rats, but not in rats with transected spinal cords. These results suggest that S2 receptor blockade does not affect intraspinal opioid antinociception. Together with evidence that there are virtually no S2 receptors in the dorsal spinal cord, supraspinal S2 receptors are implicated in the mediation of morphine-produced antinociception.