Generalization of fear in post-traumatic stress disorder.

Overgeneralization (i.e., the transfer of fear to stimuli not related to an aversive event) is part of alterations in associative fear learning in mental disorders. In the present experimental study, we investigated whether this holds true for post-traumatic stress disorder (PTSD) related to childhood abuse. We expected that fear generalization under experimental conditions reflects generalization of aversive stimuli to different social domains in real life. Sixty-four women with PTSD after childhood abuse and 30 healthy participants (HC) underwent a differential fear conditioning and generalization paradigm. Online risk ratings, reaction time, and fear-potentiated startle served as dependent variables. Based on the subjectively assessed generalization of triggered intrusions across different domains of life, PTSD participants were split into two groups reporting low (low-GEN) and high (high-GEN) generalization. PTSD patients reported a higher expectation of an aversive event. During fear conditioning, they assessed the risk of danger related to a safety cue slower and showed a blunted fear-potentiated startle toward the danger cue. During generalization testing, reaction time increased in the high-GEN patients and decreased in the HC group with increasing similarity of a stimulus with the conditioned safety cue. Alterations of fear learning in PTSD suggest impaired defensive responses in case of a high threat probability. Moreover, our findings bridge the gap between the generalization of aversive cues during everyday life and laboratory-based experimental parameters: impairments in the processing of cues signaling safety generalize particularly in those patients who report a spreading of PTSD symptoms across different domains of everyday life.

[Attachment and child development in a residential institution in Kinshasa]. / Attachement et développement des enfants abandonnés vivant en institution résidentielle à Kinshasa.

UNLABELLED: Attachment proves the child's need for a presence as well as physical and psychological protection. It contributes to the development of social and emotional skills. However, the relation between attachment, cognitive development, and physical development remains to be established. OBJECTIVE: To evaluate the effect of the quality of attachment on the cognitive and physical development of children placed in institutions for abandoned children in Kinshasa through a first study of this kind in the Democratic Republic of Congo. MATERIALS AND METHODS: Eighty-four participants, aged 4-7 years, 42 abandoned children placed in residential institutions and 42 children living in families. The evaluation focused on the quality of attachment, cognitive performance, and physical development of these children. INSTRUMENTS: attachment story completion task (ASCT), Raven's colored progressive matrices (CPM) and growth vision. The Student t-test was used to compare the children's quality of attachment, cognitive performance, and physical development. RESULTS: For the ASCT, secure attachment was more frequently found among children living in families (66.7%) than in institutions (33.3%). The CPM showed obtained a higher mean value (19.3) for children living in a family than for children living in institutions (13.3). Moreover, for children with secure attachment, the mean CPM value and height-for-age ratio were, respectively, 83.7% in family situations and 73.1% in institutions. The mean values for children with insecure attachment were lower than for those with secure attachment in families (80.7%) and institutions (70.9%). However, despite the quality of attachment, the mean values obtained in families were higher than those obtained in institutions. CONCLUSION: These results suggest that the child's development, both cognitive and physical, depends on the quality of attachment. Life in the family gives better potentialities than life in an institution regardless of the quality of attachment.

Is allicin able to reduce Campylobacter jejuni colonization in broilers when added to drinking water?

Reducing Campylobacter shedding on the farm could result in a reduction of the number of human campylobacteriosis cases. In this study, we first investigated if allicin, allyl disulfide, and garlic oil extract were able to either prevent C. jejuni growth or kill C. jejuni in vitro. Allyl disulfide and garlic oil extract reduced C. jejuni numbers in vitro below a detectable level at a concentration of 50 mg/kg (no lower concentrations were tested), whereas allicin reduced C. jejuni numbers below a detectable level at a concentration as low as 7.5 mg/kg. In further experiments we screened for the anti-C. jejuni activity of allicin in a fermentation system closely mimicking the broiler cecal environment using cecal microbiota and mucus isolated from C. jejuni-free broilers. During these fermentation experiments, allicin reduced C. jejuni numbers below a detectable level after 24 h at a concentration of 50 mg/kg. In contrast, 25 mg/kg of allicin killed C. jejuni in the first 28 h of incubation, but anti-C. jejuni activity was lost after 48 h of incubation, probably due to the presence of mucin in the growth medium. This had been confirmed in fermentation experiments in the presence of broiler cecal mucus. Based on these results, we performed an in vivo experiment to assess the prevention or reduction of cecal C. jejuni colonization in broiler chickens when allicin was added to drinking water. We demonstrated that allicin in drinking water did not have a statistically significant effect on cecal C. jejuni colonization in broilers. It was assumed, based on in vitro experiments, that the activity of allicin was thwarted by the presence of mucin-containing mucus. Despite promising in vitro results, allicin was not capable of statistically influencing C. jejuni colonization in a broiler flock, although a trend toward lower cecal C. jejuni numbers in allicin-treated broilers was observed.

Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions.

BACKGROUND: Infantile haemangioma (IH) is a benign, common and self-limiting tumour of infancy; only a minority of cases need active treatment. Currently, propranolol appears superior to classic treatments. OBJECTIVES: To document in a prospective study indications and side-effects of propranolol for complicated IH in a large patient group. METHODS: Analysis of prospectively collected data was performed on 174 patients with IH treated with propranolol in a tertiary referral centre from September 2008 to January 2012. RESULTS: The group consisted of children with a potentially threatening and/or complicated IH; the girl/boy ratio was 123/51, and the mean age at the start of treatment was 4·8 months. In 173 cases (99·4%), treatment was successful, as assessed nonquantitatively by clinical observation. This striking effect was characterized by immediate cessation of growth, softening, fading of the erythema and rapid induction of regression. The mean duration of treatment was 10·7 months. The most important adverse effects were hypotension (3·4%), wheezing (9·2%), nocturnal restlessness (22·4%) and cold extremities (36·2%). In one patient, propranolol was stopped. In 15 patients it was necessary to reduce the dose, although the lower dose was still effective. CONCLUSIONS: In this study, propranolol was effective and safe in almost all patients with complex IH. Administration of systemic medication to an infant with a benign condition requires careful consideration, as only a minority of patients with IH require an active medical intervention. A shift of the indication of propranolol for IH is evident, expanding its application for life-threatening situations or severe functional impairment to early prevention of disfigurement or cosmetically permanent sequelae. However, the indication for such an active approach should be determined by experienced physicians.

In vivo broiler experiments to assess anti-Campylobacter jejuni activity of a live Enterococcus faecalis strain.

Bacterial gastroenteritis caused by thermotolerant Campylobacter species, mainly Campylobacter jejuni, has been the most reported zoonotic disease in many developed countries in recent years. Reducing Campylobacter shedding on the farm could result in a reduction of the number of campylobacteriosis cases. In 2 independent broiler seeder experiments, in which broiler chickens were orally inoculated with 2 amounts of Enterococcus faecalis MB 5259, we established whether a live E. faecalis strain was capable of reducing cecal Campylobacter colonization in broiler chickens. In previous in vitro experiments it has been demonstrated that this E. faecalis MB 5259 displays anti-Campylobacter activity. The effect of pH and bile salts on E. faecalis MB 5259 showed that growth and survival of E. faecalis MB 5259 can be impaired during passage through the gastrointestinal tract of broiler chickens. Despite these results E. faecalis MB 5259 was capable of colonizing the broiler ceca. Contrary to the in vitro experiments, in which E. faecalis MB 5259 inhibited C. jejuni MB 4185 growth, no inhibition was observed in the in vivo experiments independent of the inoculum size.

Application of medium-chain fatty acids in drinking water increases Campylobacter jejuni colonization threshold in broiler chicks.

Campylobacteriosis is the most reported bacterial-mediated gastroenteritic disease in many developed countries. Broiler chickens are a natural host for Campylobacter spp., and contaminated poultry meat products are a major source for transmitting pathogenic Campylobacter strains to humans. Currently, no intervention measure efficiently and effectively controls this pathogen in poultry flocks. Medium-chain fatty acids (caproic, caprylic, capric, and lauric acids) show a marked anti-Campylobacter activity in vitro. However, in recent trials using our in vivo models, administering these acids to the feed of broiler chicks neither prevented nor reduced cecal C. jejuni colonization in broilers. In the present study, we examined whether a drinking water application of medium-chain fatty acids might be more effective in combating Campylobacter colonization in poultry. Although Campylobacter colonization and transmission was not reduced, we demonstrate that adding an emulsion of a mixture of caproic, caprylic, capric, and lauric acids to the drinking water of broiler chicks reduces their colonization susceptibility and prevents C. jejuni survival in drinking water. Thus, the merit of water applications of medium-chain fatty acids is the reduction of the probability of Campylobacter entry into and transmission throughout a flock.

