Union Mediation and Adaptation to Reciprocal Loyalty Arrangements

This study assesses the industrial relations application of the „loyalty-exit-voice‟ proposition. The loyalty concept is linked to reciprocal employer-employee arrangements and examined as a job attribute in a vignette questionnaire distributed to low and medium-skilled employees. The responses provided by employees in three European countries indicate that reciprocal loyalty arrangements, which involve the exchange of higher effort for job security, are one of the most desirable job attributes. This attribute exerts a higher impact on the job evaluations provided by unionised workers, compared to their non-union counterparts. This pattern is robust to a number of methodological considerations. It appears to be an outcome of adaptation to union mediated cooperation. Overall the evidence suggests that the loyalty-job evaluation profiles of unionised workers are receptive to repeated interaction and negative shocks, such as unemployment experience. This is not the case for the non-union workers. Finally, unionised workers appear to „voice‟ a lower job satisfaction, but exhibit low „exit‟ intentions, compared to the non-unionised labour.

Serological diagnosis of dengue by an Elisa inhibition method (EIM)

An ELISA Inhibition Method (EIM) was proposed for the serologic diagnosis of dengue, comparing its results with the Hemagglutination Inhibition (HI) and the IgM capture-ELISA (MAC-ELISA). Advantages and disadvantages of both methods are discussed according to sensitivity, specificity, performance and usefulness. As a conclusion we recommend the complementary inclusion of the EIM and MAC-ELISA substituting the HI for laboratories engaged in the diagnosis and surveillance of dengue.

The role of Malt1 proteolytic activity in T cell activation and lymphoma development

