Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial.

BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. OBJECTIVES: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. METHODS: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg-1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). RESULTS: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg-1 and 13 of 15 (87%) patients receiving 25 mg kg-1 , with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg-1 per day (range 0·06-0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. CONCLUSIONS: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

T-cell activation during exacerbations: a longitudinal study in refractory asthma.

BACKGROUND: Asthma exacerbations represent the main source of costs and morbidity in asthma care, and drugs specifically designed to prevent exacerbations are needed. A prerequisite is to dispose of a precise knowledge of inflammatory events leading to exacerbations. OBJECTIVE: To study T-cell activation during exacerbations from severe refractory asthmatics. METHODS: Proportions of blood T-cell interleukin (IL)-13, interferon-gamma, IL-4, IL-5, IL-10 production and of CD4+CD25+(high)CD62L+CD45RO+ [T regulatory (Treg)] cells were determined by flow cytometry. Blood cytokine mRNA was studied by reverse transcription-polymerase chain reaction and the respective protein levels were determined by cytokine beads array. Depletion of Treg cells was performed to study their activation. T-cell cytokines were detected in parallel in induced sputum. RESULTS: At baseline, T helper 2 (Th2) cells were increased in asthmatics, whereas T helper 1 (Th1) and Treg T cells were decreased. T helper 2 cells increased before exacerbations, followed by Th1 cells, in blood and induced sputum, albeit Treg cells decreased in parallel with IL-10-producing T cells. Concordant results were found at the mRNA level. The suppressive activity of Treg cells was impaired during exacerbations compared to baseline. CONCLUSIONS: New insights are given into pathophysiology of asthma exacerbations: Although at baseline T-cell activation is Th2-biased, a mixed Th1/Th2 activation occurs during exacerbations. The Treg cell deficiency found at baseline in SRA increases during exacerbations.

Bronchodilator action of inhaled nitric oxide in guinea pigs.

The effects of inhaling nitric oxide (NO) on airway mechanics were studied in anesthetized and mechanically ventilated guinea pigs. In animals without induced bronchoconstriction, breathing 300 ppm NO decreased baseline pulmonary resistance (RL) from 0.138 +/- 0.004 (mean +/- SE) to 0.125 +/- 0.002 cmH2O/ml.s (P less than 0.05). When an intravenous infusion of methacholine (3.5-12 micrograms/kg.min) was used to increase RL from 0.143 +/- 0.008 to 0.474 +/- 0.041 cmH2O/ml.s (P less than 0.05), inhalation of 5-300 ppm NO-containing gas mixtures produced a dose-related, rapid, consistent, and reversible reduction of RL and an increase of dynamic lung compliance. The onset of bronchodilation was rapid, beginning within 30 s after commencing inhalation. An inhaled NO concentration of 15.0 +/- 2.1 ppm was required to reduce RL by 50% of the induced bronchoconstriction. Inhalation of 100 ppm NO for 1 h did not produce tolerance to its bronchodilator effect nor did it induce substantial methemoglobinemia (less than 2%). The bronchodilating effects of NO were additive with the effects of inhaled terbutaline, irrespective of the sequence of NO and terbutaline administration. Inhaling aerosol generated from S-nitroso-N-acetylpenicillamine also induced a rapid and profound decrease of RL from 0.453 +/- 0.022 to 0.287 +/- 0.022 cmH2O/ml.s, which lasted for over 15 min in guinea pigs broncho-constricted with methacholine. Our results indicate that low levels of inhaled gaseous NO, or an aerosolized NO-releasing compound are potent bronchodilators in guinea pigs.

The immunosuppressant SR 31747 blocks cell proliferation by inhibiting a steroid isomerase in Saccharomyces cerevisiae.

