[Interest and difficulties in setting up pharmaceutical reconciliations for patients with dressings for complex wounds]. / Intérêts et difficultés de mise en place de conciliations pharmaceutiques pour les patients porteurs de pansements pour plaies complexes.

OBJECTIVES: The management of wounds is a commonplace activity in a patient's healthcare pathway. The involvement of the pharmacist in the management of complex dressings can help strengthen the continuity of this care thanks to the pharmaceutical reconciliation. The objective of this study was to improve the quality of information transmitted between the city and the hospital regarding complex wound dressings. METHODS: This is a prospective study consisting of two groups in three services (medicine, diabetology, vascular surgery): the control group corresponded to a classic patient care and in the intervention group, the pharmacists performed dressing reconciliations. A follow-up of the patients after coming back home was realized with healthcare professionals of city involved. RESULTS: Twenty patients were included in the control group and 19 in the intervention group. Entry conciliation has improved the quality and quantity of information on wounds transmitted between the city and the hospital. Exit conciliation has increased from 60 to 100% wound and dressing output prescriptions. One hundred percent of nurses surveyed were satisfied with the patients care. CONCLUSIONS: Reconciliation would improve information transmitted between the city and the hospital and avoid a break in the continuity of complex wounds cares. However, the time dedicated and the adhesion of the care services were difficulties encountered. This study is the first highlighting the interest of medical device reconciliation and could allow reconciliation extension toward other medical devices.

Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.

BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.

Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation.

In cystic fibrosis (CF) patients, chronic airway infection by Pseudomonas leads to progressive lung destruction ultimately requiring lung transplantation (LT). Following LT, CF-adapted Pseudomonas strains, potentially originating from the sinuses, may seed the allograft leading to infections and reduced allograft survival. We investigated whether CF-adapted Pseudomonas populations invade the donor microbiota and adapt to the non-CF allograft. We collected sequential Pseudomonas isolates and airway samples from a CF-lung transplant recipient during two years, and followed the dynamics of the microbiota and Pseudomonas populations. We show that Pseudomonas invaded the host microbiota within three days post-LT, in association with a reduction in richness and diversity. A dominant mucoid and hypermutator mutL lineage was replaced after 11 days by non-mucoid strains. Despite antibiotic therapy, Pseudomonas dominated the allograft microbiota until day 95. We observed positive selection of pre-LT variants and the appearance of novel mutations. Phenotypic adaptation resulted in increased biofilm formation and swimming motility capacities. Pseudomonas was replaced after 95 days by a microbiota dominated by Actinobacillus. In conclusion, mucoid Pseudomonas adapted to the CF-lung remained able to invade the allograft. Selection of both pre-existing non-mucoid subpopulations and of novel phenotypic traits suggests rapid adaptation of Pseudomonas to the non-CF allograft.

Visceral leishmaniasis in a lung transplant recipient: usefulness of highly sensitive real-time polymerase chain reaction for preemptive diagnosis.

We report the case of a lung transplant recipient in whom the diagnosis of visceral leishmaniasis (VL) was made by detection of parasites in a peripheral blood smear when the parasite load already reached 8.9 × 103 parasites/mL. We demonstrated that the VL diagnosis could have been done months before the development of symptoms by the use of Leishmania-specific real-time polymerase chain reaction (PCR), suggesting the role of preemptive PCR-based diagnosis in transplant recipients at risk for VL.

Overview and expert assessment of off-label use of misoprostol in obstetrics and gynaecology: review and report by the Collège national des gynécologues obstétriciens français.

The literature suggests that misoprostol can be offered to patients for off-label use as it has reasonable efficacy, risk/benefit ratio, tolerance and patient satisfaction, according to the criteria for evidence-based medicine. Both the vaginal and sublingual routes are more effective than the oral route for first-trimester cervical dilatation. Vaginal misoprostol 800µg, repeated if necessary after 24 or 48h, is a possible alternative for management after early pregnancy failure. However, misoprostol has not been demonstrated to be useful for the evacuation of an incomplete miscarriage, except for cervical dilatation before vacuum aspiration. Oral mifepristone 200mg, followed 24-48h later by vaginal, sublingual or buccal misoprostol 800µg (followed 3-4h later, if necessary, by misoprostol 400µg) is a less efficacious but less aggressive alternative to vacuum aspiration for elective or medically-indicated first-trimester terminations; this alternative becomes increasingly less effective as gestational age increases. In the second trimester, vaginal misoprostol 800-2400µg in 24h, 24-48h after at least 200mg of mifepristone, is an alternative to surgery, sulprostone and gemeprost. Data for the third trimester are sparse. For women with an unripe cervix and an unscarred uterus, vaginal misoprostol 25µg every 3-6h is an alternative to prostaglandin E2 for cervical ripening at term for a live fetus. When oxytocin is unavailable, misoprostol can be used after delivery for prevention (sublingual misoprostol 600µg) and treatment (sublingual misoprostol 800µg) of postpartum haemorrhage. The use of misoprostol to promote cervical dilatation before diagnostic hysteroscopy or surgical procedures is beneficial for premenopausal women but not for postmenopausal women. Nonetheless, in view of the side effects of misoprostol, its use as a first-line treatment is not indicated, and it should be reserved for difficult cases. Misoprostol is not useful for placing or removing the types of intra-uterine devices used in Europe, regardless of parity.