Abstract Long term contact with pathogens induces an adaptive immune response, which is mainly mediated by T and B cells. Antigen-induced activation of T and B cells is an important event, since it facilitates the transition of harmless, low proliferative lymphocytes into powerful and fast expanding cells, which can, if deregulated, be extremely harmful and dangerous for the human body. One of the most important events during lymphocyte activation is the induction of NF-xB activity, a transcription factor that controls not only cytokine secretion, but also lymphocyte proliferation and survival. Recent discoveries identified the CBM complex as the central regulator of NF-xB activity in lymphocytes. The CBM complex consists of the three proteins Carma1, Bcl10 and Malt1, in which Carma1 serves as recruitment platform of the complex and Bcl10 as an adaptor to recruit Malt1 to this platform. But exactly how Malt1 activates NF-x6 is still poorly understood. We discovered that Malt1 is a protease, which cleaves its interaction partner Bcl10 upon T and B cell stimulation. We mapped the Bcl10 cleavage site by single point mutations as well as by a proteomics approach, and used this knowledge to design a fluorogenic Malt1 reporter peptide. With this tool were we able to the first time demonstrate proteolytic activity of Malt1 in vitro, using recombinant Malt1, and in stimulated T cells. Based on similarities to a metacaspase, we designed a Malt1inhibitor, which allowed unto investigate the role of Malt1 activity in T cells. Malt1-inhibited T cells showed a clear defect in NF-xB activity, resulting in impaired IL-2 cytokine secretion levels. We also found a new unexpected role for Bcl10; the blockade of Bcl10 cleavage resulted in a strongly impaired capability of stimulated T cells to adhere to the extracellular matrix protein fibronectin. Because of the central position of the C8M complex, it is not surprising that different lymphomas show abnormal expressions of Carma1, Bcl10 and Malt1. We investigated the role of Malt1 proteolytic activity in the most aggressive subtype of diffuse large B cell lymphomas called ABC, which was described to depend on the expression of Carmal, and frequently carries oncogenic Carmal mutations. We found constitutive high Malt1 activity in all tested ABC cell lines visualized by detection of cleavage products of Malt1 substrates. With the use of the Malt1-inhibitor, we could demonstrate that Malt-inhibition in those cells had two effects. First, the tumor cell proliferation was decreased, most likely because of lower autocrine stimulation by cytokines. Second, we could sensitize the ABC cells towards cell death, which is most likely caused by reduced expression of prosurvival NF-xB target gens. Taken together, we identified Malt1 as a protease in T and B cells, demonstrated its importance for NF-xB signaling and its deregulation in a subtype of diffuse large B cell lymphoma. This could allow the development of a new generation of immunomodulatory and anti-cancer drugs. Résumé Un contact prolongé avec des pathogènes provoque une réponse immunitaire adaptative qui dépend principalement des cellules T et 8. L'activation des lymphocytes T et B, suite à la reconnaissance d'un antigène, est un événement important puisqu'il facilite la transition pour ces cellules d'un état de prolifération limitée et inoffensive à une prolifération soutenue et rapide. Lorsque ce mécanisme est déréglé ìl peut devenir extrêmement nuisible et dangereux pour le corps humain. Un des événement les plus importants lors de l'activation des lymphocytes est l'induction du facteur de transcription NFxB, qui organise la sécrétion de cytokines ainsi que la prolifération et la survie des lymphocytes. Le complexe CBM, composé des trois protéines Carmai, Bc110 et Malt1, a été récemment identifié comme un régulateur central de l'activité de NF-x8 dans les lymphocytes. Carma1 sert de plateforme de recrutement pour ce complexe alors que Bc110 permet d'amener Malt1 dans cette plateforme. Cependant, le rôle exact de Malt1 dans l'activation de NF-tcB reste encore mal compris. Nous avons découvert que Malt1 est une protéase qui clive son partenaire d'interaction BcI10 après stimulation des cellules T et B. Nous avons identifié le site de clivage de BcI10 par une série de mutations ponctuelles ainsi que par une approche protéomique, ce qui nous a permis de fabriquer un peptide reporteur fluorogénique pour mesurer l'activité de Malt1. Grâce à cet outil, nous avons démontré pour la première fois l'activité protéolytique de Malt1 in vitro à l'aide de protéines Malt1 recombinantes ainsi que dans des cellules T stimulées. La ressemblance de Malt1 avec une métacaspase nous a permis de synthétiser un inhibiteur de Malt1 et d'étudier ainsi le rôle de l'activité de Malt1 dans les cellules T. L'inhibition de Malt1 dans les cellules T a révélé un net défaut de l'activité de NF-x8, ayant pour effet une sécrétion réduite de la cytokine IL-2. Nous avons également découvert un rôle inattendu pour Bcl10: en effet, bloquer le clivage de Bcl10 diminue fortement la capacité d'adhésion des cellules T stimulées à la protéine fïbronectine, un composant de la matrice extracellulaire. En raison de la position centrale du complexe CBM, il n'est pas étonnant que le niveau d'expression de Carmai, Bcl10 et Malt1 soit anormal dans plusieurs types de lymphomes. Nous avons examiné le rôle de l'activité protéolytique de Malt1 dans le sous-type le plus agressif des lymphomes B diffus à grandes cellules, appelé sous-type ABC. Ce sous-type de lymphomes dépend de l'expression de Carmai et présente souvent des mutations oncogéniques de Carma1. Nous avons démontré que l'activité de Malt1 était constitutivement élevée dans toutes les lignées cellulaires de type ABC testées, en mettant en évidence la présence de produits de clivage de différents substrats de Malt1. Enfin, l'utilisation de l'inhibiteur de Malt1 nous a permis de démontrer que l'inhibition de Malt1 avait deux effets. Premièrement, une diminution de la prolifération des cellules tumorales, probablement dûe à leur stimulation autocrine par des cytokines fortement réduite. Deuxièmement, une sensibilisation des cellules de type ABC à ia mort cellulaire, vraisemblablement causée par l'expression diminuée de gènes de survie dépendants de NF-tcB. En résumé, nous avons identifié Malt1 comme une protéase dans les cellules T et B, nous avons mis en évidence son importance pour l'activation de NF-xB ainsi que les conséquences du dérèglement de l'activité de Malt1 dans un sous-type de lymphome B diffus à larges cellules. Notre étude ouvre ainsi la voie au développement d'une nouvelle génération de médicaments immunomodulateurs et anti-cancéreux.

