Acquired form of angioedema of the head and neck related to a deficiency in c1-inhibitor: a case report with a review of the literature.

Angioedema related to a deficiency in the C1-inhibitor protein is characterized by its lack of response to therapies including antihistamine, steroids, and epinephrine. In the case of laryngeal edema, mortality rate is approximately 30 percent. The first case of the acquired form of angioedema related to a deficiency in C1-inhibitor was published in 1972. In our paper, we present a case of an acquired form of angioedema of the oropharyngeal region secondary to the simultaneous occurrence of two causative factors: neutralization of C1-inhibitor by an autoantibody and the use of an angiotensin convertin enzyme inhibitor.

Maladie de Weil: à propos d'un cas de leptospirose acquise en Suisse [Weil's disease: a case report of acquired leptospirosis in Switzerland].

Leptospirosis is a rare disease in Switzerland. However its incidence is probably underestimated, due to its broad spectrum of presentations, including subclinical benign forms and the ictero-hemorragic form of the Weil's syndrome, whose mortality is high. We describe here a case of Weil's syndrome acquired in Switzerland with a favourable outcome under antibiotherapy. Even in the absence of any travel, the association of an acute renal insufficiency and jaundice with only moderate hepatic cytolysis should lead to the suspicion of leptospirosis. Clinical and epidemiological aspects of the disease are discussed in the article.

Monoclonal antibodies against carcinoembryonic antigen (CEA) used in a solid-phase enzyme immunoassay. First clinical results.

A solid-phase enzyme immunoassay using both mouse monoclonal and goat polyclonal antibodies against carcinoembryonic antigen (CEA) was developed. The assay detects 0.6 to 1.2 ng of CEA per ml of serum and has 3 incubation steps which can be performed in 1 day. Polystyrene balls coated with polyclonal goat anti-CEA antibodies are first incubated with heat-extracted serum samples. Bound CEA is then detected by addition of mouse monoclonal antibodies, followed by goat IgG anti-mouse IgG1 coupled to alkaline phosphatase. Results with this enzyme immunoassay using monoclonal antibodies (M-EIA) have been compared with those obtained by the conventional inhibition radioimmunoassay (RIA) using goat antiserum. Three hundred and eighty serum samples from 167 patients with malignant or non-malignant diseases and from 134 normal individuals with or without heavy smoking habits were analyzed by the 2 assays. Excellent correlation between the results of the 2 assays was obtained, but the M-EIA, using monoclonal antibodies from a single hybridoma, did not discriminate better than the conventional RIA between CEA produced by different types of carcinoma and between CEA associated with malignant or non-malignant diseases. Follow-up studies of several patients by sequential CEA determinations with the 2 assays showed that the M-EIA was as accurate as the RIA for the detection of tumor recurrences.

Heterogeneous 40Ar* distributions in naturally deformed muscovite: in situ UV-laser ablation evidence for micro structurally controlled intragrain diffusion

