Methotrexate efficacy and tolerance in plaque psoriasis. A prospective real-life multicentre study in France.

BACKGROUND: Methotrexate (MTX) is a major systemic treatment for moderate to severe plaque psoriasis. A randomized trial has recently been published evaluating a single weekly dosage (17.5mg), but few prospective real-life data are available. The main objective of this study was to prospectively evaluate the efficacy of MTX in real-life. The secondary objectives were to evaluate predictive parameters for treatment efficacy and the frequency of adverse events. PATIENTS AND METHODS: A prospective cohort involving consecutive at in 25 centres belonging to GEM RESOPSO included all adults with plaque psoriasis in whom MTX treatment was initiated. The efficacy criterion was achievement of PASI 75 at week (W) 12/16. The impact of demographic data, psoriasis characteristics (duration, topography, rheumatism), dosage (W12/16 dosage, cumulative dose after 4 weeks), and mode of administration (subcutaneous vs. oral, concomitant use of folic acid) on efficacy was evaluated. Intention-to-treat (ITT),per protocol (PP), and multivariate analyses were performed. RESULTS: Two hundred and fifty-six patients (F/M: 105/151; mean age: 45.0 years; rheumatism: 12.6%) with plaque psoriasis were included. 99 patients were not analysed at W12/16 (16 because of inefficacy, 16 because of intolerance, 56 were lost to follow-up or had data missing). PASI 75 was achieved in 98 patients, with efficacy of 38.3% in the ITT analysis and 58.3% in the PP analysis. In the ITT analysis, absence of previous use of cyclosporine (P=0.01) and a cumulative dose of MTX>60mg after 4 weeks (P<0.0001) were associated with higher PASI 75 rates. In the PP analysis, only absence of previous use of cyclosporine (P=0.0009) was associated with a better PASI 75 results. There was no association between PASI 75 and patient characteristics (including body mass index), clinical aspects of psoriasis, route of administration, combination with folic acid, or W12/16 dose. Adverse events were reported by 34.8% of patients. These consisted mainly of digestive disorders (nausea, abdominal pain), asthenia and moderate hepatic cytolysis. The frequency of adverse events was correlated with methotrexate dosage. DISCUSSION: The efficacy of MTX in plaque psoriasis in this real-life study of 256 patients is consistent with the data in the literature, including the recently published randomized trial (41% PASI 75). This rate was unaffected by patient weight, route of administration and combined use of folic acid. Absence of previous use of cyclosporine appears to be associated with better efficacy although there is no clear explanation for this. The initial dosage (high dose in the first month) appears to be associated with superior efficacy for W12/W16.

Serological evidence for the circulation of flaviviruses in seabird populations of the western Indian Ocean.

Birds play a central role in the epidemiology of several flaviviruses of concern for public and veterinary health. Seabirds represent the most abundant and widespread avifauna in the western Indian Ocean and may play an important role as host reservoirs and spreaders of arthropod-borne pathogens such as flaviviruses. We report the results of a serological investigation based on blood samples collected from nine seabird species from seven islands in the Indian Ocean. Using a commercial competitive enzyme-linked immunosorbent assay directed against the prototypic West Nile flavivirus, antibodies against flaviviruses were detected in the serum of 47 of the 855 seabirds tested. They were detected in bird samples from three islands and from four bird species. Seroneutralization tests on adults and chicks suggested that great frigatebirds (Fregata minor) from Europa were infected by West Nile virus during their non-breeding period, and that Usutu virus probably circulated within bird colonies on Tromelin and on Juan de Nova. Real-time polymerase chain reactions performed on bird blood samples did not yield positive results precluding the genetic characterization of flavivirus using RNA sequencing. Our findings stress the need to further investigate flavivirus infections in arthropod vectors present in seabird colonies.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose fingolimod (FTY720) in adolescents with stable renal transplants.

Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 ± 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 ± 240 ng·h/mL and C(max) of 3.6 ± 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups.

Identifying drivers of fox and cat faecal deposits in kitchen gardens in order to evaluate measures for reducing contamination of fresh fruit and vegetables.

