Dramatic improvement in survival after lung transplantation over time: a single center experience.

Lung transplantation (LT) is a recognized procedure for selected patients with end-stage respiratory failure. We performed 123 LT, including 32 single lung, 84 double lung, and 7 heart-lung transplantations in 48 patients with chronic obstructive pulmonary disease (COPD), 13 patients with pulmonary hypertension (PH), 33 with cystic fibrosis (CF), and 29 with interstitial lung disease (ILD) between July 1990 and January 2008. Survival was compared for periods before and after December 2001. The mean age of patients was 44.4 years (range 16-66.5 years); 84 (69%) were men. Before LT, 1 second forced expiratory volume was 28.7% +/- 18.1% and PaCO(2) = 6.3 kPa. Fifty-five patients were on noninvasive ventilation. Cold ischemia time was 320 +/- 91 minutes. Cardiopulmonary bypass (CPB) was used in 77 patients (64%). There were 18 early surgical reinterventions, 8 extracorporeal membrane oxygenations, and 38 bronchial stent insertions among 206 at-risk bronchial sutures. Crude survivals were 69%, 58%, 41%, and 18% at 1, 2, 5, and 10 years, respectively. Comparing before (n = 70 with 15 CF) vs after December 2001 (n = 53 with 17 CF), survivals were 63% vs 78%, 51% vs 71%, and 33% vs 60% at 1, 2, and 5 years, respectively (P = .01) and for CF patients, 52% vs 100%, 52% vs 94%, and 25% vs 94% at 1, 2, and 5 years, respectively (P = .005). There was significant improvement in survival before and after 2001 in 123 LT and particularly among CF patients. Improvement in survival after LT may be related to the sum of numerous changes in our practice since December 2001, including the use of pulmonary rehabilitation pre-LT, extracellular pneumoplegia, statins, macrolides for chronic rejection, monitoring of Epstein-Barr blood load, changes in maintenance immunosuppressants, as well as position movement up the coordinator nurse and learning curve.

BK2 but not BK1 receptors mediating contractile response in human umbilical arteries: role of thromboxane A2.

Bradykinin receptors have been divided into B1 and B2 subtypes. The aim of this study on human umbilical arteries was: i) to compare the recognition properties of the mediating contractions of bradykinin receptors; and ii) to assess the possible role of thromboxane A2 in a bradykinin-induced contraction of smooth muscle. Umbilical arteries were dissected and mounted in organ baths for isometric measurement of force. Our results showed that the B1 agonist [Sar1dPhe8desArg9]-bradykinin had no effect on the concentration-response 10(-9)-3 x 10(-5) mM. Cumulative additions of bradykinin (10(-9)-3 x 10(-5) mM) and of the B2 agonist [Hyp3TyrMe8]-bradykinin (10(-9)-3 x 10(-5) mM) produced dose-dependent contractions. Dose response curves to bradykinin (10(-9)-3 x 10(-5) mM) were not significantly altered by the presence of B1 selective antagonist [des-Arg9, Leu8]-bradykinin (10(-5) mM), or by the selective B2 antagonist [Thi(5,8), D-Phe7]-bradykinin (10(-5) mM). However, Hoe 140 D-Arg-[Hyp3, Thi5,D-Tic7, Oic8]-bradykinin, an antagonist of B2 responses, significantly inhibited bradykinin-induced contraction. The responses to bradykinin were unaffected by indomethacin (10(-4) mM), dazoxiben (10(-5) mM) or even by nordihydroguaiaretic acid (10(-5) mM). However, bradykinin contractions were antagonized in a noncompetitive manner by quinacrine (10(-5) mM). These results showed that bradykinin contracts human umbilical arteries essentially through B2 receptors. Moreover, the responses to bradykinin are unlikely to be mediated by the cyclooxygenase/lipooxygenase pathway. The inhibitory effects of quinacrine may be due to a specific or nonspecific effect at a cellular level on smooth muscle contractility, or due to a direct action to block Ca2+ influx at membrane level.

Role of glutathione in the detoxification of ferriprotoporphyrin IX in chloroquine resistant Plasmodium berghei.

The reduction in hemozoin content is a well known feature of chloroquine-resistant Plasmodium berghei. Using NK65-derived lines displaying increasing resistance levels, we observed an inverse relationship between the hemozoin content, and the glutathione (GSH) and glutathione S-transferase (GST) levels. Treatment of highly chloroquine-resistant-infected mice with buthionine sulfoximine (BSO), which has previously been shown to partially reverse this chloroquine resistance, led to a significant increase in hemozoin production. In vitro studies on the polymerization of ferriprotoporphirin IX (FPIX) at pH 5.0 showed that GSH partially inhibited beta-hematin synthesis, while GST had a trivial and non specific effect. Furthermore, chloroquine-sensitive parasites invading reticulocytes displayed higher GSH level and GST activity, and reduced hemozoin synthesis and susceptibility to chloroquine. We conclude that, in chloroquine resistant P.berghei, GSH can detoxify hemin within the food vacuole, thus precluding its polymerization and preventing the activity of chloroquine and other quinoline-containing drugs. It is proposed that vacuolar GSH could be ascribed to an erythrocytic origin, since the resistant lines invade reticulocytes, which contain higher levels of GSH and GST than normocytes.

