Lung epithelium-specific proteins: characteristics and potential applications as markers.
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Adult↗
Biomedical subjects
A Bernard
Publications and source records attributed to A Bernard.
[Viruses and the neuroendocrine system: model of murine obesity induced by cerebral infection by canine distemper virus].
It is currently well established that the nervous, endocrine and immune systems inter-communicate using biologically active soluble factors, synthesised and produced by these three systems themselves (e.g. immunomodulator effect of hormones, effect of substances secreted by immune cells on endocrine function.). In addition, these systems jointly express receptors for hormones, peptides, growth factors and cytokines. Immuno-neuroendocrine interactions therefore underlie physiological processes and their deregulation can result in various pathological states. By entering into complex relationships with the specialized and differentiated cells of these three systems viruses can alter inter-cellular communication and result in the appearance of pathological processes directly linked to these disturbances. In order to understand the role of viruses in the genesis of neuroimmunoendocrine pathologies, we have developed a cerebral infection model using canine distemper virus (CDV). In infected mice, this paramyxovirus, closely related to the human measles virus, induces early neurological pathologies (encephalitis) which are associated with active viral replication. Mice surviving the acute phase of infection exhibit motor deficits (paralysis and turning behaviour) or obesity during the viral persistence phase, despite the fact that the virus is no longer detectable. The obesity is characterised by hyperinsulinaemia, hyperleptinaemia and hyperplasia of the adipocytes, associated with decreased expression of the OB-Rb hypothalamic leptin receptor and modulated expression of hypothalamic monoamines and neuropeptides. These results support the viral "hit and run" theory, since the initial viral impact in the hypothalamus may be the origin of the changes in later immunoneuroendocrine communication. Thus, certain human neurodegenerative or neuroendocrine diseases may have a previous viral infection aetiology without it being possible to clearly identify the agent responsible.
Animals↗
[Coloplasty after esophagectomy in cancer. A retrospective study of morbidity and mortality].
Aim of this study has been to evaluate retrospectively morbidity and mortality of 42 colon substitutions after resection for esophageal cancer. Colon substitution was the intervention of first choice in six patients. In the other patients the stomach was useless, because of previous gastric surgery (n = 14), of gastric involvement by the tumor (n = 21) or technical problem (n = 1). Patients have been separated in 2 groups: from 1969 to 1983 (group A, n = 22), and from 1983 to 1997 (group B, n = 20). Mortality and morbidity (all eventful postoperative course) have been collected for the 30 postoperative days. Total morbidity has been 57% as 77% in group A and 35% in group B (p < 0.05). Cervical and colo-colic leak have been the most common complications. Total mortality has been 14% as 22% in group A and 5% in group B (p < 0.1). In group A 3 patients died from anastomosis leak (intrathoracic or intraabdominal) and 2 from medical complications. In group B 1 patient died from unexplained sepsis. Our results show significative decrease of morbidity and mortality in group B. These results can be compared to those of gastroplasty for cancer or coloplasty for benign disease. In cancer of the esophagus, if stomach can not be used as substitutes, colon substitution is the best alternative, which can be used without increase of mortality and morbidity.
Adenocarcinoma↗
Making the wait more bearable.
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Critical Care↗
Novel integrated optical sensor based on a grating coupler triplet.
A novel approach for accomplishing robust integrated optical biosensors is presented. The principle is based on a symmetric grating coupler structure with the inherent feature of compensating disturbances originating from different kinds of mechanical instabilities. The complete sensor system has no moving parts and provides the high sensitivities typical for integrated optical sensors based on grating couplers. The feasibility of this approach is demonstrated by determining the refractive index of liquids as well as by measuring the specific binding of biomolecules (anti-chicken IgG) to immobilized chicken IgG on the sensor chip surface.
Biosensing Techniques↗
Ligand binding to the serotonin 5HT3 receptor studied with a novel fluorescent ligand.