[Lung volume reduction (LVR) in severe emphysema: a multidisciplinary approach]. / Réduction de volume pulmonaire dans l'emphysème sévère: importance d'une prise en charge multidisciplinaire.

Most cases of emphysema are managed conservatively. However, in severe symptomatic emphysema associated with hyperinflation, lung volume reduction (LVR) may be proposed to improve dyspnea, exercice capacity, pulmonary functions, walk distance and to decrease long-term mortality. LVR may be achieved either surgically (LVRS) or endoscopically (EVLR by valves or coils) according to specific clinical criteria. Currently, the optimal approach is discussed in a multidisciplinary setting. The latter permits a personalized evaluation the patient's clinical status and allows the best possible therapeutic intervention to be proposed to the patient.

Feasibility and acceptability of rapid HIV test screening (DEPIVIH) by French family physicians.

BACKGROUND: In France, around 50,000 people were unaware of their HIV positivity at the end of 2008. The latest guidelines recommend routine screening of all adults. Family physicians have been identified as key persons for this new policy. Rapid HIV tests (RHT) have been proposed as an alternative to conventional blood tests. OBJECTIVES: The authors assessed the feasibility and acceptability of RHT test based screening in French community practice. METHOD: We made a prospective interventional study of the BioMerieux VIKIA(®) HIV 1/2 RHT among French family physicians. Data on the RHT was posted in the physician's waiting room. RESULTS: Sixty-two French physicians, mostly family practitioners, included 383 patients with a mean age of 36.2 years, from June to October 2010. Twenty-two percent (83) of these patients had never been tested for HIV. The RHT was proposed and 382 tests were accepted and performed (acceptability rate of 99.7%). Sixty-five percent of the tests were made on the patient's request. The tested population represented 1.5% of consulting patients during the study period (feasibility rate). Patients were quite satisfied but physicians less so. Test steps and capillary blood sampling were the main source of difficulty mentioned. At the end of the study, 59% of physicians were ready to continue using RHT in their daily practice. CONCLUSION: Routine RHT screening in community practice is feasible and well accepted by patients. It was the first screening test for 22% of our patients. Its feasibility was limited by capillary blood sampling technique and time constraints during consultation.

[Benefits of using rapid HIV testing at the PMU-FLON walk-in clinic in Lausanne]. / Bénéfices de l'utilisation d'un test VIH rapide à la permanence PMU-FLON.

Lab tests are frequently used in primary care to guide patient care. This is particularly the case when a severe disorder, or one that will affect patients' initial care, needs to be excluded rapidly. At the PMU-FLON walk-in clinic the use of HIV testing as recommended by the Swiss Office of Public Health was hampered by the delay in obtaining test results. This led us to introduce rapid HIV testing which provides results within 30 minutes. Following the first 250 tests the authors discuss the results as well as the benefits of rapid HIV testing in an urban walk-in clinic.

A real-life study of the use, effectiveness and tolerability of rosiglitazone in France: the AVANCE study.

