[Selection of lung transplant candidates in France in 2019]. / Sélection des candidats à la transplantation pulmonaire en France en 2019.

INTRODUCTION: In 2015, the International Society for Heart and Lung Transplantation (ISHLT) published a consensus document for the selection of lung transplant candidates. In the absence of recent French recommendations, this guideline is useful in order to send lung transplant candidates to the transplantation centers and to list them for lung transplantation at the right time. BACKGROUND: The main indications for lung transplantation in adults are COPD and emphysema, idiopathic pulmonary fibrosis and interstitial diseases, cystic fibrosis and pulmonary arterial hypertension (PAH). The specific indications for each underlying disease as well as the general contraindications have been reviewed in 2015 by the ISHLT. For cystic fibrosis, the main factors are forced expiratory volume in one second, 6-MWD, PAH and clinical deterioration characterized by increased frequency of exacerbations; for emphysema progressive disease, the BODE score, hypercapnia and FEV1; for PAH progressive disease or the need of specific intravenous therapy and NYHA classification. Finally, the diagnosis of fibrosing interstitial lung disease is usually a sufficient indication for lung transplantation assessment. OUTLOOK AND CONCLUSION: These new recommendations, close to French practices, help clinicians to find the right time for referral of patients to transplantation centers. This is crucial for the prognosis of lung transplantation.

Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides.

OBJECTIVE: Chronic psychological stress is associated with development of intestinal barrier dysfunction and impairs host defence mechanisms. The intestinal epithelium, consisting of enterocytes, endocrine cells, goblet cells and Paneth cells, is an important component of this barrier. In the present study, the impact of maternal deprivation (MD) on secretory lineages of duodenal epithelium and the involvement of the peripheral corticotropin-releasing factor (CRF) pathway were investigated. METHODS: Rat pups were deprived of their dam for 3 h/day (days 5-20). Non-deprived pups served as controls. On days 8, 13, 20, 24, 34, 44 and 84, duodenal tissues were collected for quantitative real-time PCR and immunohistochemistry studies. RESULTS: MD induced a sustained decrease in the number of Paneth and goblet cells but hyperplasia of endocrine cells. These alterations were associated with a duodenal increase of CRF, urocortin 2 and CRF receptor subtype 2 (CRFR(2)) mRNA, whereas CRFR(1) expression was decreased. The effects of MD on intestinal epithelium were inhibited by the CRFR(1)/R(2) antagonist astressin injected daily before MD. Studies using specific receptor antagonists in rats subjected to MD revealed that CRFR(1) was involved in the hyperplasia of endocrine cells and CRFR(2) in the depletion of Paneth cells. Conversely, daily injection of CRF and of the CRFR(2) agonist urocortin 2 in control rats resulted in changes in epithelial differentiation similar to MD. CONCLUSIONS: The activation of CRFR(1) and CRFR(2) induced by MD markedly altered the quantitative distribution of secretory cells of the intestinal epithelium. These alterations, in particular the depletion of Paneth and goblet cells, may create conditions leading to the development of an epithelial barrier defect.

Effect of bile salts on colonic mucus secretion in isolated vascularly perfused rat colon.

Mainly composed of mucins, mucus secreted by goblet cells in the intestinal epithelium is critically involved in the protection of the gastrointestinal mucosa. The hypothesis that bile and some bile salts can induce mucus secretion was tested in the isolated perfused rat colon. Mucus release was evaluated using enzyme-linked immunosorbent assays and supported by histological analysis. Luminal administration of bile extract (1%) provoked mucus secretion in the rat colon. Deoxycholate (0.5-10 mM) induced a dose-dependent increase in rat colonic mucus release. Chenodeoxycholate (10 mM) and hyodeoxycholate (10 mM) also evoked mucus discharge, whereas 10 mM cholate, 10 mM ursodeoxycholate, or Tween-20 did not release mucus. Taurine-conjugated bile salts (deoxycholate, hyodeoxycholate, and chenodeoxycholate) were less potent mucus secretagogues than the corresponding unconjugated forms. The deoxycholate-induced mucus discharge was not altered by pharmacological blockers (tetrodotoxin, atropine), indomethacin, mast cell stabilizers (ketotifen, doxantrazole), H1 histamine receptor antagonist (pyrilamine), or 5-HT receptor antagonists (ketanserin, ondansetron, SDZ 205-557). Our findings suggest that some bile salts, especially in the unconjugated form, may provoke colonic mucus secretion, probably through a direct action on mucus-secreting cells.

