Long-term memory deficits in temporal lobe epilepsy.

Memory complaints and deficits are common in patients with epilepsy, especially temporal lobe epilepsy (TLE), where memory-related brain structures are directly involved in the epileptic process. In recent years, substantial progress has been made in delineating memory impairment in TLE, challenging the traditional neuropsychological approach of the disorder. In particular, several lines of evidence have suggested that, beyond the apparent deficit demonstrable by standardized neuropsychological evaluations, TLE may also negatively interact with long-term memory, producing considerable loss of information of the patient's autobiographical history and an inability to maintain newly acquired information over a period of time. These observations have led to the development of innovative assessment techniques, and prompted a new domain of investigation focused on the relationships between interictal epileptiform activities and the integrity of anatomo-functional systems. The present paper reviews the available evidence for long-term memory deficits in TLE with respect to remote and very long-term memory, and discusses their putative pathophysiological mechanisms and the developing potential strategies to improve memory functioning.

Evaluating physical activity: the AQAP questionnaire and its interpretation software.

OBJECTIVES: Updating Baecke physical activity questionnaire in French, validating this version named AQAP and developing software for a personalized interpretation of the results. METHOD: Validation conducted on 702 consultants in health prevention centers aged 18-79 years: reliability of the questionnaire when self-administered, validity according to the energy expenditure per interview and reproducibility after two weeks (n=31). After two months, assessment of the questionnaire's impact on knowledge and behaviors in 320 young adults aged 18-29 years. RESULTS: The results from self- and interviewer-administered questionnaire were correlated (Kappa>0.60). Furthermore, the total physical activity index was correlated to the energy expenditure (rho=0.39, P<0.0001). The four physical activity indexes calculated from self-administrated questionnaires barely varied at the two-week interval (P ≥ 0.23, power ≥ 77%, accepted difference ± 10%). Two months later, 80% of the participants had read the interpretation software report, 55% became conscious of their physical activity level, 43% increased their physical activity level and 42% reported being aware of the relationship between physical activity and health. CONCLUSION: AQAP characteristics are satisfactory and thus this questionnaire can be used on the general population in complement of an individual or collective action to promote physical activity and in epidemiological studies for analyzing the links between individual behaviors and health.

Specific induction of fibronectin binding activity by hemoglobin in Candida albicans grown in defined media.

Fibronectin (FN) is a major component of host extracellular matrix that may play an important role in the initiation and dissemination of Candida albicans infections. Expression of FN binding requires growth of C albicans blastoconidia in complex medium, and the regulation of FN receptor expression is poorly understood. We now demonstrate that hemoglobin is a potent and specific inducer of FN receptor expression and describe a defined medium supplemented with hemoglobin that greatly and stably enhances the binding activity of C. albicans for soluble FN. Enhancement of FN binding by hemoglobin in strain 44807 was concentration dependent and was maximal at 0.1% hemoglobin with 20- to 80-fold enhancement. The hemoglobin-induced FN binding to C. albicans was saturable, with a Kd of 2.7 X 10(-8) M. Enhancement required growth of C. albicans in hemoglobin-containing medium, since simply exposing blastoconidia to hemoglobin in a nongrowing status did not enhance binding. Induction was reversible following removal of hemoglobin from the growth medium and not associated with germination. Inorganic or protein-bound iron was not sufficient for the induction, since other iron-containing proteins or inorganic iron salts were inactive. Growth in the simple medium yeast nitrogen base supplemented with hemoglobin increased cell adhesion to immobilized FN and to cultured monolayers of bovine corneal endothelial cells. These data suggest that hemoglobin may be an important regulator of FN binding activity in C. albicans and thus may play a role in its pathogenesis.

The collagen binding domain of fibronectin contains a high affinity binding site for Candida albicans.

