[Angioedema in daily practice]. / L'angio-oedème en pratique quotidienne.

The principal pathophysiologic mechanisms accounting for most cases of angioedema are reviewed as for their clinical presentations owing to the involved process. The features of the cutaneous reactions induced by foods or drugs to which the subjects are allergic, are discussed. The particular case of the amoxicillines reactions as well as the mechanisms by whom the aspirin, the NSAIDs and the ACE inhibitors induce angioedema are reminded. The description of cases lived in clinical practice illustrates the work and demonstrates the importance of anamnesis in the diagnostic approach of this affection.

[Pain in geriatrics]. / La douleur en gériatrie.

Pain is a frequent problem in aged population and often undertreated despite undesirable effects such as depression, malnutrition, sleep disturbance, decreased socialization, impaired ambulation with increased risk of falls problems, adverse effects from multiple inadequate drugs prescriptions, cognitive and behaviour impairments. Detection, diagnosis of the causes, evaluation with specific scales and adapted therapy of pain are essential to preserve quality of life and autonomy. Pharmacological therapy using the three-step analgesic ladder of W.H.O. is appropriate owing to individual age-related sensitivity which requires to follow the rule of "start low and go slow" with regular pain and side effects assessments, particularly for opioids. For chronic pain, non pharmacological strategies optimise pain management in addition to medications. Comprehensive geriatric assessment is recommended to complete the global view of the frailed patient with the help of a multidisciplinary team.

[Chronic pain in geriatrics]. / La douleur chronique en gériatrie.

Pain is frequent in communicative or no-communicative, ambulatory, institutionalized or hospitalized veterans. It is associated with severe comorbidity so much more than chronic pain could be neglected and expressed of atypical manner or masked by the absence of classical symptoms in particular in case of dementia or of sensory disorders. Pain detection by clinic examination or by pain assessment's methods and adequate approach by pharmacological and non pharmacological therapies are essential for correct pain management. On pharmacological plan, the strategy of the O.M.S. landings is applicable owing to a more particular attention to secondary effects and drugs interactions. AINS must be manipulated with prudence. There are no reasons to exclude opioides from the therapeutic arsenal but with a reduction of the starting doses, a regular adaptation and a very attentive survey. In drugs of landing 2, tramadol reveals itself as efficient and better tolerated as the codeine and dextropropoxyphene has to be to avoid. The obtaining of a satisfactory result depends on a regular assessment of the pain in a context of polydisciplinar approach (physicians, nurses, paramedicals, other care givers).

Interferon alpha prevents spontaneous apoptosis of clonal Th2 cells associated with chronic hypereosinophilia.

A recent study identified a clonal expansion of CD3(-)CD4(+)cells secreting Th2-type cytokines in 4 patients with chronic hypereosinophilia. Because interferon alpha (IFN-alpha) is used in the therapy of the idiopathic hypereosinophilic syndrome, the effects of this cytokine on the survival of clonal Th2 cells isolated from the blood of 2 patients were determined. First, these cells displayed a high rate of spontaneous apoptosis on culture in cytokine-free medium and were also sensitive to Fas-mediated apoptosis induced by soluble Fas ligand. Addition of IFN-alpha or interleukin-2 (IL-2) to culture medium resulted in significant protection against spontaneous but not Fas-induced apoptosis. Although spontaneous apoptosis of the clonal Th2 cells was clearly associated with down-regulation of both bcl-2 and bcl-x(L) levels, IFN-alpha had no significant effect on the expression of these antiapoptotic proteins, whereas addition of IL-2 resulted in higher levels of bcl-2. On the other hand, IFN-alpha decreased the numbers of cells with disrupted mitochondrial transmembrane potential both during spontaneous apoptosis and after exposure to protoporphyrin IX. Thus, IFN-alpha might promote the survival of clonal Th2 cells, an effect that could be relevant to the therapeutic approach for patients with chronic hypereosinophilia caused by clonal expansion of Th2-type cells. (Blood. 2000;96:4285-4292)

Outbreak of nosocomial multidrug-resistant Enterobacter aerogenes in a geriatric unit: failure of isolation contact, analysis of risk factors, and use of pulsed-field gel electrophoresis.