Involvement of beta1- and beta2- but not beta3-adrenoceptor activation in adrenergic PYY secretion from the isolated colon.

The secretion of PYY by endocrine L cells of the terminal gut is under the control of nutrients, the autonomic nervous system and hormones. Catecholamines, and the non-specific beta-adrenergic agonist isoproterenol induce PYY secretion from rat isolated colon or ileum. Because beta3-adrenergic receptors now appear to mediate many of the effects of catecholamines in the gastrointestinal tract, we investigated the involvement of beta1-, beta2-, and beta3-adrenoceptor stimulation in PYY secretion from the isolated, vascularly perfused rat colon. Infusion of 10(-6) M isoproterenol induced a transient increase in PYY secretion (from 36+/-4 to 87+/-20 fmol/2 min; n=7, P<0.05), that was abolished by a previous infusion of the beta1- and beta2-adrenergic blocker (and partial beta3-agonist) alprenolol (10(-6) M). The beta1-adrenergic agonist dobutamine and the beta-2 agonist terbutaline also (both at 10(-5) M) significantly stimulated PYY secretion, from 29+/-1 to 79+/-12 fmol/2 min and from 19+/-1 to 73+/-13 fmol/2 min respectively (n=7, P<0.05). Neither of the beta3-adrenergic agonists tested (BRL 37 344 (10(-5), 10(-6) M) and SR 58 611A (10(-6) M)) significantly stimulated PYY secretion, thus confirming the exclusive involvement of beta1- and beta2-receptors in beta-adrenergic agonist induced hormone secretion.

Selective involvement of calcium and calcium channels in stimulated mucin secretion from rat colon.

BACKGROUND: The cellular mechanisms involved in the mucin secretion of rat colon are unknown. The objective of the present study was thus to determine the role of extracellular calcium and of L-type calcium channels in rat intestinal mucin discharge. METHODS: The experiments were conducted using the isolated vascularly perfused rat colon. Mucin secretion was evaluated using an enzyme-linked immunosorbent assay. RESULTS: Intra-arterial bethanechol (200 microM) or luminal deoxycholate (5 mM) produced a significant mucin discharge (609% and 386% of controls, respectively). The colonic mucin output induced by these two secretagogues was significantly inhibited by arterial administration of EGTA (2 mM), verapamil (100 microM) or nifedipine (50 microM). In contrast, luminal EGTA (2 mM) had no inhibitory effect. Intra-arterial infusion of the calmodulin antagonist trifluoperazine (10 microM) also reduced mucin discharge induced by bethanechol or deoxycholate (304% and 223% of controls, respectively). Colonic mucin secretion was significantly stimulated after intra-arterial infusion of 3-isobutyl-methylxanthine (IBMX, 100 microM) or forskolin (2-20 microM). Stimulation by forskolin was unaffected by arterial EGTA, verapamil, nifedipine or trifluoperazine. CONCLUSION: In the isolated vascularly perfused rat colon, mucin discharge induced by bethanechol or deoxycholate requires extracellular calcium and the activation of voltage-dependent calcium channels of L-type. In contrast, forskolin does not appear to stimulate mucin release by increasing calcium entry.

[Malarial vectors in French Guiana: study in an epidemic focus near Cayenne (1989-1998)]. / Vecteurs de paludisme en Guyane Française: étude dans un foyer épidémique proche de Cayenne (1989-1998).