The thermodynamics and kinetics of ligand binding to the purified serotonin 5HT3 receptor and the local environment of the bound ligand were studied by fluorescence spectroscopy using a novel fluorescein-labeled ligand GR-flu [1,2,3, 9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methyl]-9-(3-amino-(N-fluo rescien-thiocarbamoyl)-propyl)-4H-carbazol-4-one]. Electrophysiological investigations demonstrated GR-flu to be an antagonist, and radioligand competition assays delivered a dissociation constant of 0.32 nM. Changes in the fluorescence intensity and anisotropy upon specific binding to the receptor yielded dissociation constants of approximately 0.2 nM. Fluorescence measurements showed that selective 5HT3 receptor ligands competed for GR-flu binding with a rank order of potency identical to that established with the radioligand [3H]-GR65630. The kinetics of GR-flu binding to the 5HT3 receptor revealed a bimolecular association process with an on-rate constant of 1.17 x 10(6) s-1 M-1 and a biphasic dissociation reaction with off-rate constants of 275 x 10(-)6 and 43 x 10(-)6 s-1. The temperature dependence of the dissociation constant yielded an enthalpic term of -26 kJ mol-1 and an entropic term of 94 J K-1 mol-1 for the binding of GR-flu to the receptor, indicating that both quantities contribute equally to the reaction. An activation enthalpy DeltaH#on and entropy DeltaS#on of binding of 50 kJ mol-1 and 43 J mol-1 K-1 were obtained, indicating that the entropy facilitates the initial steps of GR-flu binding to the 5HT3 receptor. The fluorescence anisotropy of receptor-bound GR-flu and the environmental sensitivity of the fluorescent probe suggest that the binding site has a wide entrance and that it is 0.8 pH unit more acidic than the bulk solution.
Animals↗
Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.
X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.
Amino Acid Sequence↗
[Ganglioneuroblastoma in the adult].
BACKGROUND: Ganglioneuroblastoma is commonly observed in children but rarely in adults. Therapy and prognosis are not well defined in adults. CASE REPORT: We report the case of a female adult who developed a ganglioneuroblastoma of the left adrenal gland with liver metastasis. Surgical treatment combined with radio and chemotherapy led to complete remission. DISCUSSION: The outcome in our patient and data reported in the literature suggest that a multidisciplinary approach is necessary and that initial surgical resection should be performed whenever possible. Adjuvant radiotherapy or chemotherapy have been shown to be somewhat effective in children but their true impact in adults remains to be ascertained. Follow-up after resection should include physical examination, assay of adrenal derivatives in plasma and urine and imaging.
Adrenal Gland Neoplasms↗
Role of CD46 in measles virus infection in CD46 transgenic mice.
The susceptibility of CD46 (human membrane cofactor protein) transgenic mice to measles virus (MV) infection was investigated. Cell cultures (lung and kidney) established from transgenic and control mice showed that although both could be infected only those from the CD46+ mice gave fusion. A complete round of replication with the release of infectious virus was detected exclusively in the transgenic cell cultures whose permissiveness to MV was markedly less than that of Vero cells. The ability of MV to replicate in vivo in mice was studied using both vaccine and laboratory-adapted wild-type strains of virus. After intraperitoneal and intranasal inoculations of transgenic mice, virus replication could not be detected. In contrast intracerebral inoculation induced infection in both transgenic and nontransgenic mice. Our results from in vitro infection studies support the hypothesis that CD46 is a major host cell factor involved in the MV-induced fusion process and MV entry. The studies further indicate that MV tropism is not governed solely by the expression of the CD46 gene and that the high efficiency of the replicative cycles characteristic of fully permissive host cells requires additional factors, which are lacking in both transgenic and nontransgenic mice.
Administration, Intranasal↗
Thermodynamics and kinetics of the reaction of a single-chain antibody fragment (scFv) with the leucine zipper domain of transcription factor GCN4.
Single-chain Fv (scFv) fragments of antibodies have become important analytical and therapeutic tools in biology and medicine. The reaction of scFv fragments has not been well-characterized with respect to the energetics and kinetics of antigen binding. This paper describes the thermodynamic and kinetic behavior of the high-affinity scFv fragment SW1 directed against the dimeric leucine zipper domain of the yeast transcription factor GCN4. The scFv fragment was selected by the phage display technique from the immune repertoire of a mouse that had been immunized with the leucine zipper domain of GCN4. The scFv fragment was produced in high yield in Escherichia coli inclusion bodies and refolded from the denatured state. Differential scanning calorimetry showed that SW1 was stable up to about 50 degreesC, but the subsequent thermal denaturation was irreversible (Tm approximately 68 degreesC). The scFv fragment specifically recognized the dimeric leucine zipper conformation. Two scFv fragments bound to the GCN4 dimer to form the complex (scFv)2-GCN4. Because of its repetitive structure, the rod-shaped GCN4 leucine zipper may present two similar epitopes for the scFv fragment. Surprisingly, the binding reaction was highly cooperative, that is, the species (scFv)2-GCN4 dominated over scFv-GCN4 even in the presence of a large excess of the antigen GCN4. It is speculated that cooperativity resulted from direct interaction between the two GCN4-bound scFv fragments. At 25 degreesC, the average binding enthalpy for a scFv fragment was favorable (-61 kJ mol-1), the entropy change was unfavorable, and the change in heat capacity was -1.27 +/- 0.14 kJ mol-1 K-1. As a result of enthalpy-entropy compensation, the free binding energy was virtually independent of temperature in the physiological temperature range. Antigen binding in solution could be described by a single-exponential reaction with an apparent rate constant of 1 x 10(6) M-1 s-1. Binding followed in a biosensor with the dimeric GCN4 coupled to the surface of the metal oxide sensor chip was 20 times slower.