SR 31747 is a novel immunosuppressant agent that arrests cell proliferation in the yeast Saccharomyces cerevisiae, SR 31747-treated cells accumulate the same aberrant sterols as those found in a mutant impaired in delta 8- delta 7-sterol isomerase. Sterol isomerase activity is also inhibited by SR 31747 in in vitro assays. Overexpression of the sterol isomerase-encoding gene, ERG2, confers enhanced SR resistance. Cells growing anaerobically on ergosterol-containing medium are not sensitive to SR. Disruption of the sterol isomerase-encoding gene is lethal in cells growing in the absence of exogenous ergosterol, except in SR-resistant mutants lacking either the SUR4 or the FEN1 gene product. The results suggest that sterol isomerase is the target of SR 31747 and that both the SUR4 and FEN1 gene products are required to mediate the proliferation arrest induced by ergosterol depletion.

Human lamin B receptor exhibits sterol C14-reductase activity in Saccharomyces cerevisiae.

Lamin B receptor (LBR), a nuclear protein of avian and mammalian cells, contains an hydrophobic domain that shares extensive structural similarities with the members of the sterol reductase family. To test if the sterol-reductase-like domain of LBR could be enzymatically competent, several sterol reductase-defective strains of Saccharomyces cerevisiae were transformed with a human-LBR expressing vector. LBR production did not change the ergosterol biosynthesis defect in an erg4 mutant impaired in sterol C24(28) reductase. In contrast, the sterol C14 reduction step and ergosterol prototrophy were restored in LBR-producing erg24 transformants which lack endogenous sterol C14 reductase. To test the effects of C14 reductase inhibitors on LBR activity, we constructed EMY54, an ergosterol-requiring strain that is devoid of both sterol C8-C7 isomerase and sterol C14 reductase activities. EMY54 cells recovered the capability of synthesizing ergost-8-en-3beta-ol upon transformation with a vector that expressed either yeast sterol C14 reductase or hLBR. In addition, growth in sterol-free medium was restored in these transformants. Sterol biosynthesis and proliferation of LBR-producing cells were found to be highly susceptible to fenpropimorph and tridemorph, but only moderately susceptible to SR 31747. Our results strongly suggest that hLBR is a sterol C14 reductase.

Synthetic retinoids inhibit the antigen presenting properties of epidermal cells in vitro.

The clinical efficacy of retinoids in benign and malignant skin diseases involving immune mechanisms suggests that they affect the immunologic functions of the epidermis. However, these effects have yet to be demonstrated. The action of vitamin A (retinol) and the synthetic retinoids, isotretinoin, etretinate, acitretin, and arotinoid-free acid have been studied on the lymphocyte proliferation induced by phytohemagglutinin (PHA), by the mixed lymphocyte reaction (MLR), and the mixed epidermal cell-lymphocyte reaction (MECLR). The results for PHA-induced proliferations were highly variable for all the retinoids. However, in MECLR, the synthetic retinoids consistently reduced the proliferation by 20%-30%. This occurred at therapeutic drug concentrations of about 10(-7)M. In MLR, a minor decrease of 10%-15% was only found for higher concentrations (10(-5)M). Retinol induced no effect in either reaction. Further analysis of acitretin on MECLR showed that it reduced lymphocyte proliferation in a dose-dependent fashion. This reduction was combined with a decrease in cytotoxic T-lymphocyte induction (CTL). Addition of 10(-6)M acitretin at various times also revealed that its presence at cell culture initiation was necessary to inhibit proliferation significantly. Furthermore, cell treatments prior to MECLR showed that exposure of epidermal cells to acitretin was essential to produce this inhibition, suggesting that it acts directly on epidermal cells. Consequently, it is suggested that the specific inhibitory effect of synthetic retinoids on lymphocyte activation in MECLR may partly account for their therapeutic action on the skin.

Cyclosporin A inhibits the antigen-presenting functions of freshly isolated human Langerhans cells in vitro.