AIM: The study aimed to determine the effectiveness and tolerability of rosiglitazone, and its profile in terms of treatment adherence, treated patients and prescribing recommendations under everyday conditions of care. METHODS: This was a "real-life" observational longitudinal study including patients with type 2 diabetes mellitus (T2DM) starting treatment with rosiglitazone and followed for up to 2 years. A questionnaire was completed at the time of inclusion and during routine consultations at around 6, 12, 18 and 24 months following inclusion. Information was collected on sociodemographics, clinical history, treatments, co-morbidities, laboratory data and compliance with treatment. There were three primary outcome measures: treatment response (defined as an HbA1c ≤ 8.0% or a decrease in HbA1c ≥ 0.7%); switch to insulin (as considered necessary by the physician); and occurrence of adverse events requiring a change or discontinuation of treatment. RESULTS: The evaluation included 670 patients (61.1%) treated with rosiglitazone/metformin as fixed-dose combination tablets and 427 (38.9%) with standard rosiglitazone tablets. Rates of HbA1c response, defined as an HbA1c less than or equal to 8.0% or a decrease in HbA1c greater than or equal to 0.7%, ranged from 80.6% to 92.1% depending on the follow-up time. The percentage of patients with an HbA1c less than 7% was 18.4% before rosiglitazone was prescribed, and ranged from 48.2% to 57.8% depending on the follow-up period. Sixty-two patients (6.1%, 95% CI: 4.6-7.6%) switched to insulin therapy during the follow-up period. Spontaneously reported adverse events leading to a change or discontinuation of treatment were seen in 45 patients (4.4%, 95% CI: 3.2-5.6%). CONCLUSION: Rosiglitazone showed sustained efficacy, with around 90% of patients defined as responders to the treatment in terms of reduction in HbA1c, and was relatively well tolerated. The adverse-event profile was consistent with the known effects of rosiglitazone, and no signs of increased cardiovascular ischaemic risk were observed. These results are in agreement with previous studies on rosiglitazone.

Respiratory viruses in lung transplant recipients: a critical review and pooled analysis of clinical studies.

Lung transplant recipients present an increased risk for severe complications associated with respiratory infections. We conducted a review of the literature examining the clinical relationship between viral respiratory infection and graft complications. Thirty-four studies describing the clinical impact of influenza, respiratory syncytial virus, parainfluenza, human metapneumovirus, rhinovirus, enterovirus, coronavirus, bocavirus or adenovirus were identified. The detection rate of respiratory viral infection ranged from 1.4% to 60%. Viruses were detected five times more frequently when respiratory symptoms were present [odds ratio (OR) = 4.97; 95% CI = 2.11-11.68]. Based on available observations, we could not observe an association between respiratory viral infection and acute rejection (OR = 1.35; 95% CI = 0.41-4.43). We found a pooled incidence of 18% (9/50) of bronchiolitis obliterans syndrome (BOS) in virus-positive cases compared to 11.6% (37/319) in virus-negative cases; however, limited number of BOS events did not allow to confirm the association. Our review confirms a causal relationship between respiratory viruses and respiratory symptoms, but cannot confirm a link between respiratory viruses and acute lung rejection. This is related in part to the heterogeneity and limitations of available studies. The link with BOS needs also to be reassessed in appropriate prospective studies.

RETIDIAB®: assessment of a continuing medical education website for the improvement of diabetic retinopathy management.

AIM: The aim of this study was to evaluate the efficacy of a continuing medical education (CME) website to improve ophthalmological management of diabetic retinopathy (DR). METHODS: A worldwide website called RETIDIAB® was created in which, to log on for first time, users had to take a preliminary test to evaluate their baseline level of knowledge. This allowed them free access to the entire website at any time with no time obligation. The website comprised a course of theoretical concepts and different types of training, including multiple-choice questionnaires (MCQ) focused on the course content, interpretation of diabetic fundus photographs and case reports. After perusing the entire RETIDIAB® website, users could take a second assessment test. Finally, they were asked to fill in a questionnaire evaluating the entire programme. RESULTS: A total of 137 users were registered and, of these, 109 took only the preliminary test, while 28 took the second test and evaluated the entire website; of the latter, 75% were residents and 25% were practising physicians, and 15 were male and 13 were female, ranging in age from 26 to 42 (30.2 ± 3) years. Statistically significant progress was seen between the first and second evaluations (37.3 ± 14% correct answers vs 64 ± 10%, respectively), and the average time interval between the first and second evaluations was 40 ± 20 days. In addition, users expressed a high level of overall satisfaction with the site. CONCLUSION: This pilot study demonstrated the value and effectiveness of RETIDIAB®, a new CME website exclusively devoted to DR management.

Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients.

BACKGROUND: Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. METHODS: Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction-based assays. RESULTS: BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (P < .001). We observed a significant association between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (P = .012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20-0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. CONCLUSIONS: A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infection.

Terminal differentiation of goat mammary tissue during pregnancy requires the expression of genes involved in immune functions.