Malaria has long constituted a major public health problem for French Guyana, limiting its demographic and economic development. From 1949 to 1960, due to chemoprophylaxis and DDT spraying in houses, the number of malaria cases decreased markedly. After 1975, important migratory movements contributed to increasing the incidence of malaria. In 1989, numerous cases were observed when some 500 immigrants settled in a formerly uninhabited area, known as Cabassou BP 134. It is located 7 km (S-E) from the main city of Cayenne and bordered by secondary forest and swamps. The entomological study initiated in 1990 included weekly biting-landing catches (3 hours) on human bait in houses from dusk onwards as well as locating breeding places around the settlement to collect larvae by dipping. Anopheles specimens were identified and the females dissected to detect infections by Plasmodium and also to determine the rate of parous specimens. Control measures included deltamethrin (15 mg/m2) and DDT (2 g/m2) spraying, every four months, of interior walls and thermal fogging of naled around the houses. Cold ULV aerosol of fenitrothion (500 ml/ha) was also used to treat the swamp borders. In April 1990, a health education programme was begun and in June, 288 impregnated bednets (deltamethrin 15 mg/m2) were treated. From 1990 to 1998, 1,588 (498 larvae + 1090 adults) Anopheles (Nyssorhynchus) were collected: An. aquasalis 797 (311 L + 486 A). An. braziliensis 139 (87 L + 52 A). An. darlingi 652 (100 L + 552 A). No infected female was found among the 710 dissected. The number of malaria cases decreased abruptly in the fall of 1990 when An. darlingi disappeared and only one case due to P. vivax was detected between 1995 and 1998. An. darlingi (parous rate = 72%) appears to be the main if not the sole vector of malaria in this locality. As in the past, a focus of malaria appears when immigrants from endemic countries settle in a formerly uninhabited place where An. darlingi are breeding.

Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon.

BACKGROUND: Mucins play an important protective role in the colonic mucosa. Luminal factors modulating colonic mucus release have been not fully identified. AIM: To determine the effect of some dietary compounds on mucus discharge in rat colon. METHODS: An isolated vascularly perfused rat colon model was used. Mucus secretion was induced by a variety of luminal factors administered as a bolus of 1 ml for 30 minutes in the colonic loop. Mucin release was evaluated using a sandwich enzyme linked immunosorbent assay supported by histological analysis. RESULTS: The three dietary fibres tested in this study (pectin, gum arabic, and cellulose) did not provoke mucus secretion. Luminal administration of sodium alginate (an algal polysaccharide used as a food additive) or ulvan (a sulphated algal polymer) induced a dose dependent increase in mucin discharge over the concentration range 1-25 mg/l (p<0.05 for 25 mg/l alginate and p<0.05 for 10 and 25 mg/l ulvan). Glucuronic acid and galacturonic acid, which are major constituents of a variety of fibres, produced significant mucin secretion (p<0.05). Hydrogen sulphide and mercaptoacetate, two sulphides produced in the colonic lumen by microbial fermentation of sulphated polysaccharides, did not modify mucin secretion. Among the short chain fatty acids, acetate (5-100 mM) induced a dose dependent release of mucus (p<0.05 for 100 mM acetate). Interestingly, butyrate at a concentration of 5 mM produced colonic mucin secretion (p<0.05), but increasing its concentration to 100 mM provoked a gradual decrease in mucus discharge. Propionate (5-100 mM) did not induce mucin release. Several dietary phenolic compounds (quercetin, epicatechin, resveratrol) did not provoke mucus discharge. CONCLUSIONS: Two algal polysaccharides (alginate and ulvan), two uronic acids (glucuronic acid and galacturonic acid), and the short chain fatty acids acetate and butyrate induce mucin secretion in rat colon. Taken together, these data suggest that some food constituents and their fermentation products may regulate the secretory function of colonic goblet cells.

Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation.