Inhibition of gastric secretion by a water extract from Baccharis triptera, Mart

Baccharus triptera Mart, is a widespread Compositae used in Brazilian folk medicine to treat gastrointestinal disturbances, rheumatic disease, mild fever, diabetes and as an anti-helminthic. Water extract of small branches of the plant (WE) administered to mice and rats (0.1 to 2 g/Kg, p.o) did not alter spontaneous motor activity, sleeping time induced by barbiturates or the tailflick response in mice. The extract decreased by 40 por cento the number of writhings induced by 0.8 por cento scetic acid, i.p., but did not influence paw edema induced by carrageenan or dextran in rats WE (2g/Kg, p.o.) decreased the intestinal transit of charcoal in mice by 20//. Gastric secretion in pylorus ligated rats was reduced after treatment with WE (1 and 2 g/Kg. i.p. or intraduodenal and the gastric pH was raised. The extract (1 g/Kg, p.o.) prevented gastric ulcers induced in rats by immobilization at 4ºC, but not those induced by indomethacin (10 mg/Kg, s.c.). The results indicate that WE may relieve gastrointestinal disorders by reducing acid secretion and gastrointestinal hiperactivity. Neither analgesic nor anti-inflammatory activities were detectable.

Optimization and inhibition of the adherent ability of Plasmodium falciparum-infected erythrocytes

The vast majority of the 1-2 million malaria associated deaths that occur each year are due to anemia and cerebral malaria (the attachment of erythrocytes containing mature forms of Plasmodium falciparum to the endothelial cells that line the vascular beds of the brain). A "model" system"for the study of cerebral malaria employs amelanotic melanoma cells as the "target"cells in an vitro cytoadherence assay. Using this model system we determined that the optimum pH for adherence is 6.6 to 6.8, that high concentrations of Ca²* (50mM) result in increased levels of binding, and that the type of buffer used influences adherence (Bis Tris > MOPS > HEPES > PIPES). We also observed that the ability of infected erythrocytes to cytoadhere varied from (erythrocyte) donor to donor. We have produced murine monoclonal antibodies against P. falciparum-infected red cells which recognized modified forms of human band 3; these inhibit the adherence of infected erythrocytes to melanoma cells in a doso responsive fashion. Antimalarials (chloroquine, quinacrine, mefloquine, artemisinin), on the other hand, affected adherence in an indirect fashion i.e. since cytoadherence is due, in part to the presence of knobs on the surface of the infected erythrocyte, and knob formation is dependent on intracellular parasite growth, when plasmodial development is inhibited so is knob production, and consequently adherence is ablated.

Heterogeneity of Ia antigen expression on myeloblastic leukaemias: correlation with stage of maturation defined by cytochemical markers.

The expression of Ia-like antigen (Ia) has been studied in 55 cases of acute myeloid leukaemia (AML) in correlation with the expression of both Sudan Black (SB) and naphthol AS-D chloroacetate esterase (NCAE) stains. Operationally the AML cases were divided into three groups using only NCAE expression on the leukaemic cells: the first group with early maturation stage (MS1) consisted of 30 cases with less than 10% NCAE positive cells (SB: 15-100%): the MS2 group of 14 cases with 10-70% NCAE positive cells (SB: 65-100%) and the MS3 group of 11 cases with 70-100% NCAE positive cells (SB: 89-100%). Ia expression was determined by complement-dependent cytotoxicity, immunofluorescence and immunoperoxidase methods. A similar high percentage (80%) of patients from both group MS1 and MS2 expressed Ia on the surface of 32-100% of the cells. Furthermore, individual comparison of all cases from these two groups showed no correlation between Ia, NCAE and SB expression. Only in the 11 cases from the MS3 group, which included nine cases of promyelocytic leukaemias, was there a correlation between very low expression of Ia antigen with the high NCAE expression. Thus, for AML with a low degree of differentiation the expression of Ia seems to be independent of conventional cytochemical markers of cell maturation.