Cyclosporin A (CsA) is a strong inhibitor of skin allograft rejection. It has been also reported to act, not only on helper T cells, but also on the antigen-presenting functions of mouse epidermal cells (EC) enriched in Langerhans cells (LC). We tested the effects of CsA on the human allogeneic mixed epidermal cell-lymphocyte reaction (MECLR) using whole EC and freshly isolated LC as stimulator cells. Results were as follows. 1) CsA inhibited the lymphocyte proliferative response in a dose-dependent fashion, by about 80% for a CsA concentration of 10(-7) M. To evaluate the effects of the drug on the two cell populations involved in MECLR, stimulator EC and responder PBMC were separately pulsed for 2 h with CsA, washed, and combined to form MECLR. Inhibition by CsA of the alloantigen-dependent lymphocyte proliferation appeared to be multifactorial, because CsA-pulsed EC and CsA-pulsed effector PBMC led to identical reductions of 40% each in proliferation. 2) The nature of EC sensitivity to CsA during MECLR was then analyzed after freshly separating highly purified CD1-positive LC (greater than 95%) and LC-depleted EC (mainly keratinocytes), using an immunomagnetic particle technique. When responder PBMC were cultured with CsA-pulsed LC, a highly significant reduction of lymphocyte proliferation was observed, indicating that CsA has direct effects on LC. 3) Some of the possible mechanisms by which CsA might act on LC were studied. Substantial IL-1 activity and PGE2 amounts were induced during MECLR by LC and keratinocytes, but CsA did not act via these factors. Neither did it significantly modify HLA-DR, DQ, or DP antigen expressions on EC. In conclusion, CsA directly inhibits antigen presentation by human LC. This inhibition may partly explain the beneficial effects of CsA on skin allografts and certain cutaneous immune reactions.

Monoclonal antibody labeling of mononuclear cell surface antigens in formaldehyde-fixed paraffin-embedded cutaneous tissue.

The influence of the sequential stages of conventional formaldehyde fixation and paraffin embedding of cutaneous tissue on monoclonal antibody labeling of cell surface antigens is described. The effects of variation in fixation time, dehydration, clearing, wax embedding, and enzyme treatment of cutaneous sections were examined. By curtailing fixation time, using cold ethanol dehydration, and limited cold clearing with xylene, immunoreactivity of several important monoclonal antibodies was retained. Wax embedding could be achieved at 58 degrees C for 1 h or by using low-melting-point wax at 42 degrees C for 3 h. Thus was derived an optimal processing procedure which afforded good tissue morphology and allowed reliable reproducible labeling by monoclonal antibodies to cell surface antigens.

T-cell receptor-gamma/delta bearing lymphocytes in normal and inflammatory human skin.

Murine dendritic epidermal T cells (DETC) were recently reported to express T-cell receptor (TCR)-gamma/delta chains. In a search for the human equivalent of these cells, we tested normal and lesional skin with MoAb which react with the TCR-gamma/delta heterodimer. We performed indirect immunofluorescence (IF) on epidermal sheets, and alkaline-phosphatase-anti-alkaline-phosphatase complex (APAAP) on epidermal cell smears. Frozen skin sections from normal skin and various cutaneous lymphocyte infiltrates were also studied. A few CD3+ T lymphocytes were consistently found in normal epidermis. Most of these cells appeared to be TCR-alpha/beta +, and some CD4+ or CD8+. On epidermal sheets and cell smears, only a very small TCR-gamma/delta + cell population was visualized (less than 0.1% of the total). On normal skin sections, we observed 0 to 3 gamma/delta + cells per section. When present, they were often located in the epidermal basal layer, and were round or dendritic. Double immunolabeling revealed that gamma/delta + cells differed from CD1+ Langerhans cells, and that they had a similar phenotypic pattern as gamma/delta + peripheral lymphocytes (PBL): CD2+, CD3+, CD4-, and CD8-. Immunostaining from various inflammatory skin lesions showed that the dermal infiltrates included CD3+ T lymphocytes but virtually no gamma/delta + cells. Only a few gamma/delta + cells were found in some end-evolutive infiltrates. Taken together, these results strongly suggest that normal human epidermis occasionally harbors TCR-gamma/delta complex bearing lymphocytes, which constitute a small fraction of the CD3+ cutaneous T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Sterol metabolism and ERG2 gene regulation in the yeast Saccharomyces cerevisiae.

Certain exogenously-supplied sterols, like ergost-8-enol, are efficiently converted into ergosterol in yeast. We have taken advantage of this property to study the regulation of the Delta8-Delta7-sterol isomerase-encoding ERG2 gene in an ergosterol auxotrophic mutant devoid of squalene-synthase activity. Ergosterol starvation leads to an 8-16-fold increase in ERG2 gene expression. Such an increase was also observed in wild-type cells either grown anaerobically or treated with SR31747A a sterol isomerase inhibitor. Exogenously-supplied zymosterol is entirely transformed into ergosterol, which represses ERG2 transcription. By contrast, exogenously-supplied ergosterol has little or no effect on ERG2 transcription.

