[Psychological and cognitive interventions in end-of-life support of patients with amyotrophic lateral sclerosis. A review.] / Prise en charge psychologique et cognitive au cours de l'accompagnement de fin de vie de patients atteints de sclérose latérale amyotrophique. Une revue systématique.

Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by muscle atrophy leading to complete paralysis. Once diagnosed, the average life expectancy is three to five years. In this context, palliative and end-of-life care are essential, as well as the development of cognitive and/or psychological therapies to improve the quality of life of patients. In this context, we conducted a review of the pertinent literature about psychological and cognitive interventions in end-of-life support for ALS patients. We identified 504 references out of which only four studies met our inclusion criteria. Two studies focused on dignity therapy, one study on the delay between the diagnosis and the start of psychological care in a specialized centre, and one case-report on psychological therapy combined with a computer-assisted communication system. The results of these studies, although very limited, suggest that psychological interventions may improve the management and quality of life of end-of-life ALS patients. Further studies should investigate the impact of psychological support adapted to ALS, using, for example, computer-assisted communication allowing to implement these interventions in a larger number of patients and over the long term.

La sclérose latérale amyotrophique (SLA) est une maladie neurogénérative qui se caractérise notamment par une amyotrophie progressive évoluant jusqu'à la paralysie complète du patient dont l'espérance de vie est, en moyenne, de trois à cinq ans. Les soins palliatifs et le développement de thérapies pour améliorer la qualité de vie des patients sont essentiels. Dans ce cadre, nous avons réalisé une revue de la littérature portant sur les interventions psychologiques et cognitives dans la prise en charge des patients atteins de SLA en fin de vie. Nous avons identifié 504 références dont quatre rapportant des études qui répondaient aux critères d'inclusion. Deux études portaient sur la thérapie de la dignité, une sur la rapidité d'une prise en charge psychologique dans un centre spécialisé et un rapport de cas concernait une prise en charge psychologique combinée à un système de communication assistée par ordinateur. Les résultats de ces quatre études, bien que limités, suggèrent que les interventions psychologiques pourraient améliorer la qualité de vie des patients en fin de vie. De nouvelles recherches devraient être menées pour investiguer l'impact d'une prise en charge psychologique adaptée à la SLA en utilisant, par exemple, une communication assistée afin d'implémenter ces interventions sur un plus grand nombre de patients et sur le long terme.

Anticonvulsant hypersensitivity syndrome mimicking a viral illness with skin rash: a case report.

Anticonvulsant hypersensitivity syndrome (ACHSS) is rare and defined by a group of systemic symptoms: a typical clinical triad with skin rash, high fever and lymphadenopathy, with or without multiple organ dysfunctions. Its variable presentation renders diagnosis particularly difficult yet important, as delayed diagnosis can lead to serious complications. We describe a 31-year-old woman sent to the emergency department with symptoms of high fever, peripheral lymphadenopathy, arthralgia, nausea, vomiting and a vesiculobullous eruption resembling measles. First diagnostic hypothesis was that of a viral illness. However, thorough second anamnesis pointed towards a possible drug aetiology, as the patient had been prescribed lamotrigine 8 days prior to admission. Blood analysis showed an inflammatory syndrome, thrombocytopenia and moderate lymphopenia. A few days later, results indicated old immunisation for measles. Skin biopsy revealed dermal inflammation with presence of hypereosinophilia, thereby confirming ACHSS. It is important to recognise and treat this rare reaction to anticonvulsants as early as possible in order to prevent its potentially life-threatening complications.

Stem cell characteristics of human trabecular bone-derived cells.

Human trabecular bone-derived cells (HTBs) have been used for many years as osteoblast progenitors. In this study we tested whether HTBs have stem cell characteristics; that is, whether they are pluripotent and able to self-renew. We show that HTBs readily differentiate into osteoblasts, chondrocytes, and adipocytes if subjected to the appropriate differentiating conditions. Importantly, differentiation into these three lineages is maintained in single cell clones derived by limiting dilution, following expansion over more than 20 cumulative population doublings. We conclude that cultures of HTBs are equivalent to cultures of "mesenchymal stem cells" (MSCs) isolated from bone marrow.

Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue.

Adiponectin (ApN) is thought to play a major role in the pathogenesis of the Metabolic Syndrome. Production of ApN and regulation of its related gene (apM1) have not yet been studied in human visceral adipose tissue. ApN was mainly associated with adipocyte membranes and abundantly secreted in medium from isolated adipocytes. apM1 gene expression, restricted to the adipocyte fraction of adipose tissue, decreased spontaneously when adipose explants were cultured in basal medium for 24 h while the expression of other adipose genes barely changed (PPARgamma, GAPDH) or increased (PAI-1). Unexpectedly, the fall of apM1 mRNA was prevented by the addition of actinomycin D, an inhibitor of transcription, or cycloheximide, an inhibitor of protein synthesis, and by reducing the amount of adipose tissue cultured per dish, thereby suggesting that a newly synthesized factor released by adipose tissue destabilizes apM1 mRNA. apM1 gene expression was also negatively regulated by glucocorticoids and positively by insulin and IGF-1. This regulation could contribute to the decreased apM1/ApN levels in insulin-resistant patients with obesity and the Metabolic Syndrome.

Multi-lineage potential of human mesenchymal stem cells following clonal expansion.

Bone marrow contains mesenchymal cells that can be isolated and grown in vitro. Using appropriate treatment protocols such cultures can be induced to differentiate to yield osteoblasts, adipocytes, and chondrocytes. However, previous experiments had not addressed the question whether single pluripotent stem cells exist and can give rise to these different cell lineages or whether bone marrow mesenchymal cell preparations represent a mixture of committed precursors. We have used human adult bone marrow-derived mesenchymal cells obtained from iliac crest biopsies to demonstrate clonal outgrowth after limiting dilution and we show that some clones can be expanded over more than 20 cumulative population doublings and differentiated to osteoblasts, adipocytes, and chondrocytes. Our data provide direct experimental evidence that cultures of bone marrow-derived mesenchymal cells contain individual cells that fulfil two essential stem cell criteria: (i) extensive self-renewal capacity and (ii) multi-lineage potential.

Hormonal control of plasminogen activator inhibitor-1 gene expression and production in human adipose tissue: stimulation by glucocorticoids and inhibition by catecholamines.

Plasma levels of type 1 plasminogen activator inhibitor (PAI-1), a risk factor for cardiovascular disease, are elevated in obese subjects, especially those with omental fat accumulation. We investigated the hormonal control of PAI-1 gene expression and secretion in cultured human adipose tissue. We more particularly focused on the effects of glucocorticoids, insulin, cAMP, and catecholamines in explants from the omental region. The addition of dexamethasone to the culture medium increased PAI-1 secretion in a time-dependent manner for up to 24 h. The stimulation by the glucocorticoid was preceded by a 2-fold rise in PAI-1 messenger ribonucleic acid levels between 4-8 h of culture. The effectiveness of the glucocorticoid was concentration dependent, with a half-maximal effect within a physiological range. This stimulation was also observed in sc fat, but dexamethasone-stimulated as well as basal PAI-1 secretion rates were always higher in omental fat. Unlike dexamethasone, 24-h insulin did not modify PAI-1 secretion while accelerating glucose consumption. In contrast, 24-h cAMP inhibited PAI-1 gene expression and protein production under basal conditions and in the presence of dexamethasone. This inhibition was already detectable after 1 h and was maximal after 4 h at the level of gene expression. It occurred in both omental and sc adipose tissues. Importantly, epinephrine dose dependently inhibited PAI-1 parameters, an effect that was reproduced by isoproterenol. Dexamethasone- and cAMP-induced changes in PAI-1 messenger ribonucleic acid abundance were similar in explants and isolated fat cells. In isolated stromal-vascular cells, only dexamethasone was effective. In conclusion, we provide evidence for a reciprocal regulation of PAI-1 by dexamethasone (positive effector) and cAMP/catecholamines (negative effectors) in cultured human adipose tissue. The stimulation by glucocorticoids could contribute to enhanced production of PAI-1 by adipose tissue and high plasma levels of PAI-1 associated with central obesity and thereby be a link between this disorder and cardiovascular disease. Impaired inhibition by catecholamines could also contribute, as in vivo adipose tissue responses to these hormones are usually blunted in obese individuals.