Amino Acid Sequence↗
Characterization of rat porin isoforms: cloning of a cardiac type-3 variant encoding an additional methionine at its putative N-terminal region.
In vivo, the outer mitochondrial membrane presents a restriction of diffusion for ADP in heart and slow twitch skeletal muscles, but not in fast twitch skeletal muscle. Mitochondrial porins constitute the main pathway for the transit of metabolites across the outer mitochondrial membrane. We decided, therefore, to characterize, by cloning, rat heart VDAC and to follow their expression in different striated muscles. We cloned three isoforms, one being HVDAC1-like porin (RVDAC1) whereas the other two are MVDAC3-like porins (RVDAC3 and RVDAC3v). These three isoforms are ubiquitously expressed among striated muscles. RVDAC3v differs from RVDAC3 by one additional amino acid, a Met, located between Val39 and Glu40 in RVDAC3 sequence. This study constitutes a first step in order to further characterize striated muscle porin isoforms.
Amino Acid Sequence↗
Determinants of Clara cell protein (CC16) concentration in serum: a reassessment with two different immunoassays.
Clara cell protein (CC16) is a 16 kiloDalton protein secreted by Clara cells in the lining fluid of bronchiolar and bronchial epithelium. Recently, Nomori et al., using a nephelometric latex immunoassay, reported a strong correlation between serum CC16 (sCC16) and serum lipids as well as the body mass index (BMI) [Nomori H, Horio H, Takagi M Kobayashi Y, Hirabayashi Y. Clara cell protein correlation with hyperlipidemia. Chest 1996;110:680-4]. The same authors found higher values of sCC16 in males compared to females and did not detect any significant influence of tobacco smoking. Since these results are in disagreement with previous observations showing consistently a decrease of sCC16 in smokers and no influence of sex, we have reassessed in healthy subjects the determinants of sCC16 using two different assays: a particle counting-based latex immunoassay (LIA) using polyclonal antibodies and a fluorescence enzyme immunoassay (FEIA) using monoclonal antibodies. sCC16 was determined in a group of 52 female and 44 male healthy subjects (age 18 to 66 years), including 35 smokers and 61 nonsmokers. sCC16 measured by LIA and FEIA were well correlated (r = 0.92, n = 96, P < 0.0001) with values (geometric mean and range) of 13.3 (5.2-34.5) and 14.7 (4.1-53.1) microg/l, respectively. The determinants of sCC16 measured by both techniques were traced by stepwise regression analysis using as independent variables age, sex, smoking status, BMI or serum lipids (total cholesterol and triglycerides) and the glomerular filtration rate (GFR) estimated on the basis of serum creatinine or beta2-microglobulin. Only two significant determinants emerged: tobacco smoking which correlated negatively and the GFR which correlated positively with sCC16. No influence of serum lipids, BMI, age and sex on sCC16 was detected. We think that an analytical interference with serum lipids explains the results by Nomori et al. which are not confirmed here by two independent techniques and are inconsistent with the current understanding of the physiopathology of the Clara cell and its main secretory product, CC16.
Adolescent↗
Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells.
Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab')2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the beginning of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2- NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.
Animals↗
Effect of calmodulin-inhibitors and verapamil on the nephrotoxicity of cadmium in rat.
Recent reports indicate that calmodulin inhibitors (CIs) can modify cadmium (Cd) toxicity in rodents. Pretreatment with CIs prevents Cd-induced testicular damage in mice and reduces the severity of such damage in rats. On the other hand it has been suggested that the cellular transport of Cd can be partly inhibited by the calcium-channel inhibitor, verapamil. The aim of this study was to determine whether these inhibitors can prevent the toxic effects of Cd on the kidney which is the critical organ. For that purpose, we have examined the effects of two CIs (trifluoperazine and chlorpromazine) and of verapamil on the development of tubular damage in female Sprague-Dawley rats. The animals were injected subcutaneously 5 days a week for 8 weeks with cadmium chloride (1 mg Cd/kg), alone or in association with trifluoperazine (20 mg/kg), chlorpromazine (15 mg/kg) or verapamil (2 x 5 mg/kg). The development of renal dysfunction was followed by measuring the urinary excretion of the low molecular weight protein Clara cell protein (CC16). In Cd-treated rats, the urinary excretion of CC16 started to increase from week 6 to reach at the end of experiment values more than 100-times above normal. CIs or verapamil did not influence the rise of urinary CC16 induced by Cd. The three inhibitors, by contrast, enhanced the accumulation of Cd in the liver and, at the exception of chlorpromazine, in the kidneys of Cd-treated rats. Although interfering with the metabolism of Cd, CIs and verapamil do not prevent renal damage in rats chronically exposed to this heavy metal.