We describe herein an outbreak of Enterobacter aerogenes in a geriatric acute unit with failure of contact isolation that necessitated the temporary closure of the department. We emphasize the need for guidelines for the management of multiresistant bacteria.

Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome.

Idiopathic hypereosinophilic syndrome (HES) and Gleich's syndrome are related disorders characterized by persistent or recurrent hypereosinophilia of unknown origin. Elevated IgE levels and polyclonal hypergammaglobulinaemia are considered as markers of benign outcome in this setting as they are generally associated with predominant cutaneous manifestations and favourable response to glucocorticoid therapy. In a previous study, we identified a clonal population of CD3-CD4+ Th2-like lymphocytes secreting interleukin (IL)-5 and IL-4 in peripheral blood of a patient fulfilling the diagnostic criteria of HES with associated serum hyper-IgE. We now extend this observation by describing identical findings in three additional patients, and we compare their clinical and biological parameters with five other patients with HES. Chromosomal abnormalities were detected in purified CD3-CD4+ Th2 cells from three patients, among whom one developed anaplastic null cell lymphoma. We therefore suggest that a careful search for T-lymphocyte clonality and cytogenetic changes should be included in the work-up of HES for adequate management.

T-cell receptor-independent activation of clonal Th2 cells associated with chronic hypereosinophilia.

We recently observed a clonal expansion of CD3(-)CD4(+) T cells secreting Th2-type cytokines in patients presenting chronic hypereosinophilia. As clonal T cells isolated from such patients did not spontaneously secrete cytokines in vitro, we reasoned that costimulatory signals delivered by antigen-presenting cells might be required to induce their full activation. To address this question, we investigated in two such patients the responses of CD3(-)CD4(+) T cells to dendritic cells (DC). DC elicited proliferation and production of interleukin-5 (IL-5) and IL-13 by clonal cells from patient 1 and upregulated their expression of CD25 (IL-2R-alpha). These effects were abolished when blocking monoclonal antibodies (MoAbs) against IL-2R-alpha and IL-2 were added to cocultures, indicating critical involvement of an autocrine IL-2/IL-2R pathway. Cells from patient 2 were stimulated by DC to produce Th2 cytokines only when rIL-2 or rIL-15 was added to cocultures. In both patients, addition of inhibitory MoAbs against B7-1/B7-2 or CD2 to cocultures resulted in dramatic reduction of cytokine production and inhibited CD25 upregulation. Thus, TCR/CD3-independent activation of clonal Th2 cells by DC is an IL-2-dependent process, which requires signaling through CD2 and CD28.

Recombinant interferon-alpha selectively inhibits the production of interleukin-5 by human CD4+ T cells.

The effects of recombinant IFN-alpha on the production of IL-5 by human CD4+ T cells were first analyzed on resting CD4+ T cells purified from normal PBMC and stimulated either with a combination of PMA and anti-CD28 mAb or anti-CD3 mAb cross-linked on B7-1/CD32-transfected mouse fibroblasts. We found that IFN-alpha profoundly inhibited in a dose-dependent manner IL-5 production by resting CD4+ T cells whereas IL-10 was upregulated in both systems. The addition of a neutralizing anti-IL-10 mAb to PMA and anti-CD28 mAb upregulated IL-5 production by resting CD4+ T cells but did not prevent IFN-alpha-induced IL-5 inhibition. We then analyzed the effect of IFN-alpha on the production of cytokines by differentiated type 2 helper (Th2) CD4+CD3- cells isolated from peripheral blood of two patients with the hypereosinophilic syndrome. In both cases, IFN-alpha markedly inhibited IL-5 production while it induced mild upregulation of IL-4 and IL-10. Finally, the inhibitory effect of IFN-alpha on IL-5 production was confirmed on a panel of Th2 and Th0 clones generated in vitro. In 2 out of 6 clones, IL-5 inhibition was associated with upregulation of IL-4 and IL-10. We conclude that IFN-alpha selectively downregulates IL-5 synthesis by human CD4+ T cells.

[Comparison of 2 techniques for measuring lymphocyte proliferation: tritiated methyl-thymidine incorporation and propidium iodide fluorometry]. / Comparaison de deux techniques de mesure de prolifération lymphocytaire: incorporation de thymidine methyl-tritiée et fluorimétrie à l'iodure de propidium.