Preventing foodborne pathogen contamination of raw fruit and vegetables in the field is critically important for public health. Specifically, it involves preventing faecal deposit by wildlife or domestic animals in fields of crops and kitchen gardens. The present study aims to identify the drivers of fox, dog and cat faecal deposits in kitchen gardens in order to mitigate the risk of contamination of raw produce with parasites shed in carnivore faeces. The focus was on Echinococcus multilocularis, ranked highest in the importance of foodborne parasites in Europe, but attention was also paid to other parasites of major concern - Toxoplasma gondii and Toxocara spp. During the winters of 2014 to 2016, faecal samples were collected from 192 kitchen gardens located in north-eastern France. From these samples, 77% contained scat of carnivores. Molecular analyses revealed that 59% of the 1016 faeces collected were from cats, 31% from foxes, and 10% from dogs. The ease of accessibility to kitchen gardens, the presence of food in the vicinity, and the composition of the surrounding vegetation were used to explain the distribution of fox and cat faeces. Generalized Linear Mixed Effects modelling showed that: i) fencing was not efficient in reducing cat faecal deposits, but drastically decreases those of foxes; ii) the abundance of Microtus sp. indicates a reason for the presence of both fox and cat faecal deposits, iii) the abundance of Arvicola terrestris, the proximity of fruit trees or farms and the predominance of forest and grassland around the village are all drivers of fox faecal deposits. These results point to the importance of fencing around kitchen gardens located in E. multilocularis endemic areas, particularly those surrounded by forest and grassland or close to fruit trees or farms.

Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an effective immunosuppressive treatment in renal transplant recipients but is known to have gastrointestinal side effects. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) is a new formulation for delivering MPA. This open-label, two-period, cross-over study was carried out to characterize the time course of MPA and its metabolites, mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucuronide (AcMPAG) in stable renal transplant patients (n = 40) after 28-day chronic dosing with EC-MPS (720 mg bid) or MMF (1000 mg bid). The relative abundance and exposure of all three compounds was also assessed. EC-MPS demonstrated the typical pharmacokinetic profile of an enteric-coated formulation with a delayed release of MPA compared with MMF (Tmax 2.5 versus 1.0 hours, respectively). Consistent with a similar disposition of MPA, both EC-MPS and MMF treatments resulted in the same ratio of MPAG to MPA exposure, 23:1. Furthermore, comparison of the AUC of MPAG and AcMPAG for both treatments indicated that steady state MPAG exposure was 75 to 90 times that of AcMPAG, confirming MPAG as the predominant metabolite of MPA. AcMPAG has been identified as a possible active metabolite of MPA; the present study indicates that AcMPAG may contribute around 14% of the exposure to active drug after administration of MPA. Both EC-MPS and MMF treatments were well tolerated over the 1-month period of chronic treatment. In summary, consistent with its enteric-coated design, EC-MPS delays delivery of MPA, but results in similar exposure to that provided by MMF.

Prevention of hepatitis B.

Hepatitis B is now the most commonly reported hepatitis in the United States and the physician's greatest infectious occupational hazard. Although dermatologists are at increased risk for contracting and transmitting hepatitis B virus, surveys continue to indicate that a substantial number do little to decrease this risk. We have summarized the recent developments regarding the transmission, diagnosis, and clinical presentation and course of hepatitis B virus infection, and have offered specific preventive measures to assist the dermatologist in keeping hepatitis B out of his medical practice. By employing these measures, dermatologists can do their part in contributing to the future eradication of this disease.

[Ketoprofen-induced contact photosensitivity disorders: 5 cases]. / Photosensibilisation de contract au kketoproféne. 5 Observations.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAID) are widely used in topical applications for benign diseases. Adverse skin reactions include contact eczema and photocontact dermatitis. Among the NSAID used in topical applications, arylpropionic derivatives, notably ketoprofen, are frequently implicated. CASE REPORTS: We observed 5 patients who developed eczema lesions after application of Ketum, a gel containing ketoprofen used on healthy skin after exposure to sunlight. Photoallergy explorations evidenced positive photopatch-tests for ketoprofen with UVA and total light. The anamnesis suggested a photoallergic mechanism which was confirmed by histological examination of the biopsy of a UVA positive photopatch-test and by negative photopatch-tests in 10 healthy controls. DISCUSSION: The photosensitizing potential of ketoprofen in the UVA spectrum is well known. Although the number of adverse reactions is quite small compared with widespread use, physicians should be aware of this photosensitivity and report all cases to the pharmacovigilance center.