A 30-kDa proteolytic fragment from the gelatin/collagen-binding domain of fibronectin is a potent inhibitor of fibronectin binding to Candida albicans, with a molar inhibition constant equal to that of intact fibronectin. Recombinant and proteolytic fragments from the cell-, the fibrin I-, and the heparin II-binding domains also inhibit fibronectin binding, but are 13-1000-fold less active. In suspension, binding of fibronectin to C. albicans is regulated by growth conditions and is specific, saturable, time-dependent, reversible, and divalent cation-independent. Scatchard plot analyses indicate the presence of high affinity (Kd = 1.3 x 10(-9) M) and low affinity (Kd = 1.2 x 10(-7) M) receptors. Recombinant or proteolytic fragments from four binding domains of fibronectin promote adhesion of C. albicans. A recombinant fragment corresponding to the cell-binding domain but with the sequence Arg-Gly-Asp-Ser deleted promotes C. albicans adhesion and inhibits fibronectin binding to C. albicans with the same activity as the natural sequence. Furthermore, four peptides containing the Arg-Gly-Asp-Val sequence and the peptides CS-1 and Arg-Glu-Asp-Val did not block the binding of fibronectin to C. albicans. Thus, in contrast to the specific binding of soluble fibronectin, recognition of immobilized fibronectin by C. albicans is mediated by several domains of the protein. Interactions with the cell-binding domain are not mediated by the Arg-Gly-Asp or other known recognition sequences as it has been suggested. Binding of fibronectin also did not correlate with C3d binding to the avirulent clones of C. albicans strain H12 or with iC3b binding to variants of the strain 4918.

Inhibition of fibronectin binding and fibronectin-mediated cell adhesion to collagen by a peptide from the second type I repeat of thrombospondin.

The platelet and extracellular matrix glycoprotein thrombospondin interacts with various types of cells as both a positive and negative modulator of cell adhesion, motility, and proliferation. These effects may be mediated by binding of thrombospondin to cell surface receptors or indirectly by binding to other extracellular matrix components. The role of peptide sequences from the type I repeats of thrombospondin in its interaction with fibronectin were investigated. Fibronectin bound specifically to the peptide Gly-Gly-Trp-Ser-His-Trp from the second type I repeat of thrombospondin but not to the corresponding peptides from the first or third repeats or flanking sequences from the second repeat. The two Trp residues and the His residue were essential for binding, and the two Gly residues enhanced the affinity of binding. Binding of the peptide and intact thrombospondin to fibronectin were inhibited by the gelatin-binding domain of fibronectin. The peptide specifically inhibited binding of fibronectin to gelatin or type I collagen and inhibited fibronectin-mediated adhesion of breast carcinoma and melanoma cells to gelatin or type I collagen substrates but not direct adhesion of the cells to fibronectin, which was inhibited by the peptide Gly-Arg-Gly-Asp-Ser. Thus, the fibronectin-binding thrombospondin peptide Gly-Gly-Trp-Ser-His-Trp is a selective inhibitor of fibronectin-mediated interactions of cells with collagen in the extracellular matrix.

Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lectins.

Antileishmanial chemotherapy is hampered by the location of the parasite within the phagolysosome of the macrophage, which restricts the bioavailability of many potentially useful antileishmanial drugs. In this study, the possibility of using antileishmanial drugs targeted to the infected macrophages by means of a chemical linkage to a neutral mannose-substituted poly-L-lysine carrier molecule was explored. The study was performed in an in vitro model with Leishmania donovani-infected murine macrophages. The antileishmanial activities of various synthetic constructs were compared with those of the free drugs and the pentavalent antimonial Pentostam, which was used as the positive control. The 50% effective dose of allopurinol riboside linked to the mannosylated poly-L-lysine was below 7.5 x 10(-6) M, while it was up to 3 x 10(-4) M for the free drug, indicating that the drug bound to the polymer was 50 times more active than the free drug. Control experiments with other constructs (e.g., allopurinol riboside linked to the mannose-free polymer) confirmed that the enhancement of activity was indeed achieved by means of the mannose homing device.

Heparin-binding peptides from the type I repeats of thrombospondin. Structural requirements for heparin binding and promotion of melanoma cell adhesion and chemotaxis.