Micas are commonly used in Ar-40/Ar-39 thermochronological studies of variably deformed rocks yet the physical basis by which deformation may affect radiogenic argon retention in mica is poorly constrained. This study examines the relationship between deformation and deformation-induced microstructures on radiogenic argon retention in muscovite, A combination of furnace step-heating and high-spatial resolution in situ UV-laser ablation Ar-40/Ar-39 analyses are reported for deformed muscovites sampled from a granitic pegmatite vein within the Siviez-Mischabel Nappe, western Swiss Alps (Penninic domain, Brianconnais unit). The pegmatite forms part of the Variscan (similar to 350 Ma) Alpine basement and exhibits a prominent Alpine S-C fabric including numerous mica `fish' that developed under greenschist facies metamorphic conditions, during the dominant Tertiary Alpine tectonic phase of nappe emplacement. Furnace step-heating of milligram quantities of separated muscovite grains yields an Ar-40/Ar-39 age spectrum with two distinct staircase segments but without any statistical plateau, consistent with a previous study from the same area. A single (3 X 5 mm) muscovite porphyroclast (fish) was investigated by in situ UV-laser ablation. A histogram plot of 170 individual Ar-40/Ar-39 UV-laser ablation ages exhibit a range from 115 to 387 Ma with modes at approximately 340 and 260 Ma. A variogram statistical treatment of the (40)Ad/Ar-39 results reveals ages correlated with two directions; a highly correlated direction at 310 degrees and a lesser correlation at 0 degrees relative to the sense of shearing. Using the highly correlated direction a statistically generated (Kriging method) age contour map of the Ar-40/Ar-39 data reveals a series of elongated contours subparallel to the C-surfaces which where formed during Tertiary nappe emplacement. Similar data distributions and slightly younger apparent ages are recognized in a smaller mica fish. The observed intragrain age variations are interpreted to reflect the partial loss of radiogenic argon during Alpine (similar to 35 Ma) greenschist facies metamorphism. One-dirnensional diffusion modelling results are consistent with the idea that the zones of youngest apparent age represent incipient shear band development within the mica porphyroclasts, thus providing a network of fast diffusion pathways. During Alpine greenschist facies metamorphism the incipient shear bands enhanced the intragrain loss of radiogenic argon. The structurally controlled intragrain age variations observed in this investigation imply that deformation has a direct control on the effective length scale for argon diffusion, which is consistent with the heterogeneous nature of deformation. (C) 2001 Elsevier Science B.V. All rights reserved.

Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands.

Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3₁₄₀₆₋₁₄₁₅ and NS5B₂₅₉₄₋₂₆₀₂). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.

Efficacy of clinical guideline implementation to improve the appropriateness of chest physiotherapy prescription among inpatients with community-acquired pneumonia

BACKGROUND: Although there is no strong evidence of benefit, chest physiotherapy (CP) seems to be commonly used in simple pneumonia. CP requires equipment and frequently involves the assistance of a respiratory therapist, engendering a significant medical workload and cost. AIM: To measure and compare the efficacy of two modalities of chest physiotherapy (CP) guideline implementation on the appropriateness of CP prescription among patients hospitalised for community-acquired pneumonia (CAP). PATIENTS AND METHODS: We measured the CP prescription rate and duration in all consecutive CAP inpatients admitted in a division of general internal medicine at an urban teaching community hospital during three consecutive one-year time periods: (1) before any guideline implementation; (2) after a passive implementation by medical grand rounds and guideline diffusion through mailing; (3) after adding a one-page reminder in the CAP patient's medical chart highlighting our recommendations. Death and recurrent hospitalisation rates within one year after hospitalisation were recorded to assess whether CP prescription reduction, if any, impaired patient outcomes. RESULTS: During the three successive phases, 127, 157, and 147 patients with similar characteristics were included. Among all CAP inpatients, the CP prescription rate decreased from 68% (86/127) to 51% (80/157), and to 48% (71/147), respectively (P for trend <0.01 for trend). A significant reduction in CP duration was observed after the active guideline implementation (12.0, 11.0, 7.0days, respectively) and persisted after adjustment for length of stay. Reductions in CP prescription rate and duration were also observed among CAP patients with COPD CP prescription rate: 97% (30/31), 67% (24/36), 75% (35/47), respectively (P<0.01 for trend). The mean cost of CP per patient was reduced by 56%, from $709 to $481, and to $309, respectively. Neither the in-hospital deaths, the one-year overall recurrent hospitalisation nor the one-year CAP-specific recurrent hospitalisation significantly differed between the three phases. CONCLUSION: Both passive and active implementation of guidelines appear to improve the appropriateness of CP prescription among inpatients with CAP without impairing their outcomes. Restricting CP use to patients who benefit from this treatment might be an opportunity to decrease CAP medical cost and workload.

Neutralization of Macrophage Migration Inhibitory Factor (MIF) by Fully Human Antibodies Correlates with Their Specificity for the β-Sheet Structure of MIF.