Intestinal mucus protects Campylobacter jejuni in the ceca of colonized broiler chickens against the bactericidal effects of medium-chain fatty acids.

Campylobacter jejuni is the most common cause of bacterial-mediated diarrheal disease worldwide. Because poultry and poultry products are a major source of C. jejuni infections in humans, efforts should be taken to develop strategies to decrease Campylobacter shedding during primary production. For this purpose, the efficacy of medium-chain fatty acids (MCFA) as feed additives to control C. jejuni colonization in broiler chickens was analyzed. First, the antimicrobial activity of the MCFA caproic, caprylic, and capric acid on C. jejuni was evaluated in vitro. Minimal inhibitory concentrations were 0.25 mM for caproic and 0.5 mM for caprylic and capric acids at pH 6.0 and 4 mM for all 3 compounds at pH 7.5. Time-kill curves revealed strong bactericidal properties of the tested compounds toward C. jejuni at pH 6.0. Concentrations as low as 4 mM caprylic and capric acids and 16 mM caproic acid killed all bacteria within 24 h. Capric acid had the highest activity, with concentrations of 4 mM killing all bacteria within the hour. Together these data show a profound bactericidal, dose-dependent activity of the tested MCFA toward C. jejuni in vitro. For this reason, the effect of these 3 MCFA on C. jejuni was evaluated in vivo. The addition of any of the acids to the feed, from 3 d before euthanization, was not capable of reducing cecal Campylobacter colonization in 27-d-old broilers experimentally infected with C. jejuni at 15 d of age. Using a cecal loop model, sodium caprate was not able to reduce cecal Campylobacter counts. When time-kill curves were conducted in the presence of chick intestinal mucus, capric acid was less active against C. jejuni. At 4 mM, all bacteria were killed only after 24 h. Thus, despite the marked bactericidal effect of MCFA in vitro, supplementing these acids to the feed does not reduce cecal Campylobacter colonization in broiler chickens under the applied test conditions, probably due to the protective effect of the mucus layer.

Non-pharmacological interventions for wandering of people with dementia in the domestic setting.

BACKGROUND: A number of studies exist of interventions for wandering in the institutional setting, but much less work has been done on wandering in the domestic setting. The prevalence of wandering by people with dementia is difficult to assess; wandering is not a simple or static behaviour and the reasons why people wander remain unclear. In the absence of a theory of wandering and an agreed definition of wandering, it is difficult to discover effective strategies for managing wandering and difficult to design appropriate intervention strategies. Also, the same behaviour or type of wandering might occur for different reasons in different individuals; any theoretical formulation is going to have to allow for different triggers for the behaviour and so to get a 'one size fits all' kind of explanation is unlikely. Thus what we mostly encounter in this field is a 'trial and error' approach which does not always do justice to the complex interactions of personal and environmental factors that lead people with dementia to wander. While there seems to be a consensus in the literature that in the majority of cases non-pharmacological approaches may work as well as drug treatment and with fewer side effects, in practice clinicians often resort to drugs as the first line of treatment. This review reports the lack of evidence from RCTs and discusses the range of non-pharmacological interventions that have been carried out using other study designs. OBJECTIVES: To evaluate the effectiveness and safety of non-pharmacological interventions in reducing wandering in the domestic setting by people with dementia. The secondary objective is to highlight the quality and quantity of research evidence available and to set an agenda for future research. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 11 May 2006 using the terms exit* or wander* or elopement or ambulat* or walk*. This Register contains records from all major healthcare databases and many ongoing trial databases and is updated regularly. SELECTION CRITERIA: Randomised clinical trials comparing intervention with no intervention or usual treatment ('standard care') or another intervention. DATA COLLECTION AND ANALYSIS: No suitable trials of non-pharmacological interventions for the prevention and management of wandering in the domestic setting were found. MAIN RESULTS: As no randomised controlled trials were found, no results can be reported. AUTHORS' CONCLUSIONS: There is an urgent need for randomised controlled trials of non-pharmacological interventions for wandering in the domestic setting.

The paediatric liver transplantation program at the Université catholique de Louvain.