Study of cytokine gene expression in small cell samples: use in induced sputum.

Sputum examination is being increasingly used as a non-invasive method for the study of airway inflammation. However, the technical applications of sputum are still limited because of the small number of cells recovered. In attempt to extend applications of sputum examinations, we developed and standardised, the reverse transcriptase-polymerase chain reaction (RT-PCR), a sensitive and specific technique of detection of mRNA, in induced sputum samples. Total RNA were extracted from samples containing as few as 50 to 80,000 cells, using a phenol-chloroform extraction method. RT-PCR was successfully tested on beta-actin, interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and tumour necrosis factor-beta (TGF-beta) genes. This protocol provides a simple technique to extract total RNA from a few number of induced sputum cells. It permits the semi-quantitatively study of cytokine gene expression in airways with simple means.

Inhaled cigarette smoke selectively reverses human hypoxic vasoconstriction.

The acute effects of the inhaled gas phase of cigarette smoke on pulmonary (PAP) and systemic (SAP) arterial pressures and on plasma arterial cGMP content were compared with those of inhaling 10, 20 and 80 ppm nitric oxide (NO) in one healthy adult volunteer spontaneously breathing a hypoxic gas mixture. Hypoxia (FIO2 0.12) induced a sustained, stable pulmonary vasoconstriction. Inhaled NO induced a dose-dependent fall in PAP; plasma cGMP rose from 39.4 (hypoxia) to 164 pmol/ml (hypoxia plus 80 ppm NO). Exposure to cigarette smoke induced a rapid, consistent and reversible fall in PAP; plasma cGMP rose from 45.5 (hypoxia) to 138 pmol/ml (hypoxia plus cigarette smoke). Neither NO nor cigarette smoke inhalation induced any change in SAP. These data suggest that exposure to cigarette smoke is able selectively to reverse acute hypoxic vasoconstriction in humans without causing systemic vasodilation, an effect likely mediated through the NO-cGMP pathway.

Portal and hepatic arterial blood flow measurements of human transplanted liver by implanted Doppler probes: interest for early complications and nutrition.

Hepatic artery thrombosis and early acute rejection are severe complications of orthotopic liver transplantation (OLT). Their rapid detection is most desirable. The purpose of this study was to assess the usefulness of monitoring hepatic artery (HABF) and portal vein (PVBF) blood flows during the first week after OLT. At the end of operation, microprobes were sutured to the vessels, and their connecting tubes were externalized and connected to a pulsed Doppler flowmeter operating at 8 MHz. In 10 patients (ages ranged from 2 to 54 years) of 106, measurements of HABF and PVBF were done during alternative clamping of both vessels and before and after abdominal closure, every 12 hours during 7 days, and at day 7, before and after a 150 gm carbohydrate meal. At day 7 the probes were pulled out by gentle traction without complication, and all patients were allowed to go home. Reciprocal increase of flow during selective clamping was only observed for HABF (+45.8% +/- 47.6%; p less than 0.01). Abdominal closure decreased both HABF and PVBF by 13.8%, p less than 0.01, and 26%, p less than 0.05, respectively. In seven cases no significant variation of HABF and PVBF was observed during 7 days. In two patients with histologically confirmed early acute rejection, a marked decrease of diastolic HABF, without modification in PVBF, was the first manifestation and was rapidly corrected by boluses of steroids. In one patient disappearance of systolic and diastolic HABF led us to diagnose an arterial obliteration caused by a plicature, which was successfully surgically treated in the emergency department. In all patients, after oral ingestion of the carbohydrate meal, and only after this type of diet, a significant and deep decrease (-87%, p less than 0.001) of HABF was observed between 7 and 120 minutes without any change in PVBF. Such an effect was not observed in control patients. We conclude that this Doppler flowmetric technique with implantable microprobes is useful for rapid diagnosis of and strategy in treating early complications and is a new tool for pathophysiologic study of OLT consequences.

