[The concept of narrative insight in schizophrenia: A systematic review]. / Le concept d'insight narratif chez les personnes souffrant de schizophrénie : une revue systématique de la littérature.

AIM: The aim of this systematic revue of literature is to examine articles dealing with the narrative insight (patient's explanatory models of his difficulties) in patients suffering from schizophrenia. In addition to the theoretical interest of this work, it would make it possible to better adjust the clinical practices concerning the stories of patients about their disorders. METHOD: A study was conducted using the databases ScienceDirect, Medline, PsychInfo and PubPsych using the key words "narrative insight", "cultural insight", "subjective insight", "narrative awareness", "mental illness", and "psychiatric disorder". This search by keywords led to eighty-six results; abstracts of all the articles were consulted. Then the authors selected and studied all articles corresponding to inclusion criteria and compared their results and reached agreement by consensus in case of difference. The theme of the study was to focus on the concept of narrative insight or any other close concept mentioning an explanatory model of mental and/or psychiatric disorders, moving away from the biomedical model. Nine articles were selected based on the inclusion criteria (articles published in peer reviewed journals, where the both the resume and article are accessible; articles dealing with narrative insight of people suffering from schizophrenia). RESULTS: The authors of these articles agree that awareness of mental illness, insight, is a narrative act in which people give a personal meaning to their disorder. The most popular biomedical model used has many limitations and is the subject of many controversies. Results of the conducted study suggest considering narrative insight as adaptive strategies to mental illnesses. Indeed the process of narrative insight essentially consists in the patient adapting his life story to his conceptions and his values. To tell the story of one's own troubles with one's own values and beliefs gives meaning that helps protect identity and give back hope. This concept is considered to be dynamic and multidimensional. In addition, studies highlight its positive effects including the simultaneous presence of several models, which would have a greater favorable impact on the prognosis than the medical explanation alone. CONCLUSION: It seems necessary to take into account the concept of narrative insight in order to evaluate insight of patients suffering from mental illness. This implies that the evaluation methods of insight as well as the clinical practice must evolve to adapt to the culture and subculture of the patient. This could have beneficial effects on the well-being of patients, therapeutic relations, access to treatment as well as psychiatric research, as well as limit controversies around this topic. It would be interesting to confirm this new conception of insight and the therapeutic relations by carrying out new studies as well as by starting to take it into account in patient care.

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp

Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that procoagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease

MiniSOX9, a dominant-negative variant in colon cancer cells.

Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.

The occluding loop of cathepsin B prevents its effective inhibition by human kininogens.

Kininogens, the major plasma cystatin-like inhibitors of cysteine cathepsins, are degraded at sites of inflammation, and cathepsin B has been identified as a prominent mediator of this process. Cathepsin B, in contrast to cathepsins L and S, is poorly inhibited by kininogens. This led us to delineate the molecular interactions between this protease and kininogens (high molecular weight kininogen and low molecular weight kininogen) and to elucidate the dual role of the occluding loop in this weak inhibition. Cathepsin B cleaves high molecular weight kininogen within the N-terminal region of the D2 and D3 cystatin-like domains and close to the consensus QVVAG inhibitory pentapeptide of the D3 domain. The His110Ala mutant, unlike His111Ala cathepsin B, fails to hydrolyze kininogens, but rather forms a tight-binding complex as observed by gel-filtration analysis. K(i) values (picomolar range) as well as association rate constants for the His110Ala cathepsin B variant compare to those reported for cathepsin L for both kininogens. Homology modeling of isolated inhibitory (D2 and D3) domains and molecular dynamics simulations of the D2 domain complexed with wild-type cathepsin B and its mutants indicate that additional weak interactions, due to the lack of the salt bridge (Asp22-His110) and the subsequent open position of the occluding loop, increase the inhibitory potential of kininogens on His110Ala cathepsin B.

CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium.

A deletion of the transcription factor SOX9 gene in the mice intestine affects the morphology of the colon epithelium and leads to hyperplasia. Nevertheless, direct transcriptional targets of SOX9 in this tissue are still unknown. A microarray analysis identified the tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as a possible SOX9 target gene and we demonstrate here that SOX9 upregulates CEACAM1 in human colonic cells. Moreover, CEACAM1 expression is reduced in colon of SOX9-deficient mouse, suggesting an important function for SOX9 in the transcriptional activation of the CEACAM1 gene. We further identified SOX9-binding sequences in the human and rat CEACAM1 promoters, and an electrophoretic mobility shift together with a chromatin immunoprecipitation provided an additional evidence of the SOX9 binding to the human promoter. In addition, we established that histone acyl-transferase p300 behaves as an SOX9 co-activator of the rat and human CEACAM1promoters. These results highlight CEACAM1 as the first direct target of SOX9 identified in the colon epithelium.