Rôle de l'activation de c-Jun N-terminal kinase (JNK) dans un modèle de glaucome chez le rat et neuroprotection par inhibition de la voie de JNK

RESUME : Dans ce travail effectué chez le rat adulte, l'excitotoxicité rétinienne est élicitée par injection intravitréenne de NMDA. Les lésions en résultant sont localisées dans la rétine interne. Elles prennent la forme de pycnoses dans la couche des cellules ganglionnaires (corps cellulaires des cellules ganglionnaires et amacrines déplacées) et dans la partie interne de la couche nucléaire interne (cellules amacrines). Cette localisation est liée à la présence de récepteurs au glutamate de type NMDA sur ces cellules. L'activation de ces récepteurs entraîne un influx calcique et l'activation de diverses enzymes (phospholipase A, calpaïnes, calmoduline, synthase d'oxyde nitrique). La signalisation se poursuit en aval en partie par les voies des Mitogen Activated Protein Kinase (MAPK) : ERK, p38, ]NK. Dans les expériences présentées, toutes trois sont activées après l'injection de NMDA. Dans les cascades de signalisation de JNK, trois kinases s'ancrent sur une protéine scaffold. Les MAPKKK phosphorylent MKK4 et MKK7, qui phosphorylent JNK. JNK a de nombreuses cibles nucléaires (dont le facteur de transcription c-Jun) et cytoplasmiques. La voie de JNK est bloquée par l'inhibiteur peptidique D-JNKI-1 en empêchant l'interaction de la kinase avec son substrat. L'inhibiteur est formé de 20 acides aminés du domaine de liaison JBD et de 10 acides aminés de la partie TAT du virus HIV. L'injection intravitréenne de D-JNKI-1 permet une diminution des taux de JNK et c-Jun phosphorylés dans les lysats de rétine. L'effet prépondérant est la restriction importante des altérations histologiques des couches internes de la rétine. L'évaluation par électrorétinogramme met en sus en évidence une sauvegarde de la fonction cellulaire. Ce travail a ainsi permis d'établir la protection morphologique et fonctionnelle des cellules de la rétine interne par inhibition spécifique de la voie de JNK lors d'excitotoxicité. SUMMARY Excitotoxicity in the retina associates with several pathologies like retinal ischemia, traumatic optic neuropathy and glaucoma. In this study, excitotoxicity is elicited by intravitreal NMDA injection in adult rats. Lesions localise in the inner retina. They present as pyknotic cells in the ganglion cell layer (ganglion cells and displaced amacrines) and the inner nuclear layer (amacrine cells). These cells express NMDA glutamate receptors. The receptor activation leads to a calcium flow into the cell and hence enzyme activation (phospholipase, calpains, calmodulin, nitric oxide synthase). The subsequent signaling pathways can involve the Mitogen Activated Protein Kinases (MAPK): ERK, p38 end JNK. These were all activated in our experiments. The signaling cascade organises around several scaffold proteins. The various MAPKKK phosphorylate MKK4 and MKK7, which phosphorylate JNK. JNK targets are of nuclear (c-Jun transcription factor) or cytoplasmic localisation. The peptidic inhibitor D-JNKI-1, 20 amino acids from the JNK binding domain JBD coupled to 10 amino acids of the TAT transporter, disrupts the binding of JNK with its substrate. Intravitreal injection of the inhibitor lowers phosphorylated forms of JNK and c-Jun in retinal extracts. It protects strongly against histological lesions in the inner retina and allows functional rescue.

Angiotensin-converting enzyme inhibition by hydroxamic zinc-binding idrapril in humans.

The new angiotensin-converting enzyme (ACE) inhibitor idrapril acts by binding the catalytically important zinc ion to a hydroxamic group. We investigated its pharmacodynamic and pharmacokinetic properties in 8 healthy men: Increasing doses of 1, 5, and 25 mg idrapril as well as placebo or 5 mg captopril were administered intravenously (i.v.) at 1-week intervals. Six of the subjects received 100 mg idrapril orally (p.o.) last, and two ingested oral placebo as a double-blind control. Blood pressure (BP) and heart rate (HR) remained unchanged. No serious side effects were observed. ACE inhibition in vivo was evaluated by changes in the ratio of specifically measured plasma angiotensin II (AngII) and AngI concentrations determined by high-performance liquid chromatography/radioimmunoassay (HPLC/RIA) techniques. Plasma ACE activity in vitro was estimated by radioenzymatic assay; it was suppressed by > or = 93% at 15 min after injection of 25 mg idrapril or 5 mg captopril and by 96% 2 h after idrapril intake. Mean AngII levels were decreased dose dependently at 15 min after idrapril injections. At the same time, plasma renin activity (PRA) and AngI increased according to the doses. The AngII/AngI ratio was clearly related to plasma idrapril levels (r = -0.88, n = 60). Oral idrapril inhibited ACE maximally at 1-4 h after dosing, when < 7% of initial ACE activity was observed in vitro and in vivo. Idrapril is a safe and efficient ACE inhibitor in human subjects. It is well absorbed orally. Besides having a slightly slower onset of action, idrapril has pharmacodynamic effects comparable to those of captopril.