Postprandial release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L cells results from both nutrient transit in the ileal lumen and neural drive of endocrine cells. The adrenosympathetic system and its effectors have been shown to induce secretion of L cells in vivo or in vitro. Because these transmitters act through three receptors, beta, alpha1, alpha2, coupled to different intracellular pathways, we evaluated the responses of L cells to specific agonists, using the model of isolated vascularly perfused rat ileum. General stimulation of adrenergic receptors with epinephrine (10(-7) M) induced significant GLP-1 and PYY secretions (94+/-38 and 257+/-59 fmol/8 min respectively) which were abolished upon propranolol (10(-7) M) pretreatment and strongly decreased upon infusion with 10(-8) M prazosin. Blockade of alpha2-receptors with idazoxan (10(-8) M) did not alter epinephrine-induced peptide secretion. The beta-adrenergic agonist isoproterenol (10(-6) M) infused for 30 min induced a transient release of GLP-1 and PYY (integrated release over the 8 min of the peak secretion: 38+/-16 and 214+/-69 fmol for GLP-1 and PYY respectively, P<0.05). Because terbutaline but not dobutamine or BRL 37,344 (10(-5) M) induced significant GLP-1 and PYY secretions (135+/-30 and 305+/-39 fmol/8 min respectively), isoproterenol-induced secretions are suggested to result mainly from stimulation of the beta2-isoreceptor type. In contrast, the alpha1-agonist phenylephrine (10(-7) M) did not stimulate peptide release. When co-infused with 10(-6) M or 10(-7) M isoproterenol, 10(-7) M phenylephrine raised GLP-1 release to 174+/-53 and 108+/-28 fmol/8 min respectively (vs 38+/-16 and 35+/-10 fmol/8 min for isoproterenol alone, P<0.05) whereas PYY secretion was not significantly increased. Clonidine (10(-7) M), an alpha2-agonist, induced a moderate and delayed increase of GLP-1 and PYY but abolished the isoproterenol-induced peptide secretion. Our results showed that general stimulation of adrenergic receptors stimulates the secretory activity of ileal endocrine L cells. The net peptide secretion results from the activation of the beta2-isoreceptor type. Additionally, GLP-1 and PYY secretions are positively modulated by alpha1-receptor stimulation and inhibited by alpha2-receptor activation upon beta-receptor occupation.

Effects of neurotransmitters, gut hormones, and inflammatory mediators on mucus discharge in rat colon.

The effect of potential mediators of mucus secretion was investigated in the isolated vascularly perfused rat colon by using a sandwich enzyme-linked immunosorbent assay for rat colonic mucin and by histochemical analysis. Bethanechol (100-200 microM), bombesin (100 nM), and vasoactive intestinal peptide (VIP, 100 nM) provoked a dramatic mucin discharge (maximal response at 900, 900, and 600% of control loops, respectively). VIP-stimulated mucin secretion was abolished by tetrodotoxin, whereas atropine was without effect. In contrast, both tetrodotoxin and atropine significantly decreased mucin release induced by bombesin. Isoproterenol or calcitonin gene-related peptide was without effect. Serotonin (1-5 microM) and peptide YY (10 nM) evoked mucin discharge, whereas glucagon-like peptide-1 did not release mucin. Finally, bromolasalocid (20 microM), interleukin-1beta (0.25 nM), sodium nitroprusside (1 mM), and dimethyl-PGE2 (2.5 microM) induced mucus discharge. The results demonstrated a good correlation between the immunological method and histological analysis. In conclusion, these findings suggest a role for the enteric nervous system, the enteroendocrine cells, and resident immune cells in mediation of colonic mucus release.

Influence of the thyroid hormone status on tyrosine hydroxylase in central and peripheral catecholaminergic structures.