The Paediatric Liver Transplant Program at Saint-Luc University Clinics constitutes a substantial single centre experience, including 667 transplantations performed between March 1984 and April 2003, and the history of this program reflects the tremendous progress in this field since twenty years. Liver transplantation in children constitutes a considerable undertaking and its results depend on multiple, intermingled risk factors. An analysis of the respective impact of several surgical and immunological parameters on patient/graft outcome and allograft rejection after paediatric liver transplantation showed a significant learning curve effect as well as the respective impact of pre-transplant diagnosis on survival and of primary immunosuppression on the rejection incidence. The introduction of living related liver transplantation in 1993 not only permitted to provide access to liver replacement in as many as 74% more candidate recipients, but also resulted in better graft survival and reduced retransplantation rate. The results of a recent pilot study suggest that steroid avoidance is not harmful, and could even be beneficial for paediatric liver recipients, particularly regarding growth, and that combining tacrolimus with basiliximab (anti-CD25 chimeric monoclonal antibody) for steroid substitution appears to constitute a safe alternative in this context. The long-term issues represent the main future challenges in the field, including the possibility of a full rehabilitation through immunosuppression withdrawal and tolerance induction, the development of adolescence transplant medicine, and the risk of early atherogenesis in the adulthood.

Sequential and simultaneous feature positive discriminations: occasion setting and configural learning in human Pavlovian conditioning.

Using a conditioned suppression preparation, the authors investigated sequential (X --> A+/A-) versus simultaneous (XA+/A-) feature positive (FP) discrimination learning in humans. The sequential discrimination was expected to be resolved by means of a Feature X Modulated Target A-US association and the simultaneous discrimination by a feature X-US association. After sequential FP training, extinction of Feature X did not affect discriminative X --> A/A responding (Experiment 1), and X transferred its modulatory ability only to new targets, B, that had also been modulated (Experiment 2). This suggests that the sequential FP discrimination indeed resulted in occasion setting. Unlike expected, Feature X Extinction did not affect discriminative XA/A responding after simultaneous FP training (Experiment 3), while at the same time Feature X did show the predicted nonselective transfer to new targets, B (Experiment 4). J. M. Pearce's (1987) configural learning theory can account for most but not all findings of Experiments 3 and 4.

Inhibition of volume-regulated anion channels by dominant-negative caveolin-1.

Caveolae are flask-shaped invaginations of the plasma membrane formed by the association of caveolin proteins with lipid rafts. In endothelial cells, caveolae function as signal transduction centers controlling NO synthesis and mechanotransduction. We now provide evidence that the endothelial volume-regulated anion channel (VRAC) is also under the control of the caveolar system. When calf pulmonary artery endothelial (CPAE) cells were transfected with caveolin-1 Delta1-81 (deletion of amino acids 1 to 81), activation of VRAC by hypotonic cell swelling was strongly impaired. Concomitantly, caveolin-1 Delta1-81 disturbed the formation of caveolin-1 containing lipid rafts as evidenced by sucrose density gradient centrifugation. In nontransfected cells, endogenous caveolin-1 typically associated with low-density, detergent-resistant lipid rafts. However, transient expression of caveolin-1 Delta1-81 caused a redistribution of endogenous caveolin-1 to high-density, detergent-soluble membrane fractions. We therefore conclude that the interaction between caveolin-1 and detergent-resistant lipid rafts is an important prerequisite for endothelial VRAC activity.

Inhibition of VRAC by c-Src tyrosine kinase targeted to caveolae is mediated by the Src homology domains.

We used the whole cell patch-clamp technique in calf pulmonary endothelial (CPAE) cells to investigate the effect of wild-type and mutant c-Src tyrosine kinase on I(Cl,swell), the swelling-induced Cl- current through volume-regulated anion channels (VRAC). Transient transfection of wild-type c-Src in CPAE cells did not significantly affect I(Cl,swell). However, transfection of c-Src with a Ser3Cys mutation that introduces a dual acylation signal and targets c-Src to lipid rafts and caveolae strongly repressed hypotonicity-induced I(Cl,swell) in CPAE cells. Kinase activity was dispensable for the inhibition of I(Cl,swell), since kinase-deficient c-Src Ser3Cys either with an inactivating point mutation in the kinase domain or with the entire kinase domain deleted still suppressed VRAC activity. Again, the Ser3Cys mutation was required to obtain maximal inhibition by the kinase-deleted c-Src. In contrast, the inhibitory effect was completely lost when the Src homology domains 2 and 3 were deleted in c-Src. We therefore conclude that c-Src-mediated inhibition of VRAC requires compartmentalization of c-Src to caveolae and that the Src homology domains 2 and/or 3 are necessary and sufficient for inhibition.