Signaling in human osteoblasts by extracellular nucleotides. Their weak induction of the c-fos proto-oncogene via Ca2+ mobilization is strongly potentiated by a parathyroid hormone/cAMP-dependent protein kinase pathway independently of mitogen-activated protein kinase.

Extracellular nucleotides acting through specific P2 receptors activate intracellular signaling cascades. Consistent with the expression of G protein-coupled P2Y receptors in skeletal tissue, the human osteosarcoma cell line SaOS-2 and primary osteoblasts express P2Y1 and P2Y2 receptors, respectively. Their activation by nucleotide agonists (ADP and ATP for P2Y1; ATP and UTP for P2Y2) elevates [Ca2+]i and moderately induces expression of the c-fos proto-oncogene. A synergistic effect on c-fos induction is observed by combining ATP and parathyroid hormone, a key bone cell regulator. Parathyroid hormone elevates intracellular cAMP levels and correspondingly activates a stably integrated reporter gene driven by the Ca2+/cAMP-responsive element of the human c-fos promoter. Nucleotides have little effect on either cAMP levels or this reporter, instead activating luciferase controlled by the full c-fos promoter. This induction is reproduced by a stably integrated serum response element reporter independently of mitogen-activated protein kinase activation and ternary complex factor phosphorylation. This novel example of synergy between the cAMP-dependent protein kinase/CaCRE signaling module and a non-mitogen-activated protein kinase/ternary complex factor pathway that targets the serum response element shows that extracellular ATP, via P2Y receptors, can potentiate strong responses to ubiquitous growth and differentiative factors.

Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity.

The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhibitory effect was already detectable at 10 nmol/L insulin and was also observed in subcutaneous fat. Although a lowering of intracellular cAMP concentrations is involved in some of the effects of insulin on adipose tissue, this cannot account for the present finding, because the addition of cAMP to the medium also decreased ob mRNA and leptin secretion (regardless of whether dexamethasone was present). In conclusion, glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene and could contribute to the metabolic abnormalities associated with central obesity by para/endocrine actions of hyperleptinemia on adipocytes and liver. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion, and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.

The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers.

The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using the human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrioxamine (FO) and L1(3)-Fe, respectively. We report an apparent permeability coefficient (Papp) value for DFO of 0.170 x 10(-7) +/- 0.080 cm s-1. The Papp value of L1 was 1.297 x 10(-5) +/- 0.133 cm s-1. The Papp values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 10(-7) +/- 0.065 cm s-1 and 2.356 x 10(-6) +/- 0.365 cm s-1, respectively. We have shown that the transport of DFO and FO is similar in the Caco-2 cell system. The transport of L1, however, is greatly reduced when complexed to iron. The value for total uptake after 60 min for DFO into the Caco-2 cells was 1.49 +/- 0.09 x 10(-3) nmol per filter. The values for total uptake after 60 min for L1 and L1(3)-Fe were 0.37 +/- 0.03 nmol per filter and 0.04 +/- 0.01 nmol per filter, respectively. Our results indicate that the poor oral bioavailability of DFO can be attributed to the low epithelial permeability of the molecule coupled with its size (mol wt 656). In contrast, the oral bioavailability observed with L1 is due to the high lipophilicity and low molecular weight (mol wt 139) of the molecule. We believe that these differences between the two molecules account for L1 being better orally absorbed than DFO.

Iron absorption by CaCo 2 cells cultivated in serum-free medium as in vitro model of the human intestinal epithelial barrier.