[Rectal self-mutilation, rectal bleeding and Prader-Willi syndrome]. / Automutilation rectale, rectorragies et syndrome de Prader-Willi.

UNLABELLED: Prader-Willi syndrome is a genetic disorder characterized by infantile hypotonia, obesity, hypogonadism and mental retardation. Individuals with Prader-Willi syndrome manifest a severe skin picking behavior, including rectal picking. CASE REPORT: We report the case of a girl (12 years old) with this syndrome in whom rectal picking resulted in rectal bleeding and solitary rectal ulcer. CONCLUSION: Caregivers of children with Prader-Willi syndrome should be aware of a potential rectal picking behavior, which results in significant bleeding. Early recognition of such a behavior helps to avoid misdiagnosis.

Valyl-tRNA synthetase from Escherichia coli MALDI-MS identification of the binding sites for L-valine or for noncognate amino acids upon qualitative comparative labeling with reactive amino-acid analogs.

Bromomethyl ketone derivatives of L-valine (VBMK), L-isoleucine (IBMK), L-norleucine (NleBMK) and L-phenylalanine (FBMK) were synthesized. These reagents were used for qualitative comparative labeling of Escherichia coli valyl-tRNA synthetase (ValRS), an enzyme with Val/Ile editing activity, in order to identify the binding sites for L-valine or noncognate amino acids. Labeling of E. coli ValRS with the substrate analog valyl-bromomethyl ketone (VBMK) resulted in a complete loss of valine-dependent isotopic [32P]PPi-ATP exchange activity. L-Valine protected the enzyme against inactivation. Noncognate amino acids analogs isoleucyl-, norleucyl- and phenylalanyl-bromomethyl ketones (IBMK, NleBMK and FBMK) were also capable of abolishing the activity of ValRS, FBMK being less efficient in inactivating the synthetase. Matrix-assisted laser desorption-ionization mass spectrometry designated cysteines 424 and 829 as the target residues of the substrate analog VBMK on E. coli ValRS, whereas, altogether, IBMK, NleBMK and FBMK labeled His266, Cys275, His282, His433 and Cys829, of which Cys275, His282 and His433 were labeled in common by all three noncognate amino-acid-derived bromomethyl ketones. With the exception of Cys829, which was most likely unspecifically labeled, the amino-acid residues labeled by the reagents derived from noncognate amino acids were distributed between two fragments 259-291 and 419-434 in the primary structure of E. coli ValRS. In fragment 419-434, Cys424 was specifically labeled by the substrate analog VBMK, while His433 was labeled in common by all the used bromomethyl ketone derivatives of noncognate amino acids, suggesting that the synthetic site where aminoacyl adenylate formation takes place on E. coli ValRS is built up of two subsites. One subsite containing Cys424 might represent the catalytic locus of the active center where specific L-valine activation takes place. The second subsite containing His433 might represent the binding site for noncognate amino acids. The fact that Cys275 and His282, fragment 259-291, were labeled by IBMK, NleBMK and FBMK, but not by the substrate analog VBMK, suggests that these residues might be located at or near the editing site of E. coli ValRS. Comparison of fragment 259-291 with all the available ValRS amino-acid sequences revealed that His282 is strictly conserved, with the exception of its replacement by a glycine in a subgroup corresponding to the archaebacteria. Because a nucleophile is needed in the editing site to achieve hydrolysis of an undesired product at the level of the carbonyl group thereof, it is proposed that the conserved His282 of E. coli ValRS is involved in editing.

[Advantages and constraints of recent multichannel selective analyzers]. / Avantages et contraintes des analyseurs sélectifs multiparamétriques récents.

The analyzers have been defined as follows: the analyzers are multiparametric (at least 5 parameters available simultaneously), selective, operating patient by patient, list price on May 1, 1984 below 1,000,000 francs, and distributed in France after January 1, 1981. This definition applies in particular to systems already widely used in French Laboratories, such as the Technicon RA 1000, and the Hitachi Boehringer 705. It also applies to systems distributed more recently, such as the Kone "Progress" and the Coultronics "Dacos". Based on data provided by the manufacturers (technical instructions, operating instructions, evaluation reports, etc) and data provided by a certain number of users, we have tried to appraise the advantages and constraints of these analyzers with respect to the following points: required environment (installation, electrical current, temperature), training of personnel, ease of adaptation, work organization, rhythms, operating cost, ease of use, verification of correct function, format of results, maintenance, etc. Lastly, we discuss the problem of the reliability of the results (precision, accuracy), in particular the problems of referencing in substrate assays, and the problems of accuracy in the measurement of enzymatic activities, considering the current norms of standardization.