Pancreatic stone protein: quantification in pancreatic juice by enzyme-linked immunosorbent assay and comparison with other methods.

To quantitate pancreatic stone protein (PSP), a competitive radioimmunoassay using monoclonal antibodies to PSP extracted from pancreatic stones and a sandwich enzyme-linked immunosorbent assay (ELISA) using monospecific polyclonal antibodies to the secretory forms of PSP (PSP S) were established. When PSP concentrations were measured in pancreatic juice by radioimmunoassay, no difference could be found between patients suffering from chronic calcifying pancreatitis and other diagnostic groups. Yet, with the ELISA technique involving polyclonal antibodies, decreased concentrations were found in chronic calcifying pancreatitis patients when compared to controls (p less than 0.001), chronic alcoholics without pancreatic symptoms, or obstructive pancreatitis patients. These discrepancies are discussed. The monoclonal antibodies recognizing the C-terminal part of PSS S (PSP S1), results from the radioimmunoassay indicate that the concentration of that polypeptide is identical in the juice of controls and patients. Results from the ELISA obtained with polyclonal antibodies raised against PSP S2-5 molecules, i.e., recognizing the PSP S1 part and the N-terminal portion of the molecule, indicate that the differences observed reflect differences in the juice concentration of that N-terminal peptide.

Biochemical, cellular and pharmacological activities of a human neuropeptide FF-related peptide.

We report on the biochemical, cellular and pharmacological activities of SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2), a peptide sequence contained in the human neuropeptide FF (neuropeptide FF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor. Quantitative autoradiography revealed that, in the superficial layers of the rat spinal cord, SQA-neuropeptide FF displayed the same high affinity for [125I]1DMe ([125I]D-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2) binding sites (Ki = 0.33 nM) as did neuropeptide FF (Ki = 0.38 nM). In acutely dissociated mouse dorsal root ganglion neurones, SQA-neuropeptide FF reduced by 40% the depolarisation-induced rise in intracellular Ca2+ as measured with the Ca2+ indicator, Fluo-3. In mice, 1DMe and SQA-neuropeptide FF dose-dependently inhibited the antinociceptive effect of intracerebroventricular (i.c.v.) injections of morphine, but SQA-neuropeptide FF was less potent than 1DMe. Furthermore, SQA-neuropeptide FF, as well as 1DMe, produced marked hypothermia following third ventricle injections in mice. These data demonstrate that the human peptide, SQA-neuropeptide FF, exhibits biochemical and pharmacological properties similar to those of neuropeptide FF or neuropeptide FF analogues, and belongs to the neuropeptide FF family.

A low-salt medical water reduces irritancy of retinoic acid in facial acne.

Although effective medications are available for the treatment of acne, tolerance problems may preclude adequate treatment regimens such as topical retinoic acid, and reduce patient compliance. The present study was conducted to evaluate whether a medical water (Avène) in conjunction with retinoic acid may improve local tolerance in acne. A controlled, open, randomised, multicentric study was completed after 28 days of treatment in 69 acne patients, 34 applying a retinoic acid preparation alone, and 35 applying retinoic acid in association with the water spray used ad libitum. Topical retinoic acid treatment induced prominent signs of irritation in both groups. However, a statistically significant reduction between the two treatment groups could be demonstrated on scaling at all assessment visits (p< or =0.02, Wilcoxon test). No significant water effect on erythema, burning and itching was shown during the treatment period. The overall tolerance assessed by the investigator was significantly improved with the water (p = 0.04, Wilcoxon). Taken together, water with a low mineral content appears to be a promising adjunctive treatment for improving the tolerance of topical retinoids in acne.

Change in bile salt dependent lipase in human breast milk during extended lactation.