We investigated the effect of hyper- and hypothyroidism on tyrosine hydroxylase protein concentration in the locus coeruleus (divided into anterior and posterior parts), the substantia nigra and the adrenals of adult rats. Rats were made hypothyroid with propylthiouracile (PTU, 0.02% in drinking water for 21 days) or hyperthyroid by thyroxine injection (100 or 250 micrograms/kg/day), for 3 or 17 days. PTU treatment resulted in statistically significant decrease of tyrosine hydroxylase in the anterior locus coeruleus (-13%) and the adrenals (-14%). After thyroxine treatment, in the anterior locus coeruleus, tyrosine hydroxylase was significantly higher (2 way ANOVA) after the 3 day treatment than after the 17 day treatment: tyrosine hydroxylase showed a trend to increase the 3 day treatment (+20% with the 250 micrograms/kg dose) and to decrease after the 17 day treatment (-15% with the 250 micrograms/kg dose). In the adrenals, tyrosine hydroxylase was increased by the 3 day treatment (+42% after the 250 micrograms/kg dose), but this increase was not observed after 17 days of treatment. Tyrosine hydroxylase was not altered in the posterior locus coeruleus and the substantia nigra, whatever the treatment. Together, our results support the hypothesis that in the anterior locus coeruleus and in the adrenals tyrosine hydroxylase level is positively modulated by thyroid hormones. After long-term treatment (17 days) this effect is not observed.

[A note on Psorophora lineata (Humboldt, 1819) (Diptera, Culicidae) in French Guiana]. / Note sur Psorophora lineata (Humboldt, 1819) (Diptera, Culicidae) en Guyane française.

Psorophora lineata, a very large-sized mosquito, has rarely been collected in French Guiana. From specimens obtained in 1942-1991, data on morphology, bionomics, local distribution and disease relations are given. P. lineata may be considered as a potential vector of arboviruses.

Response of noradrenaline and dopamine to hypoxia and sympathectomy: evidence for an independent dopaminergic reactivity.

In order to assess the status of dopamine in the periphery, we submitted rats to sympathectomy (with guanethidine), to hypoxia, and to both, and measured the concentration and turnover of noradrenaline and dopamine in peripheral organs. Sympathectomy decreased noradrenaline content by 96-99% in all the organs tested. In contrast, dopamine content, which was decreased by 90% in the heart, was not significantly changed in the bladder or lungs. Based on dopamine decrease after guanethidine, and on dopamine:noradrenaline ratios in organs, we conclude that in the heart the dopamine is contained mostly in noradrenergic terminals. In other organs it appears to be contained in non-noradrenergic structures. These are found in: the bladder, stomach, lungs, and kidneys, in decreasing importance. We estimated the turnover of noradrenaline by measuring the decrease of its concentration after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine. Among the five organs studied, the turnover of noradrenaline was increased by long-term hypoxia (10% O2, 15 days) in the heart only (+140%). An increase of sympathetic activity during hypoxia was also found in the kidneys and lungs as shown by the increase in turnover of dopamine that was suppressed by sympathectomy. Hypoxia induced large increases in dopamine concentration in the stomach and the lungs (70 and 190% respectively). These increases were not abolished by sympathectomy and we propose that they are related to a chemosensory function of dopamine-containing paraganglia in the stomach and the lung.

Preganglionic sympathetic fibres modulate dopamine turnover in rat carotid body during long-term hypoxia.

To assess the influence of sympathetic efferents on the dopamine function of carotid bodies, rats were exposed to long-term hypoxia (10% O2 in nitrogen for 1 or 3 weeks) after unilateral removal of the superior cervical ganglion. In the intact carotid bodies. long-term hypoxia increased the content and turnover of dopamine (DA). The dopaminergic response to hypoxia was reduced but not abolished by the ganglionectomy. To determine whether pre- or postganglionic sympathetic fibres are involved in the control of the dopamine function, rats were exposed to hypoxia either after unilateral transection of the preganglionic cervical trunk or after selective destruction of the postganglionic fibres by guanethidine. The preganglionic transection blunted the dopaminergic response to hypoxia whereas guanethidine had no effect. It is concluded that the sympathetic efferents may activate the synthesis and release of dopamine in glomus cells during long-term hypoxia. The sympathetic efferents responsible for the modulation of dopamine function are probably preganglionic fibres.