In vitro lymphocyte mitogenic stimulation by phytohemagglutinin A was determined in 20 subjects, comparing tritiated thymidine incorporation and nuclear propidium iodide fluorescence. Unexpectedly, no correlation could be found between the two measures. The pitfalls of both methods are reviewed and discussed. The inability to validate one test by the other restricts the interpretation of the results obtained with one method and prevents their generalization. Without another gold-standard at the present time, specific and limited method-dependent norms should be defined.

Thiobarbiturate and fructosamine assays: significance and interest of the borohydride blank.

The acute-phase reaction (APR) induces the production by the liver of short-lived glycoproteins. The carbohydrate moiety of these proteins is thought to interfere with the thiobarbiturate (TBA) and nitroblue tetrazolium colorimetric tests which are used for assaying non-enzymatic glycosylation (NEG) of serum proteins. The aim of the present study was to assess the effect of the APR on the specificity of the colorimetric tests in non-diabetic and diabetic subjects. A positive correlation was found between C-reactive protein (CRP), an APR glycoprotein, and non-specific TBA reactivity as determined after borohydride reduction (BH4-resistant TBA, BR-TBA), both in non-diabetics (r = 0.61; P < 0.01) and diabetics (r = 0.68; P < 0.01). The BH4-sensitive specific TBA (SP-TBA) was not influenced by glycoproteins, and its increase in diabetics was correlated with the nitroblue tetrazolium assay (r = 0.89; P < 0.01). An independent effect of diabetes and APR on non-specific TBA was also demonstrated, suggesting an effect of hyperglycaemia on both protein glycation and glycosylation. TBA with borohydride reduction is an attractive tool for the study of complex glycoproteins in diabetes.

Immunodeficiency in aging.

Immune senescence is a multifaceted physiological syndrome of decline in the mechanisms of defence. Cofactors such as age-related associated diseases and malnutrition frequently seen in this category of the population, severely worsen the defect leading to the "immune compromised host" status. Frequency, morbidity and mortality of infections are undoubtedly largely influenced by such parameters. To date, adequate risk assessment and preventive medicine are the best approach to improve the chances of the elderly patient.

Lymphocyte subsets in major depressive patients. Influence of anxiety and corticoadrenal overdrive.

We studied 26 inpatients (17 females; mean age +/- SD: 41.2 +/- 14.3 years) who met the DSM III criteria for a major depressive episode and had a mean (+/- SD) Hamilton Depression Score of 19.3 +/- 8.0. All patients were drug free and medically healthy at the time of experimentation. We found a significant correlation between the CD4/CD8 ratio and the Hamilton Anxiety Score (r = 0.57, p less than 0.005). When splitting our sample in dexamethasone suppression test suppressors (DST-S) and nonsuppressors (DST-NS), this relationship appeared only in DST-NS (DST-NS: r = 0.81, p less than 0.005; DST-S: r = 0.20, p = NS). These results are discussed in terms of heterogeneity among major depressive disorders and possible relationships between catecholaminergic activity and the immune system.

Changing pattern of CD5+ CD20+ double positive lymphocytes with ageing and cytotoxic chemotherapy.

In this cross-sectional clinical study, it was found that two subtypes of CD5+ B-lymphocytes existed either with CD5-high and CD20-low or CD5-low and CD20-high expression, as determined by dual fluorescence analysis with fluorochrome-labeled monoclonal antibodies on a FACScan flowcytometer. In the normal healthy subjects (n = 20), the CD20 positive cells could be broken down into 3 subsets: CD5(2+) CD20+, 25.4 +/- 3.0% (mean +/- S.E.M.), CD5+ CD20(2+), 18.4 +/- 2.4% and CD5- CD20(2+), 56.2 +/- 2.7%. Similar values were observed in a group of patients (n = 29) suffering from a wide variety of benign or untreated malignant disorders. The CD5(2+) CD20+ subset was typically related to age (Spearman coefficient of correlation rho = 0.77, P less than 0.001 in healthy subjects and rho = 0.46, P = 0.02 in pathological cases). The CD5+ CD20(2+) subpopulation was a salient feature of newborns and little infants (n = 6, 75.4 +/- 2.4%, P less than 0.01). The CD5- CD20(2+) subset was characteristically depressed in patients treated with cytotoxics (n = 21, 41.2 +/- 3.6%, P = 0.001). As far as cytotoxic chemotherapy may represent a model of accelerated ageing, it is worth noting that, in patients treated with cytotoxics, the CD5 CD20 pattern was frequently disturbed in a hyperyoung or hyperaged picture. That age and cytotoxics can affect CD5 expression on CD20+ lymphocytes, suggests some specific B-dysregulation and should be put together with the known emergence of autoantibodies, paraproteinemias and lympho-plasmocytic tumors with age and chemotherapy.