Pre-extinction of sensory preconditioned electrodermal activity.

In the present study, sensory preconditioning of human electrodermal activity was demonstrated. In the first phase of the experiment, two pairs of neutral pictures of human faces were presented (A/B and C/D) sequentially. In the second phase, one picture of one pair was immediately followed by an electrocutaneous stimulus (B+), and one picture of the other pair was not (D-). In the third phase the other picture of each pair (A and C) was tested. The effect of A and C alone presentations (pre-extinction) between the first and the second phase was investigated. When only those participants that showed reliable B+/D- differentiation were considered, the extinction group did not show stronger conditioned electrodermal activity to A than to C, whereas the control group did. These findings suggest that sensory preconditioning of anticipatory/preparatory responding only occurs when the pre-conditioned stimulus (A) actually predicts the conditioned stimulus (B).

Subjective barriers to prevent wandering of cognitively impaired people.

BACKGROUND: People with dementia often wander, at times putting themselves at risk and presenting challenges to carers and institutional staff. Traditional interventions to prevent wandering include restraint, drugs and locked doors. Cognitively impaired people may respond to environmental stimuli (sounds, images, smells) in ways distinct from healthy people. This has led to trials of visual and other selective barriers (such as mirrors, camouflage, grids/stripes of tape) that may reduce wandering. OBJECTIVES: We assess the effect of subjective exit modifications on the wandering behaviour of cognitively impaired people. The second objective is to inform the direction and methods of future research. SEARCH STRATEGY: The search strategy includes electronic searches of relevant bibliographic and trials databases, citation indices and relevant medical journals. SELECTION CRITERIA: Randomized controlled trials and controlled trials provide the highest quality evidence, but interrupted time series are also considered as they may contribute useful information. Participants are people with dementia or cognitive impairment who wander, of any age, and in any care environment - hospital, other institution, or their own home. Interventions comprise exit modifications that aim to function as subjective barriers to prevent the wandering of cognitively impaired people. Locks, physical restraints, electronic tagging and other types of barrier are not included. DATA COLLECTION AND ANALYSIS: The criteria for inclusion or exclusion of studies are applied independently by two reviewers. All outcomes that are meaningful to people making decisions about the care of wanderers are recorded. These include the number of exits or carer interventions, resource use, acceptability of the intervention and the effects on carer and wanderer anxiety or distress. heterogeneity of clinical area, of study design and of intervention was substantial. MAIN RESULTS: No randomized controlled or controlled trials were found. The other experimental studies that we identified were unsatisfactory. Most were vulnerable to bias, particularly performance bias; most did not classify patients according to type or severity of dementia; in all studies, outcomes were measured only in terms of wandering frequency rather than more broadly in terms of quality of life, resource use, anxiety and distress; no studies included patients with delirium; no studies were based in patients' homes. REVIEWER'S CONCLUSIONS: There is no evidence that subjective barriers prevent wandering in cognitively impaired people.

The emotional stroop task and chronic pain: what is threatening for chronic pain sufferers?

Using a computer version of the emotional stroop task, it was investigated whether chronic pain patients display an involuntary attentional shift towards pain-related information (sensory, affective pain words and injury related words). Multiple regression analyses were used to investigate which pain and psychosocial variables (pain severity, pain-related fear, pain catastrophizing and negative affect) were predictive of attentional bias. Results indicated: (1) that there was an attentional bias towards the sensory pain words; and (2) that current pain intensity was predictive of the effect. No other attentional effects were found. The results are discussed in terms of possible reasons for the difficulty of demonstrating attentional bias in chronic pain patients.

Differential effects of injections of anti-mu and anti-delta monoclonal antibodies on B-cell populations in adult mice: regulation of xenoreactive natural antibody-producing cells.