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.

In vitro and in vivo tumor models for studies of distribution of radiolabelled monoclonal antibodies and fragments.

Colon carcinoma multicellular spheroids were incubated in vitro with radiolabelled MAbs. The more rapid penetration of fragments as compared to intact MAbs was clearly demonstrated. For the study of antibody localization in tumors in vivo, the model of nude mice with ligated kidneys was used. Although very artificial, this model allowed to demonstrate that, without urinary excretion, Fab fragments accumulated more rapidly into the tumor than intact MAbs and disappeared faster from the blood. This difference was less striking for F(ab')2 fragments. In the liver a decreased accumulation of both types of fragments as compared to intact MAbs was observed. Concerning radioimmunotherapy we think that Fab fragments are not useful because of their too short half-life in the circulation and in tumor and because they will probably be too toxic for the kidneys. Intact MAbs and F(ab')2 fragments have each their advantages. Intact MAbs show highest tumor accumulation in mice without ligated kidney, however, they remain mostly on the periphery of tumor nodules, as shown by autoradiography. F(ab')2 fragments have been found to penetrate deeper into the tumor and to accumulate less in the liver. It might be therefore an advantage to combine intact MAbs with F(ab')2 fragments, so that in the tumor two different regions could be attacked whereas in normal tissues toxicity could be distributed to different organs such as to the liver with intact MAbs and to the kidney with F(ab')2 fragments.

Radioimmunotherapy of human colon carcinoma by 131I-labelled monoclonal anti-CEA antibodies in a nude mouse model.

A mixture of 3 MAbs directed against 3 different CEA epitopes was radiolabelled with 131I and used for the treatment of a human colon carcinoma transplanted s.c. into nude mice. Intact MAbs and F(ab')2 fragments were mixed because it had been shown by autoradiography that these 2 antibody forms can penetrate into different areas of the tumor nodule. Ten days after transplantation of colon tumor T380 a single dose of 600 microCi of 131I MAbs was injected i.v. The tumor grafts were well established (as evidenced by exponential growth in untreated mice) and their size continued to increase up to 6 days after radiolabelled antibody injection. Tumor shrinking was then observed lasting for 4-12 weeks. In a control group injected with 600 microCi of 131I coupled to irrelevant monoclonal IgG, tumor growth was delayed, but no regression was observed. Tumors of mice injected with the corresponding amount of unlabelled antibodies grew like those of untreated mice. Based on measurements of the effective whole-body half-life of injected 131I, the mean radiation dose received by the animals was calculated to be 382 rads for the antibody group and 478 rads for the normal IgG controls. The genetically immunodeficient animals exhibited no increase in mortality, and only limited bone-marrow toxicity was observed. Direct measurement of radioactivity in mice dissected 1, 3 and 7 days after 131I-MAb injection showed that 25, 7.2 and 2.2% of injected dose were recovered per gram of tumor, the mean radiation dose delivered to the tumor being thus more than 5,000 rads. These experiments show that therapeutic doses of radioactivity can be selectively directed to human colon carcinoma by i.v. injection of 131I-labelled anti-CEA MAbs.

Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice.

During one week, beginning 18 days after transplantation, nude mice bearing human colon carcinoma ranging from 115 to 943 mm3 (mean 335 mm3) were treated by repeated intravenous injections of either iodine-131-(131I) labeled intact antibodies or 131I-labeled corresponding F(ab')2 fragments of a pool of four monoclonal antibodies (MAbs) directed against distinct epitopes of carcinoembryonic antigen (CEA). Complete tumor remission was observed in 8 of 10 mice after therapy with F(ab')2 and 6 of the animals survived 10 mo in good health. In contrast, after treatment with intact MAbs, tumors relapsed in 7 of 8 mice after remission periods of 1 to 3.5 mo despite the fact that body weight loss and depression of peripheral white blood cells, symptoms of radiation toxicity, and the calculated radiation doses for liver, spleen, bone, and blood were increased or equal in these animals as compared to mice treated with F(ab')2.