Conjugation and deamination of circulating dopamine: relationship between sulfated and free dopamine in man.

In order to assess the importance of conjugation in dopamine metabolism, we infused dopamine (20 nmol/kg/min, 1 h) to seven male subjects, then measured the kinetics of free and conjugated dopamine and DOPAC (deaminated dopamine) in plasma both during and after the infusion. Dopamine increased as early as 2 min after the start of the infusion, then reached a plateau and remained elevated on a level of 25 times the basal value. Dopamine sulfate and DOPAC followed very similar patterns and increased continuously from the 30th and 20th min, respectively, until the end of the infusion (5.18- and 5.76-fold, respectively), but only dopamine sulfate remained elevated (1.65-fold) on the first day following infusion. DOPAC glucuronide increased moderately (2.58-fold) at the end of the experiment, but neither dopamine glucuronide nor DOPAC sulfate were increased despite high precursor circulating levels. Free DOPAC and dopamine sulfate levels during infusion were correlated with dopamine levels when all subjects were pooled. In addition, within a subject dopamine sulfate to dopamine correlations were found with slopes varying in a range of 1 to 15. Our results show that sulfation is significantly involved in the metabolism of circulating dopamine and is not easily saturated, suggesting that dopamine sulfate may be an index of endogenous dopamine release.

Plasma free and sulphated catecholamines after ultra-long exercise and recovery.

We investigated the early and late effects of two types of ultra-long exercise on sympatho-adrenal and dopaminergic activity. With this aim both free and sulphoconjugated plasma catecholamines (CA), noradrenaline (NA), adrenaline (A), and dopamine (DA) were determined in two groups of athletes immediately after completion of 24-h running or a 10-h triathlon and on recovery during the next 1-3 days. Both races stimulated the sympathetic activity, but differences were observed in the CA pattern: the 24-h run induced a marked elevation of free and sulphoconjugated NA (+175% and +180%, respectively) but failed to alter significantly A and DA levels. The triathlon challenge increased the three conjugated CA (NA sulphate +350%; A sulphate +110%; DA sulphate +270%) and to a lesser extent free CA (NA +45%; A +30%). On the first post-exercise morning, a sustained intense noradrenergic activity was still present in the 24 h-runners, as evidenced by the large increase in free and sulphated NA levels (+140% and +100%, respectively). Such a prolonged activity was also indicated after completion of the triathlon, by the increase of NA sulphate (+140%) observed on the 1st recovery day. However, after the triathlon there was a decreased release of A from the adrenal medulla for several days. These data show that both types of ultralong exercise are able to induce for several hours a sustained sympathetic activation during the test and in the recovery period. Furthermore, the study shows that plasma conjugated CA may provide delayed and cumulative indexes of sympathetic activation, complementary to the instantaneous markers such as free CA.

Catecholamines and fuels after an ultralong run: persistent changes after 24-h recovery.

This study examined the alterations induced by an ultralong distance run (169 +/- 6 km in 24 h) and by prolonged postrace recovery (24 h) on blood fuel metabolites and catecholamines in seven trained subjects. Ten minutes after the race, plasma concentrations of glycerol and free fatty acids (FFA) were decreased twofold. Plasma glucose was unchanged. Plasma concentrations of free norepinephrine (NE) and free dopamine (DA) increased from 2.73 +/- 0.28 to 5.41 +/- 1.11 nmol.l-1 and from 0.45 +/- 0.13 to 0.62 +/- 0.18 nmol.l-1 whereas free epinephrine (E) and insulin were unchanged; 24 h after the race, plasma glycerol and FFA concentrations remained elevated (twofold) and TG decreased twofold compared with resting levels. Concomitantly, plasma NE and DA levels remained elevated, respectively, 6.23 +/- 0.41 and 0.77 +/- 0.13 nmol.l-1. These data show that the alterations in circulating fuel metabolites and NE induced by the ultralong race were still present 24 h later. The involvement of lipid metabolism and catecholamines in processes of post-exercise recovery is discussed.