A cell culture system consisting of confluent monolayer of human enterocyte-like CaCo 2 cells, cultivated in a serum-free nutritive medium, on microporous synthetic membranes has been used as an in vitro model of the intestinal epithelial barrier. The uptake of 55ferric citrate, as well as the transepithelial passage from the apical to the basolateral pole, have been studied. CaCo 2 cells accumulate iron in a time- and concentration-dependent process, largely specific from the apical pole. When 55ferric citrate is added at the apical pole, radioiron appears at the basal pole and the clearance rate is approximately four times higher than in the opposite direction; the amounts of 55Fe increase with the concentration in iron citrate and the duration of incubation. At least two concurrent mechanisms could be involved in iron absorption across monolayers of CaCo 2 cells. A first route would correspond to a paracellular passage of the metal from the apical to the basal pole. The second route would involve a selective intake of iron at the apical pole and could require a reduction of ferric iron, prior to the entry. Iron accumulated by the cells would, for a minor part, be stored within ferritin, whereas the major part would be excreted at the basolateral pole, either as low molecular weight material of undetermined chemical composition but from which iron is easily mobilized by apotransferrin or associated with neosynthesized apotransferrin. Vesicular transport and protein synthesis seem to be required.

Iron absorption by intestinal epithelial cells: 1. CaCo2 cells cultivated in serum-free medium, on polyethyleneterephthalate microporous membranes, as an in vitro model.

Iron absorption by intestinal epithelial cells, passage onto plasmatic apotransferrin, and regulation of the process remain largely misunderstood. To investigate this problem, we have set up an in vitro model, consisting in CaCo2 cells (a human colon adenocarcinoma line, which upon cultivation displays numerous differentiation criteria of small intestine epithelial cells). Cells are cultivated in a serum-free medium, containing 1 microgram/ml insulin, 1 ng/ml epidermal growth factor, 10 micrograms/ml albumin-linoleic acid, 100 nM hydrocortisone, and 2 nM T3 on new, transparent, Cyclopore polyethyleneterephthalate microporous membranes coated with type I collagen. Cells rapidly adhere, grow, and form confluent monolayers; after 15 days, scanning electron microscopy reveals numerous uniform microvilli. Domes, which develop on nonporous substrata, are absent on high porosity membranes. Culture medium from upper and lower compartments of microplate inserts and cell lysates were immunoprecipitated after labeling with [3H]glucosamine and leucine; analysis was done by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by autoradiography. [3H]transferrin is found mainly in the lower compartment and in cells; [3H]apolipoprotein B is released in both compartments, and fibronectin almost entirely recovered in the lower compartment; [3H]transferrin receptors and ferritin are only present in cell lysates. Binding experiments also show that transferrin receptors are accessible from the lower compartment. These results suggest that CaCo2 cells, cultivated in synthetic medium on membranes of appropriate porosity, could provide an in vitro model of the intestinal barrier, with the upper compartment of the culture insert corresponding to the apical pole facing the intestinal lumen and the lower one to the basal pole in contact with blood.

Long-term follow-up of the Senning operation for transposition of the great arteries in children under 3 months of age.

Twenty-six patients aged 6 days to 3 months (mean 57 days) underwent a Senning procedure for transposition of the great arteries. Twenty-two had intact ventricular septum and four had a small ventricular septal defect. They were followed up for 1 month to 8 years (mean 4 years). There were no late deaths. At late examination, 25 patients were asymptomatic and there was no clinical or echographic evidence of caval or pulmonary venous obstruction. Growth was normal in all but two patients. Neurologic assessment was abnormal in eight patients. The electrocardiogram showed sinus rhythm in 22 patients and asymptomatic arrhythmias in four. Twenty-three patients underwent cardiac catheterization and angiographic studies 2 to 72 months postoperatively (mean 15 months), which demonstrated effective left and right atrial contraction. An atrial shunt was noted in one patient and a ventricular shunt in one. Two infants (8%) had a residual left ventricular outflow tract obstruction (gradients of 26 and 37 mm Hg). Two had mild superior vena caval obstruction (gradients of 4 and 5 mm Hg). We conclude that the Senning procedure can be performed in early infancy with good results and a low incidence of late complications.