Terminal differentiation of mammary tissue into a functional epithelium that synthesizes and secretes milk occurs during pregnancy. The molecular mechanisms underlying this complex process are poorly understood, especially in ruminants. To obtain an overview of the ruminant mammary gland's final differentiation process, we conducted time-course gene expression analysis of five physiological stages: four during pregnancy (P46, P70, P90, and P110) and one after 40 days of lactation (L40). An appropriate loop experimental design was used to follow gene expression profiles. Using three nulliparous (pregnancy) or primiparous (lactation) goats per stage, we performed a comparison starting from nine dye-swaps and using a 22K bovine oligoarray. Statistical analysis revealed that the expression of 1,696 genes varied significantly at least once in the study. These genes fell into 19 clusters based on their expression profiles. Identification of biological functions with Ingenuity Pathway Analysis software revealed several similarities, in keeping with physiological stages described in mice. As in mice, expression of milk protein genes began at midpregnancy, and genes regulating lipid biosynthesis were induced at the onset of lactation. During the first half of pregnancy, the molecular signature of goat mammary tissue was characterized by the expression of genes associated with tissue remodeling and differentiation, while the second half was mainly characterized by the presence of messengers encoding genes involved in cell proliferation. A large number of immune-related genes were also induced, supporting recent speculation that mammary tissue has an original immune function, and the recruitment of migrating hematopoietic cells possibly involved in the branching morphogenesis of the mammary gland. These data hint that the induction of differentiation occurs early in pregnancy, very likely before P46. This period is therefore crucial for obtaining a healthy and productive mammary gland.

Case report: human herpesvirus 6 reactivation associated with colitis in a lung transplant recipient.

Whereas human herpesvirus 6 (HHV-6) reactivation is frequent in solid organ transplant recipients, symptomatic disease is rare. A case of colitis associated with HHV-6B reactivation was observed in a lung transplant recipient. This case report suggests that symptomatic HHV-6 infection may occur in the absence of detectable viremia.

Disposition of valganciclovir during continuous renal replacement therapy in two lung transplant recipients.

OBJECTIVES: To determine whether valganciclovir 450 mg every 48 h for cytomegalovirus (CMV) prophylaxis provides appropriate ganciclovir exposure in solid organ transplant recipients during continuous renal replacement therapy (CRRT). PATIENTS AND METHODS: Ganciclovir pharmacokinetics was intensively studied in two lung transplant recipients under valganciclovir 450 mg every 48 h over one dosing interval. In vitro experiments using blank whole blood spiked with ganciclovir further investigated exchanges between plasma and erythrocytes. RESULTS: Ganciclovir disposition was characterized by apparent total body clearance of 3.3 and 5.8 L/h, terminal half-life of 16.9 and 14.1 h, and apparent volume of distribution of 60.3 and 104.9 L in Patients 1 and 2, respectively. The observed sieving coefficient was 1.05 and 0.96, and the haemofiltration clearance was 3.3 and 3.1 L/h. In vitro experiments confirmed rapid efflux of ganciclovir from red blood cells into plasma, increasing the apparent efficacy of haemofiltration. CONCLUSIONS: A valganciclovir dosage of 450 mg every 48 h appears adequate for patients under CRRT requiring prophylaxis for CMV infection, providing concentration levels in the range reported for 900 mg once daily dosing outside renal failure.

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells.

MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4alpha, and a membrane-bound growth factor-like subunit, MUC4beta. MUC4 mRNA contains unique 5' and 3' coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7-19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer. To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is comparable with that of wild-type MUC4 (930 kDa) but represents only 10% of VNTR. Stable ectopic expression of mini-MUC4 in two human pancreatic cancer cell lines, Panc1 and MiaPaCa, showed that MUC4 minigene expression follows a biosynthesis and localisation pattern similar to the wild-type MUC4. Expression of MUC4 resulted in increased growth, motility, and invasiveness of the pancreatic cancer cells in vitro. Ultra-structural examination of MUC4-transfected cells showed the presence of increased number and size of mitochondria. The MUC4-expressing cells also demonstrated an enhanced tumorigenicity in an orthotopic xenograft nude mice model, further supporting a direct role of MUC4 in inducing the cancer properties. In conclusion, our results suggest that MUC4 promotes tumorigenicity and is directly involved in growth and survival of the cancer cells.

Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells.

The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre- and post-confluent cells were treated with demethylating agent 5-aza-2'-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms.

MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell density-dependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.