Two hundred eighty-one milk samples collected from Zaïrian nonprivileged, undernourished mothers, in series of nine groups from 1 month to 18 months after parturition, and 66 milk samples collected from French privileged mothers in series of four groups from 2 days to 16 months postpartum, were analyzed for their lactose, lipid and protein contents. In addition, the activity of bile salt-dependent lipase (esterase), which may play an important role in the newborn infant's lipids digestion, was measured. After the first month postpartum, independent of the nutritional state of the mother, sugar and protein concentrations were identical. Lipid content of French mothers' milk was lower in transitional milk, but appeared constant in mature milk with an average value of 29.1 +/- 5.8 mg/mL of milk. In Zaïrian mothers' milk, the lipid content of mature milk plateaued at around 50-55 mg/mL independent of the stage of lactation. Bile salt-dependent lipase showed constant esterase activity within the lactation stage in privileged mothers' milk, but decreased by almost 80-90% during the first four months of lactation in undernourished mothers. The data suggest that milk from nonprivileged mothers may lose some of its ability to hydrolyze milk lipid esters, which could also be of consequence to the infant's normal growth in view of its effect on the esters of the lipid-soluble vitamins A, E and D.

Characterization of a monoclonal antibody against a mucin-type glycoprotein in human sweat.

We report the preparation and characterization of an IgG2 monoclonal antibody (MAb), HSMA, prepared against a human pooled sweat extract (HPSE). The major component of HPSE was a mucin-type molecule, as revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) stained with periodic acid-Schiff (PAS) reagent. By immunoblotting, HSMA revealed a smear in the high molecular weight range, typical of mucins. In enzyme-linked immunosorbent assay (ELISA), HSMA failed to react with HPSE fractions isolated after anionic exchange gel chromatography. Similarly, radio-immunobinding assays demonstrated no reactivity between HSMA and A, B, H, and Lewis blood group-related structures. The immunohistological labeling on normal skin showed that HSMA reacted with the cells of eccrine sweat glands, and to a lesser extent, with sebaceous glands and epidermal cells. Periodate treatment in situ abolished these reactions, thus suggesting the carbohydrate structure of the HSMA-epitope. In indirect immunofluorescence (IF) studies, HSMA also reacted with other exocrine glands, e.g. mammary glands, sublingual glands, mixed sero-mucous glands of the trachea, and in the pancreas. Sparse positive cells were also observed in the testis, kidney, thyroid and digestive tract.

Topical retinaldehyde treatment in oral lichen planus and leukoplakia.

The aim of this exploratory study was to assess the efficacy of a natural metabolite of vitamin A, retinaldehyde 0.1%, vehicled in a gel in 17 patients with oral lichen planus and in 13 patients with oral leukoplakia, twice daily for 2 months. Our investigation was clinical, histological, immunohistochemical through the expression of markers of cell terminal differentiation and biochemical by using two-dimensional gel electrophoresis of cytokeratins (CK). In addition, the activity of retinaldehyde was studied ex vivo on surviving buccal mucosa. Retinaldehyde gel 0.1% showed good clinical efficacy, resulting in 6% disappearance and 82% improvement of the lesions in lichen planus and 17% disappearance and 75% improvement in leukoplakia. This was confirmed with immunohistochemistry, which revealed down-regulation of filaggrin and CK-10 as markers of terminal differentiation in both diseases. The effects of retinaldehyde in these two diseases were further demonstrated in the ex vivo surviving mucosal model, resulting in histological disappearance of keratinization in 80% of the lichen planus fragments and 40% of the leukoplakia fragments, associated with down-regulation of filaggrin and CK-10.

[Postoperative enoximone in coronary surgery. Systemic and coronary hemodynamics and regional systolic function]. / Enoximone en postopératoire de chirurgie coronaire. Hémodynamique systémique et coronaire, et fonction systolique régionale.

The effects of Enoximone (50 mg in 20 minutes) on systemic, pulmonary and coronary haemodynamics and on regional systolic function were examined after surgical myocardial revascularisation in 5 patients without overt cardiac failure. The flow in mammary artery grafts and the study of regional systolic function were assessed by Doppler probes implanted during the operation. Enoximone increased Qc and Qco without changing blood pressure or cardiac output, due to arterial vasodilatation and inotropic stimulation. Pulmonary vasodilatation resulted in hypoxemia which must be prevented. The increase in VO2 was unrelated to oxygen transport suggesting a specific drug related effect.