An inhibition ELISA to determine alpha macroglobulin levels in mouse plasma

A sensitive method for quantifying mouse plasma alpha-macroglobulins (AM) using an inhibition ELISA is described. AM are important plasmaproteinase inhibitors that possibly act also as immunomodulatory molecules. The standard protocol develope in our experiments involves coating well with 10 µg/ml A2M in carbonate buffer, followed by incubation with a 1:1 (v/v) mixture of the plasma to be tested (diluted 1/1000) and goat anti-AM (diluted 1/1250). This is followed by further incubation, first with the enzyme-conjugated antibody and with the substrate prior to the reading of absorbance levels of the reaction products. Standard curve samples must be included in each plate, employing known amounts of the purified Murine Alpha-2-Macroglobulin (MuA2M) used for coating, with concentrations ranging from 0.001 to 10 µg/ml. Using test samples in triplicates and a 6-point standard curve in a single ELISA plate, 25 plasma samples can be tested accurately. The method offers an useful tool for establishing AM levelsin small samples of mouse plasma.

Neuroprotection in cerebral ischemia : an effect of c-Jun N-terminal kinase inhibition on the inflammatory response

RESUMESuite à un accident vasculaire cérébral (AVC) ischémique, les cellules gliales ducerveau deviennent activées, de nombreuses cellules inflammatoires pénètrent dans letissu lésé et sécrètent une grande variété de cytokines et chémokines. Aujourd'hui, ilexiste des interrogations sur les effets bénéfiques ou délétères de cette inflammation surla taille de la lésion et le pronostic neurologique.Ce projet vise à évaluer l'effet d'un peptide neuroprotecteur, D-JNKI1, inhibiteur de lavoie pro-apoptotique de signalisation intracellulaire c-Jun N-terminal kinase (JNK), surl'inflammation post-ischémique.Nous montrons d'abord que la microglie est largement activée dans toute la région lésée48 h après l'induction d'une ischémie chez la souris. Cependant, malgré l'inhibition dela mort neuronale par D-JNKI1 évaluée à 48 h, nous n'observons de modification ni del'activation de la microglie, ni de son nombre. Ensuite, nous montrons que le cerveaupeut être protégé même s'il y a une augmentation massive de la sécrétion de médiateursinflammatoires dans la circulation systémique très tôt après induction d'un AVCischémique. De plus, nous notons que la sécrétion de molécules inflammatoires dans lecerveau n'est pas différente entre les animaux traités par D-JNKI1 ou une solutionsaline, bien que nous ayons obtenu une neuroprotection significative chez les animauxtraités.En conclusion, nous montrons que l'inhibition de la voie de JNK par D-JNKI1n'influence pas directement l'inflammation post-ischémique. Ceci suggère quel'inhibition de l'inflammation n'est pas forcément nécessaire pour obtenir en hautdegré de neuroprotection du parenchyme lésé après ischémie cérébrale, et que lesmécanismes inflammatoires déclenchés lors d'une ischémie cérébrale ne sont pasforcément délétères pour la récupération du tissu endommagé.SUMMARYAfter cerebral ischemia, glial cells become activated and numerous inflammatory cellsinfiltrate the site of the lesion, secreting a large variety of cytokines and chemokines. Itis controversial whether this brain inflammation is detrimental or beneficial and how itinfluences lesion size and neurological outcome.This project was aimed at critically evaluating whether the neuroprotective peptide DJNKI,an inhibitor of the pro-apopotic c-Jun N-terminal kinase (JNK) pathway,modulates post-ischemic inflammation in animal models of stroke. Specifically, it wasasked whether JNK inhibition prevents microglial activation and the release ofinflammatory mediators.In the first part of this study, we showed that microglia was activated throughout thelesion 48 h after experimental stroke. However, the activation and accumulation ofmicroglia was not reduced by D-JNKI1, despite a significant reduction of the lesionsize. In the second part of this project, we demonstrated that neuroprotection measuredat 48 h occurs even though inflammatory mediators are released in the plasma veryearly after the onset of cerebral ischemia. Furthermore, we found that secretion ofinflammatory mediators in the brain was not different in groups treated with D-JNKI1or not, despite a significant reduction of the lesion size in the treated group.Altogether, we show that inhibition of the JNK pathway using D-JNKI1 does notinfluence directly post-stroke inflammation. Inhibition of inflammation is therefore notnecessarily required for neuroprotection after cerebral ischemia. Thus, post-strokeinflammation might not be detrimental for the tissue recovery.