[Cutaneous Scedosporium infection revealed by bullous-necrotic purpura]. / Scédosporiose cutanée révélée par un purpura bullo-nécrotique.

BACKGROUND: Non-mycetomatous cutaneous scedosprium is an uncommon mycosis observed in immunodepressed subjects. We report a case with an inaugural presentation of bullous and necrotic purpura. CASE REPORT: A 79-year-old man on intermittent corticosteroid therapy for bronchospasm was admitted for bullous and necrotic purpura and fever. Subcutaneous nodules with a sporotrichoid aspect developed despite wide-spectrum antibiotics. Microbiology samples cultured on Sabouraud medium evidenced Scedosporium apiospermum. The pathogenic nature of the infection was proven on a skin biopsy showing numerous myceleal filaments with Gomori-Grocott staining despite negative PAS. No pulmonary involvement was evidenced. The patient was treated unsuccessfully with itraconazole. A Pseudomonas lung infection was fatal. DISCUSSION: Scedosporium apiospermum, an ubiquitous ascomycetes anamorphous to Pseudallescheria boydii, is the cause of a growing number of human infections due to widespread use of immunosuppressors. Skin and lung localizations predominate. The inaugural bullous and necrotic purpural skin manifestations in this case are unusual. In addition, the patient was only minimally immunodepressed and despite demonstrated in vitro sensitivity, itraconazole was ineffective clinically. Treatment is not well defined, but surgery is essential in combination with empirically chosen antifungals.

[Family ecology, social networks and suicidal behavior in the school milieu]. / Ecologie de la famille, réseau social et comportements suicidaires en milieu scolaire.

This article sums up the outcome of a research project conducted in Montreal schools in 1987 and 1988, and focusing on how family ecology and social networks relate to strong suicidal tendencies among teenagers. Two groups were involved in the study: one with 78 suicidal persons, the other with 72 non-suicidal persons. Teenagers in each group were interviewed separately. All subjects reported high lack of attention from at least one of the two parents. Results also show that parents of suicidal teens experience permanent break-ups less frequently in comparison to the other group. However, families of suicidal teens tend to experience deeper changes in the structure of the family unit following an initial separation. With respect to moving, there are no significant differences, whether in the number of moves or the important people, have access to as many different kinds of support and report the same number of conflicts. In all these comparisons, however, suicidal teenagers do name a proportionately higher number of adults. This leads the authors to hypothesize that a higher rate of parental separation among non-suicidal teens could represent a protective factor rather than a vulnerability factor, as is usually suggested. In terms of social networks, the fact that suicidal teens seek out adults to a greater degree could impede on their socializing with peers and, therefore, on their social integration.

[Family structure, parent-child relationships and suicidal behavior in high-school.]. / Structure familiale, relations parents-enfants et conduites suicidaires à l'école secondaire.

A study made on a sample of 2,327 Montréal area students of third, fourth and fifth year of High School shows that suicidal behaviors ("les suicidaires") account for 13.2 % of youth interrogated, and that 6.7 % admit to having attempted suicide. The suicidal behavior rate is higher among girls than boys and it is lower in schools where the proportion of allophones is over 50 %. The separation of parents and the father's negligence are factors that contribute to raising the rate of suicidal behavior. However, a deceased father or mother has no effect on the rate. The rate of suicidal behavior is at its highest when there is a substitute parent. A relation exists, however, between a father's level of scolarity and the family structure. When students come from an unbroken home, there are fewer suicidal subjects when the father has a high rather than a low level of scolarity ; this difference disappears when the family is separated. However, the authors have noticed a greater rate of separation among parents with a higher level of scolarity. As for the higher rate of suicidal behaviors among girls, it is not entirely connected to poor parent-child relations. The data suggest to the authors that parent conflicts could possibly perturb girls more than boys. And finally, although serious health problems are associated to a higher rate of suicidal behavior, this link is relatively indépendant of the quality of parent-child relations.

[Comparative study of school integration of suicidal adolescents and of non-suicidal victims of parents' neglect]. / Etude comparative de l'intégration scolaire chez des adolescents suicidaires et non suicidaires victimes de carence d'attention parentale.