Animals↗
The B1Pi --> X1Sigma+ System of Scandium Monoiodide.
Rotational analyses have been carried out on eight thermically excited emission bands of the infrared B1Pi --> X1Sigma+ system of scandium monoiodide between 4000 to 5000 cm-1, recorded by Fourier transform spectrometry. Rotational constants and energies are obtained for X1Sigma+ (v = 0, 1, 2) and B1Pi (v = 0-4) levels from which equilibrium constants of the states are derived. Perturbational effects are observed in the bands with v" = 1 that are interpreted as consequences of the avoided crossing of X1Sigma+ (v = 1) and a3Delta1 (v = 0) at J = 70. A treatment of the perturbation is made using an effective 2 x 2 matrix representation of the rotational energies of the two levels. Copyright 1998 Academic Press.
Journal Article↗
Electronic States of Lanthanum Monoiodide: Preliminary Data from High-Resolution LIF Spectroscopy.
Fluorescence spectra of lanthanum monoiodide excited by the Ar+ 501.7-nm laser line have been observed and analyzed. Seven (sub)states are characterized. Preliminary rovibrational data are obtained for the four low-lying states (I-IV). The first two can be ascribed as X1Sigma and a3Delta: III does have Omega = 1, and IV is possibly 1Delta. The 11 laser-excited levels are tentatively grouped into three entities. Copyright 1998 Academic Press.
Journal Article↗
Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans.
OBJECTIVES: a) To investigate the functional consequences of sepsis on the beta-adrenergic signal transduction in human circulating lymphocytes; b) to appreciate sepsis-associated catecholamine and cytokine release. DESIGN: Experimental, comparative study. SETTING: Research laboratory in a university hospital. SUBJECTS: Healthy controls (n = 10); critically ill patients who were not septic (n = 7); septic patients with severe sepsis or septic shock (n = 11). MEASUREMENTS AND MAIN RESULTS: Experiments were carried out using freshly isolated peripheral blood mononuclear cells (PBMC). We measured beta-adrenergic receptor (betaAR) number and affinity, and intracellular cAMP content at baseline and after the pharmacological stimulation of each component of the beta-adrenergic complex: betaAR with isoproterenol, Gs-protein with sodium fluoride (NaF), adenylate cyclase with forskolin. Catecholamine (adrenaline, noradrenaline) and cytokine (TNFalpha, IL-1alpha, IL-1beta, IL-6) serum levels were measured. In both septic and non-septic patients we observed a similar 40 % down-regulation of betaARs compared to controls, and a reduced basal and isoproterenol-stimulated cAMP accumulation (p < 0.05). The cAMP production elicited by NaF or forskolin was lower in septic patients than in the controls (p < 0.01). Forskolin-stimulated cAMP accumulation was significantly lower in septic patients than it was in non-septic ones (p < 0.001). Catecholamine serum concentrations were increased in the two patient groups without any significant difference. Elevated cytokine serum levels were detected in 45% of the septic patients (versus 14% of non-septic patients p < 0.05). CONCLUSIONS: Patients presenting with severe sepsis or septic shock have extended postreceptor defects of the beta-adrenergic signal transduction. This finding suggests a heterologous desensitization of adenylate cyclase stimulation.
Adenylyl Cyclases↗
GABA modulates cytotoxicity of immunocompetent cells expressing GABAA receptor subunits.
C57 black mouse splenic T lymphocytes effector cells were co-cultivated with Balb/c mouse splenic cells for sensitization; P815 DBA mouse mastocytoma target cells were then added and specific T cell-dependent cytotoxicity determined. This cytotoxicity increased after gamma-aminobutyric acid (GABA) treatment of the sensitized effectors, but decreased after GABA treatment of the targets. These GABA effects seemed to be specific since they were partially mimicked by linear but not ramified GABA analogues. Furthermore, they were likely mediated by GABAA receptor since GABAA receptor subunit mRNAs and protein could be demonstrated in effector or target immune specific cells, suggesting that under yet to be defined circumstances, GABA may affect T cell functions.
Animals↗