Pre-hatching maternal effects inhibit nestling humoral immune response in the tawny owl Strix aluco

Although evidence is accumulating that mothers can transfer antibodies to their offspring, little is known about the consequences of such a transfer to the offspring immune system. Because maternal antibodies are effective only during a short period of time after their transfer to offspring, one hypothesis is that maternal antibodies provides a transitory antigen-specific protection to offspring, thus lessening the need for offspring to mount their own humoral immune response towards these specific antigens. In birds, this scenario predicts that offspring immune response towards a specific antigen is inhibited to a larger extent in hatchlings than in older nestlings. We tested this hypothesis in tawny owls Strix aluco by cross-fostering clutches between nests and then challenging siblings with a vaccine either two times (at 4- and 11-d-old) or only one time at 11-d-old to compare the strength of the humoral response between nestlings born from mothers with naturally high and low levels of antibodies against this vaccine. Because maternal antibodies are expected to be effective only during a short period of time after hatching, we predict that maternal antibodies should inhibit the immune response of nestlings vaccinated from the fourth day after hatching more than in nestlings vaccinated only at a later age. As expected, the inhibitory effect of maternal antibodies was stronger in nestlings vaccinated soon after hatching than in siblings injected at a later age. Therefore, in wild avian populations pre-hatching maternal effects may confer offspring with a transitory immune protection in the first days following hatching.

Striking immunodominance hierarchy of naturally occurring CD8+ and CD4+ T cell responses to tumor antigen NY-ESO-1.

Immunodominance has been well-demonstrated in many antiviral and antibacterial systems, but much less so in the setting of immune responses against cancer. Tumor Ag-specific CD8+ T cells keep cancer cells in check via immunosurveillance and shape tumor development through immunoediting. Because most tumor Ags are self Ags, the breadth and depth of antitumor immune responses have not been well-appreciated. To design and develop antitumor vaccines, it is important to understand the immunodominance hierarchy and its underlying mechanisms, and to identify the most immunodominant tumor Ag-specific T cells. We have comprehensively analyzed spontaneous cellular immune responses of one individual and show that multiple tumor Ags are targeted by the patient's immune system, especially the "cancer-testis" tumor Ag NY-ESO-1. The pattern of anti-NY-ESO-1 T cell responses in this patient closely resembles the classical broad yet hierarchical antiviral immunity and was confirmed in a second subject.

Anti-60kDa heat shock protein antibodies in fetal serum : a biomarker for unexplained small for gestational age fetuses

Rapport de synthèseObjectifsLe retard de croissance intrautérin (RCIU) est un problème affectant 10% des grossesses et est associé à une morbidité périnatale importante. Dans environ 80% des cas, une étiologie ou un facteur de risque majeur peuvent être identifiés. Mais près de 20% des cas sont considérés comme inexpliqués. La heat shock protéine 60kDa (HSP60) est une protéine fortement immunogène dont la synthèse est considérablement augmentée lors de conditions non- physiologiques. Les HSP60 humaines et bactériennes partagent un haut degré d'homologie de séquence ce qui peut engendrer une maladie auto-immune à la suite d'une infection bactérienne. Nous avons supposé que les RCIU inexpliqués pourraient être la conséquence d'une sensibilisation à l'HSP60 humaine.MéthodesLes RCIU inexpliqués ont été identifiés par mesure échographique avec un doppler normal, sans anomalies décelables chez la mère ou le foetus. Les sera foetaux ont été obtenus par cordocentèse, effectuée lors d'analyse du caryotype en cas de RCIU inexpliqué (groupe d'étude) ou pour le dépistage d'une incompatibilité Rhésus (groupe témoin). Ils ont été testés pour l'antigène HSP60 et les IgG et IgM anti-HSP60 par ELISA ainsi que pour d'autres paramètres immunitaires et hématologiques.RésultatsLes paramètres maternels sont similaires entre les 12 cas du groupe d'étude et les 23 cas du groupe contrôle. L'âge gestationnel moyen lors de la cordocentèse est de 29 semaines. Les IgM anti-HSP60 sont détectés dans 12 cas d'étude (100%) mais dans aucun cas contrôle (p <0,00017), les IgG anti-HSP60 dans 7 cas d'étude (58%) et un seul dans le groupe contrôle (p <0,001). Trois des quatre cas avec les taux d'IgM les plus élevés sont décédés. Il n'y a pas de différences entre les deux groupes quant aux taux d'antigène HSP60 ou d'autres marqueurs immunologiques ou hématologiques.ConclusionLes foetus avec un RCIU inexpliqué expriment un taux élevé d'anticorps IgM et IgG contre l'HSP60 humaine et le taux d'IgM est un facteur prédictif de la mortalité foetale. La détection de ces anticorps indique qu'une perturbation placentaire et une réaction auto-immune foetale liée à l'HSP60 sont associées à ce retard de développement chez le foetus.