BACKGROUND: The depletion of differential B cell and xenoreactive natural antibodies (XNA) by anti-delta and anti-mu injections was analyzed in adult mice. Sequential treatment with anti-delta and then anti-mu induces a complete depletion of B cells and XNA and represents a potential approach to induce xenograft tolerance. METHODS: Adult mice were injected with anti-mu, anti-delta, anti-delta then anti-mu, or control isotype monoclonal antibodies from day 0 to day 14. The different B-cell populations were analyzed by FACS and immunohistology. Ig production was tested by ELISA. XNA were analyzed by FACS. RESULTS: Anti-mu injections induced a depletion of IgMhigh, immature B cells, marginal zone B cells, and B1 cells and an increase of IgG-XNA production. Anti-delta injections induced mature conventional IgDhigh B-cell depletion and increased IgM-XNA production. Interestingly, sequential injections of anti-delta then anti-mu induced a depletion of immature B cells, mature B cells (MZ, B2, and B1), and XNA. CONCLUSIONS: These results demonstrate that mature B-cell depletion in adult mice can be obtained by mAb injections and depends on the surface immunoglobulin cross-linking threshold. Indeed, anti-mu mAb depleted IgMhigh B cells (MZ and B1) and anti-delta, IgDhigh B cells (B2). The differential B-cell suppression shows that conventional B cells are responsible in the IgG-XNA production and MZ and B1 cells in the IgM-XNA production. Sequential repeated injections of anti-delta then anti-mu mAb depleted all B-cell populations and suppressed the whole XNA production.

Saccharomyces boulardii upgrades cellular adaptation after proximal enterectomy in rats.

BACKGROUND: Saccharomyces boulardii is a non-pathogenic yeast which exerts trophic effects on human and rat small intestinal mucosa. AIMS: To examine the effects of S boulardii on ileal adaptation after proximal enterectomy in rats. METHODS: Wistar rats, aged eight weeks, underwent 60% proximal resection or transection and received by orogastric intubation either 1 mg/g body wt per day lyophilised S boulardii or the vehicle for seven days. The effects on ileal mucosal adaptation were assessed eight days after surgery. RESULTS: Compared with transection, resection resulted in mucosal hyperplasia with significant decreases in the specific and total activities of sucrase, lactase, and maltase. Treatment of resected animals with S boulardii had no effect on mucosal hyperplasia but did upgrade disaccharidase activities to the levels of the transected group. Enzyme stimulation by S boulardii was associated with significant increases in diamine oxidase activity and mucosal polyamine concentrations. Likewise, sodium dependent D-glucose uptake by brush border membrane vesicles, measured as a function of time and glucose concentration in the incubation medium, was significantly (p<0.05) increased by 81% and three times respectively in the resected group treated with S boulardii. In agreement with this, expression of the sodium/glucose cotransporter-1 in brush border membranes of resected rats treated with S boulardii was enhanced twofold compared with resected controls. CONCLUSION: Oral administration of S boulardii soon after proximal enterectomy improves functional adaptation of the remnant ileum.

Depressed urokinase activity in bronchoalveolar lavage fluid from patients with sarcoidosis, silicosis or idiopathic pulmonary Rbrosis: relationship to disease severity.

Intraalveolar fibrinolysis, is regulated by the concerted actions of plasmin, plasminogen activators (PAs), and their specific inhibitors (PAIs). This event is considered as a critical step in the pathogenesis of pulmonary fibrosis. The aim of this study was to evaluate whether local PA activity can be held as a marker of fibrosis in chronic interstitial lung disorders (ILD). Changes in both PA activity and PA-related proteins (urokinase-type PA (uPA), tissue-type PA (tPA), PAI-1 and PAI-2) were assessed in bronchoalveolar fluid (BALF) of 60 subjects: 18 healthy controls, 18 non-fibrotic sarcoidosis patients, 16 patients with idiopathic pulmonary fibrosis (IPF) and eight silicotic patients with established fibrosis. We observed a significant decrease of BALF PA activity in the three groups of patients as compared with controls. Reduction in BALF PA activity was compatible with lower uPA protein levels associated, especially in IPF patients, with an increased occurrence of PAI-1 and PAI-2 antigens. Soluble tPA antigen was never detected either in control subjects or in patients. Most importantly, the reduction in BALF PA activity and uPA protein levels was found to be most severe in patients with advanced fibrotic disease, namely IPF, while moderate and only weak alterations were found in silicosis and non-fibrotic sarcoidosis, respectively. In addition, significant positive correlations were found between BALF PA activity and functional impairment as assessed by TLC % and DLCO%. Finally, the reduction in uPA and PA activity levels observed in BALF from sarcoidosis patients was found to be proportional to the degree of BAL lymphocytosis. These findings indicate that an intense reduction in BALF PA activity is associated with severe stages of the parenchymal disease, possibly reflecting the degree of the fibrotic process.