Schistosoma mansoni: in vitro adhesion of parasite eggs to the vascular endothelium. Subsequent inhibition by a monoclonal antibody directed to a carbohydrate epitope.

Schistosoma mansoni eggs come into direct contact with the vascular endothelium, particularly in the postcapillary venules of the mesenteric tract (oviposition site). We investigated the adhesion of eggs to endothelial cells in a static in vitro assay and in a flow-based in vitro assay. Live S. mansoni eggs rapidly attached, in a time-dependent manner, to the human endothelial cell line ECV 304, but not KOH-treated eggs. Activation of ECV monolayers with interleukin-1 promoted live S. mansoni eggs adhesion. An in vitro flow-based assay of human umbilical vein endothelial cells (HUVEC) showed the influence of wall shear stresses on the attachment of eggs to endothelial cells, particularly under postcapillary venule shear stress conditions. Interleukin-1 activation of HUVEC promoted adhesion between live eggs and endothelial cells. Higher wall shear stresses were needed to obtain the detachment of eggs from activated endothelial cells than control cells. Preincubation of interleukin-1-activated HUVEC, in a static in vitro assay, with monoclonal antibodies specific for intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 significantly decreased adhesion of live eggs. Previous studies have shown that a monoclonal antibody specific for a schistosome carbohydrate epitope abundant in eggs is related to the Lewis X antigen. In this study, the anti-Lewis X-specific monoclonal antibody was used for adhesion-inhibition assays. Preincubation of eggs with this monoclonal antibody significantly decreased adhesion of live eggs to interleukin-1-activated HUVEC cultured in vitro. These results suggest that surface adhesion molecules, expressed by endothelial cells under conditions of interleukin-1 activation, directly participate in egg adhesion and that egg carbohydrate antigens play an important role in live S. mansoni egg adhesion to the vascular endothelium.

Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin).

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

High-level chloroquine resistance of Plasmodium berghei is associated with multiple drug resistance and loss of reversal by calcium antagonists.

The chloroquine resistance of Plasmodium falciparum is reversed in vitro by numerous compounds, including calcium antagonists, which could enhance the accumulation of the drug in the parasite food vacuole. However, this mechanism of resistance could be insufficient when the resistance level increases. Using in vitro drug trials on strains of Plasmodium berghei displaying various chloroquine-resistance levels, we confirmed previous results obtained in vivo in the chloroquine-resistant strains of P. berghei are cross-resistant to related drugs (amodiaquine, quinine and mefloquine), the resistance levels to these drugs being related to their analogy to chloroquine. Furthermore, we showed that high-level resistant lines were associated with a loss of drug potentiation by verapamil and nicardipine in vivo, but that the reversal rates obtained in vitro are of low significance. We conclude that the parasite is able to escape the activity of these reversing agents.

Pharmacodynamics and tolerance of two nadroparin formulations (10,250 and 20,500 anti Xa IU x ml(-1)) delivered for 10 days at therapeutic dose.

Venous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i.d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU x ml(-1) respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU x kg(-1) b.i.d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU x kg(-1) o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC(0-12 h) plus AUC(12-24 h) (treatment A) and the AUC(0-24 h) (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC(0-12 h) were slightly but significantly lower than the AUC(12-24 h) suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 +/- 0.25), in relation with the anti-IIa activity (0.3 +/- 0.1 IU x ml(-1)).

[Immunofluorescence reaction of antibodies directed against the intestinal epithelium of Schistosoma mansoni. VI. Immunolocalization of a carbohydrate epitope at different developmental stages]. / Etude par la réaction d'immunofluorescence des anticorps dirigés contre l'épithélium intestinal de Schistosoma mansoni. VI. Immunolocalisation d'un épitope glucidique aux différents stades évolutifs.

In the course of previous works, we described an IgM monoclonal antibody directed to a carbohydrate epitope located on the gut epithelium surface of the Schistosoma mansoni adult worm. We provided evidence that this epitope was present in all stages of the parasite and was particularly abundant in eggs. The current work was performed in order to specify the epitope localisation, at each stage, by immunohistochemical techniques. The epitope appears to be located on the peripheral membranes of the adult worm, while it is produced by the alive miracidium in the eggs located in the tissues and subsequently spread out inside the periovular granuloma. Moreover, in adult worms, the observed structure presents itself as a soluble form in organic solvents; on the other hand, in eggs, the epitope was essentially found made of an hydrosoluble substance. These datas can explain why, in experimentally infected mice, the epitope is mainly determined in urines at the sixth week of infestation, when eggs are settled down in the tissues. Besides, the inhibition of the monoclonal antibody fixation by a pentose which contains the Lewis X antigen, painted out that the carbohydrate structure recognised by the monoclonal antibody could be the Lewis X antigen or a very closed structure.