Synthetic peptides derived from the type I repeats of human platelet thrombospondin containing a consensus sequence Trp-Ser-Xaa-Trp bind to heparin, promote cell adhesion, and inhibit heparin-dependent interactions of melanoma cells with extracellular matrix components (Guo, N. H., Krutzsch, H. C., Nègre, E., Vogel, T., Blake, D. A., and Roberts, D. D. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 3040-3044). In the present study, we further examined the structural requirements for activity of these peptides. The minimal active sequence for heparin or sulfatide binding based on inhibition studies is Trp-Ser-Pro-Trp, although an octapeptide is required for optimal activity. The 2 Trp residues and the Ser residue are essential. Peptides with more than 2 residues between the Trp residues are inactive. The Pro residue is essential for activity of the pentapeptide Trp-Ser-Pro-Trp-Ser, but some larger peptides with substitutions for the Pro residue are active. For direct high affinity binding to heparin, both the consensus sequence and a flanking sequence of basic amino acids are essential. Peptides containing the consensus sequence promote cell adhesion and act cooperatively with the adjacent basic amino acid sequence to promote cell spreading. Chemical modification of the Trp residues in the peptides with amino-terminal basic amino acids abolished both cell adhesion and heparin-binding. Peptides containing the consensus sequence and basic amino acids are chemotactic for A2058 human melanoma cells. The functional importance of this novel heparin and sulfatide-binding motif is suggested by its conservation in other members of the thrombospondin gene family, complement components, and in many members of the cytokine receptor and transforming growth factor beta superfamilies.

Heparin- and sulfatide-binding peptides from the type I repeats of human thrombospondin promote melanoma cell adhesion.

Peptides from the three type I repeats of human endothelial cell thrombospondin, containing the consensus sequence-Trp-Ser-Xaa-Trp-, bind to sulfated glycoconjugates including heparin and sulfatide. The peptides are potent inhibitors for the binding of thrombospondin, laminin, or apolipoprotein E to these ligands. The thrombospondin peptides that inhibit heparin binding, but not adjacent peptides from the thrombospondin sequence containing the previously identified adhesive motif Val-Thr-Cys-Gly, promote melanoma cell adhesion when immobilized on plastic. Melanoma cell adhesion to the immobilized peptides is inhibited by soluble recombinant heparin-binding fragment of thrombospondin. The peptides also inhibit heparin-dependent binding of thrombospondin or laminin to human melanoma cells. The active peptides lack any previously identified heparin-binding consensus sequences and most do not contain any basic amino acids. Studies with homologous peptides showed that the tryptophan residues are required for binding. Adjacent basic residues in the second type I repeat enhance binding to heparin but not to sulfatide. Thus the type I peptides of thrombospondin define a distinct class of heparin-binding peptides.

Endocytosis mediated by monocyte and macrophage membrane lectins--application to antiviral drug targeting.

Sugar receptors, or membrane lectins, have been evidenced at the surface of various normal and tumour cells using fluoresceinylated neoglycoproteins (glycosylated bovine serum albumin (BSA]. By flow cytometry we have shown that macrophages bind and internalize mannosylated and 6-phosphomannosylated ligands in acidic compartments. Freshly isolated monocytes and U937, a promonocytic cell line, lack a mannose-specific receptor, but express mannose-6-phosphate (Man-6P) membrane lectin. Neoglycoproteins are potent drug carriers: muramyl dipeptide (MDP), an immunoactivator, when bound to Man-BSA or Man-6P-BSA, is 100 times more efficient than free MDP in activating macrophages; in vivo, it enables eradication of lung metastases in mice. Recently, neutral glycosylated biodegradable and nonimmunogenic polymers, were synthesized and found to be as efficient as neoglycoproteins. Antiviral drug conjugates were more active than the free drug, inhibiting the multiplication of virus (herpes) in human macrophages in vitro.

Drug targeting: anti-HSV-1 activity of mannosylated polymer-bound 9-(2-phosphonylmethoxyethyl)adenine.

The antiviral drug, 9-(2-phosphonylmethoxyethyl) adenine (PMEA) was linked to a synthetic and neutral polymer bearing mannosyl residues to allow its internalization by macrophages via membrane lectins. PMEA bound to the mannosylated polymer was more efficient in vitro than free PMEA in preventing lysis of human macrophages by herpes virus.