Partial inhibition of hemocyte agglutination by Lathyrus odoratus lectin in Crassotrea virginica infected with Perkinsus marinus

Quantitative determinations of agglutination of hemocytes from oysters, Crassostrea virginica, by the Lathyrus odoratus lectin at five concentrations revealed that clumping of hemocytes from oysters infected with Perkinsus marinus is partially inhibited. Although the nature of the hemocyte surface saccharide, which is not D(+)-glucose, D(+)mannose, or alpha-methyl-D-mannoside, remains to be determined, it may be concluded that this molecule also occurs on the surface of P. marinus. It has been demonstrated that the panning technique (Ford et al. 1990) is qualitatively as effective for determining the presence of P. marinus in C. virginica as the hemolymph assay method (Gauthier & Fisher 1990).

Persistent inhibition of FLIP(L) expression by lentiviral small hairpin RNA delivery restores death-receptor-induced apoptosis in neuroblastoma cells.

Neuroblastoma represents the most common and deadly solid tumour of childhood, which disparate biological and clinical behaviour can be explained by differential regulation of apoptosis. To understand mechanisms underlying death resistance in neuroblastoma cells, we developed small hairpin of RNA produced by lentiviral vectors as tools to selectively interfere with FLIP(L), a major negative regulator of death receptor-induced apoptosis. Such tools revealed highly efficient in interfering with FLIP(L) expression and function as they almost completely repressed endogenous and/or exogenously overexpressed FLIP(L) protein and fully reversed FLIP(L)-mediated TRAIL resistance. Moreover, interference with endogenous FLIP(L) and FLIP(S) significantly restored FasL sensitivity in SH-EP neuroblastoma cell line. These results reveal the ability of lentivirus-mediated shRNAs to specifically and persistently interfere with FLIP expression and support involvement of FLIP in the regulation of death receptor-mediated apoptosis in neuroblastoma cells. Combining such tools with other therapeutic modalities may improve treatment of resistant tumours such as neuroblastoma.

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone.

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.

Infections and functional impairment in nursing home residents: a reciprocal relationship.

OBJECTIVES: To determine the relationship between infections and functional impairment in nursing home residents. DESIGN: Prospective cohort study (follow-up period, 6 months). SETTING: Thirty-nine nursing homes in western Switzerland. PARTICIPANTS: A total of 1,324 residents aged 65 and older (mean age 85.7; 76.6% female) who agreed to participate, or their proxies, by oral informed consent. MEASUREMENTS: Functional status measured every 3 months. Two different outcomes were used: (a) functional decline defined as death or decreased function at follow-up and (b) functional status score using a standardized measure. RESULTS: At the end of follow-up, mortality was 14.6%, not different for those with and without infection (16.2% vs 13.1%, P=.11). During both 3-month periods, subjects with infection had higher odds of functional decline, even after adjustment for baseline characteristics and occurrence of a new illness (adjusted odds ratio (AOR)=1.6, 95% confidence interval (CI)=1.2-2.2, P=.002, and AOR=1.5, 95% CI=1.1-2.0, P=.008, respectively). The odds of decline increased in a stepwise fashion in patients with zero, one, and two or more infections. The analyses predicting functional status score (restricted to subjects who survived) gave similar results. A survival analysis predicting time to first infection confirmed a stepwise greater likelihood of infection in subjects with moderate and severe impairment at baseline than in subjects with no or mild functional impairment at baseline. CONCLUSION: Infections appear to be both a cause and a consequence of functional impairment in nursing home residents. Further studies should be undertaken to investigate whether effective infection control programs can also contribute to preventing functional decline, an important component of these residents' quality of life.