Endothelium activation related increase of soluble intercellular adhesion molecule-1 in human schistosomiasis. Lack of correlation with serology.

Soluble intercellular adhesion molecule-1 (sICAM-1) level was measured in sera from 41 patients with Schistosoma mansoni schistosomiasis and compared with the sICAM-1 level in 41 healthy subjects. A significant increase in serum sICAM-1 was observed in patients with schistosomiasis compared with control subjects. As they were inhabitants of the French Antilles, the patients were, however, not settled in a malaria endemic zone, allowing this cause of sICAM-1 enhancement to be eliminated. No correlation was found between the level of sICAM-1 and the schistosomiasis serological titre. Such results favour the hypothesis of an activation of vascular endothelial cells due to egg deposition.

[Epidemiology of certain endemic parasitic diseases in the town of Guadalupe (Republic of Sao Tome and Principe). II. Other endemic parasitic diseases]. / Epidémiologie de certaines endémies parasitaires dans la ville de Guadalupe (République de Saõ Tomé et Príncipe). II. Autres endémies parasitaires.

Stool, blood and urine specimens have been collected from 380 inhabitants of all age groups living in the small town of Guadalupe in May 1992. The seroprevalence of Falciparum malaria (96%), toxoplasmosis (73.3%), have been measured.

[Epidemiology of certain endemic parasitic diseases in the town of Guadalupe (Republic of Sao Tome and Principe) I. Schistosomiasis intercalatum and intestinal worms]. / Epidémiologie de certaines endémies parasitaires dans la ville de Guadalupe (République de Saõ Tomé et Príncipe). I. Schistosomose à S. intercalatum et verminoses intestinales.

Schistosomiasis intercalatum in known to exist in Saõ Tomé since 1988, (Corachan et al.). It is transmitted by Bulinus forskalii, (Brown et al., 1989). Stool, blood and urine specimens have been collected from 380 inhabitants of all age groups living in the small town of Guadalupe close to the Agua Traz river and Agua Polino. The prevalence of schistosomiasis by detection of S. intercalatum eggs in a 10 mg stool thick smear (Kato technique) is 25.5%. An excreted Schistosoma polysaccharide antigen, detected by means of a monoclonal antibody (Ripert et al., 1992), is found in 49.1% of the urine samples. Patients voiding S. intercalatum eggs in stools have been treated with praziquantel (40 mg/kg body weight), as recommended by WHO Expert Committee on Schistosomiasis, but it might be wise to also treat persons excreting antigen in urine. The prevalence of intestinal helminthiasis, ascariasis (73.7%), trichuriasis (73.7%) and necatoriasis have been measured.

Plasmodium berghei: implication of intracellular glutathione and its related enzyme in chloroquine resistance in vivo.

Glutathione (GSH) plays a critical role in the detoxication and the protection of cells against oxidative stress. In the present study we examined the relationship between the intracellular GSH levels as well as glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPx) activities and how they relate to Plasmodium berghei resistance to chloroquine. Resistant strains (CQR30 and CQR60) were selected in vivo from a sensitive strain (NK65). Marked increases in GSH levels and GST activity within resistant parasites were observed, compared to sensitive parasites. On the other hand, GR and GPx activities were similar in sensitive and resistant parasites. Treatment with chloroquine did not influence the intracellular level of GSH, but it was found to significantly decrease GR activity. Intracellular depletion of GSH, by a nontoxic concentration of buthionine sulfoximine (BSO), significantly sensitized the resistant parasites to chloroquine. These results suggest that the P. berghei resistance results from altered GSH and GST levels and activity, respectively, which enable the detoxification of chloroquine in resistant parasites.

Conformational studies of the beta-subunit of the high affinity IgE receptor: circular dichroism and molecular modelling.