Leukocyte and lymphocyte subsets after a short pharmacological stress by intravenous epinephrine and hydrocortisone in healthy humans.

Nine healthy volunteers received epinephrine and hydrocortisone intravenously in order to assess the typical acute response to a brief stress, of leukocyte and lymphocyte subsets, acute phase reactants and lymphocyte reactivity to T and B mitogens. At 10 min., all leukocyte subsets were increased, especially mononuclear cells. At 1 hour, moderate lymphopenia and monocytopenia occurred. At 6 hours, neutrophilia and eosinopenia were observed. During the lymphocytic early wave, all the lymphocyte subset counts increased, particularly T-suppressive/cytotoxic and natural killer cells. As a consequence, the percentage of T cells decreased and the CD4/CD8 ratio fell. No changes in acute phase reactants occurred over the 24 hours of the study. All leukocyte and lymphocyte subsets were normalized and mitogen reactivity was unchanged 24 hours after the stress. These typical shifts in leukocyte subsets could probe the adrenocortical and medullary response to an environmental stressor.

Effect of age, sex and health status on human lymphocyte functions: demonstration of a sex-related defect in suppressor cell function.

The mitogenic response of human lymphocytes and the short-lived suppressor cell function on concanavalin A response were studied as dependent variables in 194 patients using multiple regression analysis, with health status and sex as dummy variables, and age as an explicative one. This study confirms a decrease of the lymphocyte functional response to mitogens with aging. A sex-related defect in suppressor cell function is put forward in females independently of age. An inverse linear relationship is found between the functional response to pokeweed mitogen (T and B mitogen) and suppressor cell function in males but not in females. No such relationship is found with the pure T mitogens (Con A and phytohemagglutinin-A). The present study suggests that a defect in short-lived suppressor cells can play some role in the greater incidence and prevalence of autoimmune diseases in women while the depressed lymphocyte response of old people cannot be explained by modifications of the activity of these suppressor cells.

Specific effect of age on lectin-induced mitogenesis of lymphocytes from diseased patients.

Using several models of multivariate analysis, it is found that age per se is a specific determinant on the in vitro lymphocyte response to phytohemagglutinin A in a random sample of 30 diseased patients. Depending upon the used model, sex and lymphocyte subsets appear as other significant variables. The multiple regression coefficients reach 0.85. A 2% fall per decade is expected for phytohemagglutinin A responsiveness expressed in 1n cpm.

In vitro effects of flunarizine on human lymphocytes.

Flunarizine, a slow-channel calcium entry blocker used as a vasodilator, interferes in vitro with human lymphocyte functions. It prevents lymphocytes from capping sheep erythrocytes, an effect which is probably due to the disconnection of the membrane from its cytoskeletal control. Flunarizine antagonizes both colchicine and cytochalasin B effects upon capping. Although the mitogen-induced lymphocyte stimulation has been shown to be sensitive to calcium depletion or calcium entry blocking by Verapamil, an enhanced response to phytohaemagglutinin A was observed with flunarizine. This suggests a differential sensitivity of the lymphocytes to calcium-entry blockers.

Effect of dipyridamole upon thymidine incorporation and capping in human lymphocytes.

Dipyridamole is a potent inhibitor of tritiated thymidine incorporation by PHA-stimulated human lymphocytes. This effect is unrelated to the length of culture, to the level of response in untreated cultures, or to the proliferative index. This suggests that dipyridamole principally effects the membrane transport of thymidine. Dipyridamole inhibits sheep-erythrocyte-capping by E-rosettes. This effect cannot be mimicked by theophylline or cyclic nucleotides and cannot be reverted by adenosine. Pharmacological studies with colchicine and cytochalasin B suggest interference with cytoskeletal functions, probably of microtubules. This could be another site of action of dipyridamole beyond phosphodiesterase inhibition and adenosine metabolism.