This research analyzes school integration of a sample of 150 adolescents lacking parental attention. A group of 78 suicidal students is compared to a group of 72 non-suicidals. Students are 14 to 17 years old and are recruited in six schools of the Montreal region. Suicidal adolescents do not experience more problems of discipline, absenteeism, academic performance or relationship with their peers than non suicidal adolescents. However they appear less motivated in school than non suicidal adolescents being more frequently late in class. They also participate less in extracurricular activities offered by the school and experience more conflicts with the school's adults than non-suicidals. Moreover, suicidal adolescents have more characteristics related to dropping out than non suicidals. Finally, the differences observed regarding school integration highlight some signs of vulnerability associated with suicidal behaviour during adolescence when they lack parental attention.

Characterization of cytochrome P450 2E1 activity by the [14C]nitrosodimethylamine breath test.

The objective of this study was to measure the rate of demethylation of nitrosodimethylamine in vivo in the rat and determine its value to assess CYP2E1 activity in intact animals. Nitrosodimethylamine labeled with 14C on both methyl groups was administered to rats and exhaled 14CO2 was collected during 2-3 h. The nitrosodimethylamine breath test was increased by inducers of CYP2E1, such as ethanol (+139%) and 4-methylpyrazole (+115%), and decreased by the inhibitor diallyl sulfide (-53%). In addition, the nitrosodimethylamine breath test was not changed significantly by inducers specific for other cytochrome P450 such as beta-naphthoflavone, dexamethasone, and phenobarbital. The specificity of the induction by 4-methylpyrazole and of the inhibition by diallyl sulfide for CYP2E1 was determined using the [14C]caffeine (CYP1A2), [14C]aminopyrine (CYP2C11), and [14C]erythromycin (CYP3A2) breath tests. 4-Methylpyrazole treatment caused a small increase of the caffeine (+33%) and aminopyrine (+9%) breath tests and no change of the erythromycin breath test. Diallyl sulfide treatment led to a small decrease of the caffeine breath test (-33%) and of the aminopyrine breath test (-13%) but a 23% increase of the erythromycin breath test. It is concluded that the [14C]nitrosodimethylamine breath test is useful to assess CYP2E1 activity in vivo in the rat.

Suicidal attempts and ideations among adolescents and young adults: the contribution of the father's and mother's care and of parental separation.

Parental care was analyzed separately with the PBI for both father and mother or their surrogate to assess its association with suicidal behavior (attempt or serious ideation). The study was conducted on two French-speaking samples from Montreal: the first included 2,327 high school students and the second 701 young adults (18 to 24) reached by phone. Results showed poor care of father to be highly associated with suicidal behavior in the highschool group. Poor care of the mother and parental divorce obtained a lower association. In the second sample, only poor care of the father was significantly associated with suicidal behavior. The conclusion is that more attention should be focused on the father and that parental divorce may have a short-term effect but not a lasting influence when poor care is absent.

Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis.

Liver diseases are associated with a decrease in hepatic drug elimination, but there is evidence that cirrhosis does not result in uniform changes of cytochrome P450 (CYP) isoenzymes. The objective of this study was to determine the content and activity of four CYP isoenzymes in the bile duct ligation and carbon tetrachloride (CCl4)-induced models of cirrhosis. The hepatic content of CYP1A, CYP2C, CYP2E1, and CYP3A was measured by Western blot analysis. CYP activity in vivo was evaluated with breath tests using substrates specific for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), nitrosodimethylamine (CYP2E1), and erythromycin (CYP3A). Bile duct ligation resulted in biliary cirrhosis; CYP1A, CYP2C and CYP3A content was decreased and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas CYP2E1 content and the nitrosodimethylamine breath test were unchanged compared with controls. CCl4 treatment resulted in cirrhosis of varying severity as assessed from the decrease in liver weight and serum albumin. In rats with mild cirrhosis, CYP content was comparable with controls except for a decrease in CYP2C. The activity of CYPs was also unchanged except for an increase in CYP2E1 activity. In rats with more severe cirrhosis, the content of all four CYP isoenzymes and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas the nitrosodimethylamine breath test was unchanged. In both models of cirrhosis, there was a significant correlation between the breath tests results and the severity of cirrhosis as assessed from serum albumin levels. These results indicate that content and the catalytic activity of individual CYP enzymes are differentially altered by cirrhosis in the rat and also suggest that drug probes could be useful to assess hepatic functional reserve.