The receptor with high affinity for immunoglobulin E (Fc epsilon RI) on mast cells and basophils plays an important role in mediating many of the pathophysiological phenomena associated with allergy. Fc epsilon RI is a tetrameric complex, alpha beta gamma2, of non-covalently attached subunits: one IgE-binding alpha-subunit with the binding site in the extracellular part of the chain, one beta-subunit and a dimer of disulphide linked gamma-subunits. In the present work, prediction of the three-dimensional structure of the four membrane-spanning segments of the beta-subunit has been achieved using rules of helix-helix packing arrangements and molecular dynamics calculations. It yielded a four-helix bundle with specific Van der Waals interactions between the helices. This four-helix bundle was used as a framework upon which to calculate the conformation of the beta-subunit excluding the C and N terminal cytoplasmic tails, but including the three chains that connect the four helices in the bundle. Separately, these synthetic 11, 17 and 29 residue bridge peptides were examined by circular dichroism (CD) spectroscopy and a degree of alpha-helical content in these bridge peptides was found. Additional molecular modelling of the bridge peptides indicate the central residues of these as the location of the helical moieties. Finally, in the model proposed for the beta-subunit, for each pair of consecutive transmembrane (TM) helices and its bridge peptide, a helix-loop-helix-loop-helix motif was found.

[Study by the immunofluorescence reaction of antibodies directed against antigens of the gut epithelium of Schistosoma mansoni. V. Modulation of granulomatous reaction around the egg under the influence of an IgM monoclonal antibody]. / Etude par la réaction d'mmunofluorescence des anticorps dirigés contre les antigènes de l'épithélium intestinal de Schistosoma mansoni. V. Modulation de la réaction granulomateuse autour de l'oeuf sous l'influence d'un anticorps monoclonal de classe IgM.

The periovular granulomatous reaction has been reduced in vivo by an IgM monoclonal antibody. The granulomatous reaction has been obtained either in unsensitized, or sensitized as well as immunized mouse. The granulomatous reduction could be explained by a decrease in egg viability, owing to the fact that the monoclonal antibody is lethal against an in vitro miracidium suspension.

[Evaluation of an indirect hemagglutination test for the serodiagnosis of amebiasis]. / Evaluation d'un test d'hémagglutination indirecte amibiase (HAI) pour le serodiagnostic de l'amibiase.

167 sera have been tested to appreciate the value of an indirect hemagglutination test (Amibiase HAI FUMOUZE) comparatively to an agglutination test of sensibilized particles of latex (Bichro latex Amibe Fumouze BLA) Amibiase HAI test comes out as sensitive and specific for the detection of antibodies in patients suffering from visceral amoebiasis. But some antibodies are also detected in patients with an antecedent of amoebiasis, as it is usually the case with some other techniques. A high positivity of the indirect hemagglutination test, and the concordance between the test HAI and the BLA one are in favour of a visceral amoebiasis. While lower rates or discrepancy between the two tests may evoke an hidden infestation in patients coming out or originated from endemic zones.

Etude epidemiologique du foyer de bilharziose a schistosoma intercalatum de Bata (Guinee Equatoriale)

Un antigene polysaccharidique caracteristique du genre schistosoma excrete dans l'urine est mis en evidence; avant et apres traitement par le praziquantel (40 mg/kg) dans la ville de Bata; ou un foyer de bilharziose a schistosoma intercalatum a ete identifie. Le test de detection urinaire de l'antigene met en jeu un anticorps monoclonal et fait appel a la technique d'inhibition de l'hemagglutination passive. Parmi les 779 sujets examines 145; soit 18;6 pour cent d'entre eux eliminent des oeufs de schistosoma intercalatum dans leurs selles et 305; soit 39;1 pour cent excretent de l'antigene dans les urines; ce qui dans la bilharziose traduit l'existence d'une profonde impregnation antigenique de l'organisme

Enquete paludometrique dans trois villages de la vallee de la Kadei; Cameroun

L'enquete paludometrique menee en janvier 1991 dans trois villages riverains de la riviere Kadei a l'Est du Cameroun revele un paludisme hyperendemique. L'indice plasmodique des enfants de 2 a 9 ans est de 63;5 pour cent. La formule parasitaire montre la preponderance de plasmodium falciparum et la presence de plasmodium malariae et de plasmodium ovale. La reaction d'immunofluorescence met en evidence un indice serologique eleve et une acquisition precoce des anticorps antipalustres; reflets d'une transmission intense. La pression medicamenteuse est restee tres faible dans la population traditionnelle et la construction d'un barrage ne devrait pas modifier la morbidite palustre en raison d'une transmission deja tres intense dans la region

Etude epidemiologique des filarioses (onchocercose; loase; mansonellose); dans la vallee de la Kadei (Cameroun)

L'etude des filarioses est realisee dans trois villages proche du site prevu pour la construction d'un barrage sur la riviere Kadei (Cameroun oriental). La presence des microfilaires d'onchocerca volvulus est determinee par l'examen des biopsies cutanees. La prevalence parasitologique (37;9 pour cent) et les caracteristiques lesionnelles observees indiquent que l'onchocercose sevit dans la region au niveau de mesoendemie et se presente un facies de foret. Compte tenu de l'ecologie des vecteurs; cette etude d'impact montre que le barrage prevu ne devrait pas modifier d'une facon notable l'ecologie regionale et la transmission des filarioses dans la region