Muramyl dipeptide bound to poly-L-lysine substituted with mannose and gluconoyl residues as macrophage activators.

Poly-L-lysine modified with mannose derivatives, the residual cationic charges of which being neutralized by N-acylation, were synthesized and used as carriers of a macrophage activator (N-acetylmuramyl dipeptide, MDP). The influence of the acylating agent on the targeting efficiency was investigated: a hydrosolubilizing group such as a gluconoyl moiety led to very efficient carrier conjugates, while an acetyl group did not. The effect of sugar and acyl content of the polymers was assessed using these compounds as inhibitors of red blood cell agglutination by Concanavalin A. The binding and specific endocytosis of poly-L-lysine substituted with several mannose derivatives and gluconoyl residues (GlcAx-, Man(y)-PLK) have been determined by a quantitative flow cytometry analysis. MDP bound to these conjugates was much more efficient in vitro than free MDP in macrophage cytostasis assays.

[Presternal ileum and right colon for benign esophageal stenosis. Very long-term checking]. / Iléo-côlon droit présternal pour sténoses oesophagiennes bénignes. Contrôles à très longue échéance.

Long-term follow up results are analyzed of 10 patients treated by pre-sternal right ileocolic grafts for an esophageal stenosis of a benign nature. Operation in 7 cases had been performed 28 (1 case), 26 (2 cases), 19 (1 case), 16 (1 case), 11 (1 case) and 6 (1 case) years previously. Functional results were generally very satisfactory. Two cologastric anastomotic ulcers were heated by coloduodenal and colojejunal reimplantation respectively. One patient operated upon for stenosis due to chemicals developed malpighian cancer of the cervical esophago-ileal anastomosis 12 years later, but secondary malnutrition did not occur following a gastric bypass operation. Although overall functional results could be considered as very satisfactory, there is a risk of anastomotic cologastric ulcers developing (2 cases), but the risk can be eliminated by routine implantation of colon into duodenum or jejunum. The gastric bypass achieved failed to produce any clinical manifestations in patients operated upon, some of whom have been followed up for nearly 30 years.

[Reinforcement cerclage of dystrophic aortic rings]. / Cerclage de renforcement dans les dystrophies de l'anneau aortique.

Reinforcement of a dystrophic aortic ring with a purse string suture makes it possible to obtain perfect coaptation between prosthesis and ring whilst inducing sclerosis. The technique described here was used by the authors in 30 patients operated upon since June, 1980, and none of these needed reoperation for leakage. These results contrast most favourably with those previously obtained in similar anatomical conditions with conventional prosthesis insertion.

[Long-term course of patients with Smeloff-Cutter aortic valve prosthesis]. / Evolution à long terme des malades porteurs de prothèse de Smeloff-Cutter en position aortique.

The long-term results (5 to 12 years) of 77 patients with Smeloff-Cutter aortic valve prostheses are reported. These patients were comparable in age, preoperative clinical condition and type of aortic valve replacement. The postoperative follow-up period of this series was however significantly longer. The 5 year survival rate was of 87%. The causes of death included thromboembolism, infectious endocarditis and cardiac failure. Mortality was higher in the first 5 postoperative years : 2,4% patient-years compared to 1,5% patient-years in the following years. Thromboembolism and neurological complications were particularly rare, representing a risk of 1,04% patient-years but these complications were lethal in half the cases in which they occurred. No haemolytic complications were observed. Infective endocarditis always occurred in patients with a history of infection, the complication usually being late (after 3 years). The life expectancy of patients seen after 5 years is at least 5 additional years in 80% of cases. The haemodynamic profile of the prosthesis did not degrade with time. After 5 years, 58,6% of patients in functional Class IV at operation were in Class I or II afterwards. 84,4% of patients operated in functional Class III were in Class I or II, and 93% operated in functional Class II were in Class I or III. A control of 3 prostheses carried out by the Cutter laboratory after 10 and 11 years' function shows practically no deterioration of the prosthesis. The low incidence of thromboembolism, the absence of haemolysis and long-term deterioration of the prosthesis are particularly valuable characteristics of this prosthesis in the aortic position.