Prevention of age-associated dementia.

The advancement of medical sciences during the last century has resulted in a considerable increase in life expectancy. As more people live to old age, one of the most fundamental questions of the 21st century is whether the number of individuals suffering from dementia will also continue to increase. Alzheimer's disease (AD) accounts for the majority of cases of dementia in the elderly, but there is currently no curative treatment available. Several strategies have been introduced for treatment, the most recent strategy of which was the immunization of patients using antibodies against Abeta, which is a naturally occurring, even though misfolded peptide in the AD brain. Both active and passive immunization routes have been shown to reduce the pathology associated with Abeta accumulation in brains of genetically designed animal models. However, despite tremendous efforts, no unequivocal proof of therapeutic efficacy could be shown in AD patients. Particularly, the persistence of the neurofibrillary tangles in immunized brains and the issue of inducing cerebral amyloid angiopathy are major limiting factors of antibody therapy. Furthermore, physical activity, a healthy immune system and nutritional habits are suggested to protect against the onset of age-associated dementia. Thus, accumulative evidence suggests that an early integrated strategy, combining pharmacological, immunological, nutritional and life-style factors, is the most pragmatic approach to delay the onset and progression of age-associated dementia.

Immune response to hepatitis B vaccination in HIV-positive adults with isolated antibodies to HBV core antigen.

OBJECTIVE: To investigate the merits of vaccination against hepatitis B virus (HBV) in HIV-positive individuals with isolated antibodies to hepatitis B core antigen (anti-HBc). METHODS: HIV-positive patients with isolated anti-HBc and CD4 counts >200 cells/mm(3) received HBV vaccination. An antibody titre to hepatitis B surface antigen (anti-HBs titres) ≥10 IU/L one month post-vaccination was termed an anamnestic response; a titre <10 IU/L was termed a primary response. Patients with primary responses received a 3-dose vaccine course. Anti-HBs titres in all responders were measured 12 and 24 months post-vaccination. RESULTS: 37 patients were studied: 19 (51%) were co-infected with hepatitis C; median CD4 count was 443 cells/mm(3). 8/37 patients (22%) elicited an anamnestic response. 29/37 patients (78%) elicited a primary response. After a 3-dose vaccine course, 15/25 primary responders (60%) achieved anti-HBs titres ≥10 IU/L. HIV acquisition through injecting drug use was the only independent predictor of an anamnestic response (OR 22.9, CI 1.71-306.74, P=0.018). Median anti-HBs titres for anamnestic and primary responders were 51 IU/L (13-127) and 157 IU/L (25-650) respectively. Of all responders, 12/23 (52%) retained anti-HBs titres ≥10 IU/L at 24 months. Anti-HBs duration was not significantly different between anamnestic and primary responders. CONCLUSIONS: 23/37 HIV-positive patients (62%) with isolated anti-HBc achieved anti-HBs titres ≥10 IU/L after 1-3 vaccine doses. However, duration of this immune response was short-lived (