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.

Difficult intubation and extubation in adult anaesthesia.

OBJECTIVE: To provide an update to French guidelines about "Difficult intubation and extubation in adult anaesthesia 2006". DESIGN: A consensus committee of 13 experts was convened. A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Few recommendations were ungraded. METHODS: The panel focused on 6 questions: 1) Why must oxygen desaturation be avoided during intubation and what preoxygenation and oxygenation techniques should be used to prevent it? 2) Should videolaryngoscopes be used instead of standard laryngoscopy with or without a long stylet to achieve a better success rate of intubation after the first attempt during anticipated difficult intubation off fiberoptic intubation? 3) Should TCI or target controlled inhalation anaesthesia (TCIA) be used instead of bolus sedation for airway control in the event of suspected or proven difficulty in a patient spontaneously breathing? 4) What mode of anaesthesia should be performed in patients with difficult intubation criteria and potentially difficult mask ventilation? 5) In surgical patients, what criteria predict difficulties encountered during postoperative tracheal extubation? 6) Should decision trees and algorithms be employed to direct decision-making for the management of difficult intubation, whether foreseen or not? (based on the information from the preceding five issues). Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. The analysis of the literature and the recommendations were then conducted according to the GRADE® methodology. RESULTS: The SFAR Guideline panel provided 13 statements on difficult intubation and extubation in adult anaesthesia. After two rounds of discussion and various amendments, a strong agreement was reached for 99% of recommendations. Of these recommendations, five have a high level of evidence (Grade 1±), 8 have a low level of evidence (Grade 2±). No recommendation was provided for one question. CONCLUSIONS: Substantial agreement exists among experts regarding many strong recommendations for the best care of patients with difficult intubation and extubation in adult anaesthesia.

Atrophic scar formation in patients with acne involves long-acting immune responses with plasma cells and alteration of sebaceous glands.

BACKGROUND: Possible outcomes of acne lesions are atrophic scars, which may cause serious psychological distress. Current treatments for postacne scarring often require invasive procedures. Pathophysiological studies on acne scarring have only investigated the first week of papule life. OBJECTIVES: To study the pathophysiology of atrophic scar formation to identify molecular and cellular pathways that can lead to new therapies for the prevention of acne scarring. METHODS: Large-scale gene expression profiling and immunohistochemistry analysis were performed on uninvolved skin and papules in both scar-prone (SP) and non-scar-prone (NSP) patients with acne, at different time points. RESULTS: Gene expression and immunohistochemistry analyses showed a very similar immune response in 48-h-old papules in SP and NSP populations, characterized by elevated numbers of T cells, neutrophils and macrophages. However, the immune response only persisted in SP patients in 3-week-old papules, and was characterized by an important B-cell infiltrate. Transient downmodulation of sebaceous gland markers related to lipid metabolism was observed in 48-h-old papules in NSP patients, followed by normalization after 3 weeks. In contrast, in SP patients a drastic reduction of these markers persisted in 3-week-old papules, suggesting an irreversible destruction of sebaceous gland structures after inflammatory remodelling in SP patients with acne. CONCLUSIONS: Long-lived acne papules are characterized by a B-cell infiltrate. A relationship exists between the duration and severity of inflammation and the alteration of sebaceous gland structures, leading to atrophic scar formation in acne.

Adapalene 0.1%/benzoyl peroxide 2.5% gel reduces the risk of atrophic scar formation in moderate inflammatory acne: a split-face randomized controlled trial.

BACKGROUND: The efficacy of current topical acne treatments in mitigating the potential for acne scarring is not known. OBJECTIVE: To evaluate the effect of adapalene 0.1%/benzoyl peroxide 2.5% (A/BPO) gel compared to vehicle in reducing the risk of acne scarring. METHODS: Multicentre, randomized, investigator-blinded, vehicle-controlled, split-face study conducted over 6 months. Subjects were adults with active moderate facial acne vulgaris and at least 10 atrophic acne scars at baseline. Efficacy evaluations included counts of atrophic acne scars and primary acne lesions as well as a Scar Global Assessment (SGA; 5-point scale). RESULTS: After 6 months treatment, scar counts remained stable with A/BPO while increasing by approximately 25% with vehicle (mean scar count 11.58 vs. 13.55, respectively, at Month 6; P = 0.036). The percentage of subjects with a SGA of 'almost clear' (hardly visible scars) increased from 9.7% to 45.2% with A/BPO, whereas it did not change with vehicle (P = 0.0032). Total acne lesion counts decreased by 65% with A/BPO and 36% with vehicle (mean lesion count 8.5 vs. 16.1, respectively, at Month 6; P < 0.001). LIMITATIONS: Relatively small study group (31 subjects). CONCLUSION: Topical long-term treatment with A/BPO is effective in reducing the risk of atrophic scars and improving the global severity of scarring.

An observational cross-sectional survey of rosacea: clinical associations and progression between subtypes.

BACKGROUND: Few studies have evaluated differences between rosacea subtypes in epidemiological associations and clinical features. The natural history of rosacea is unknown and progression between subtypes has been implied but not formally evaluated. OBJECTIVES: To assess associations between the four rosacea subtypes [erythematotelangiectatic (ETR), papulopustular (PPR), phymatous (PHY) and ocular], including quantitative and qualitative details on primary and secondary features of rosacea. A secondary objective was to evaluate for the potential of progression between subtypes. METHODS: This cross-sectional study recruited subjects with rosacea from Northern Germany and comprised clinical evaluation by a dermatologist and a survey of demographics and onset of rosacea-associated signs and symptoms. RESULTS: A total of 135 subjects with rosacea were enrolled. PHY was more frequently associated with PPR than ETR (P < 0·001). Compared with ETR, PPR was significantly associated with facial burning/stinging (P = 0·001), phymas (P < 0·001) and oedema (P < 0·001); and during flushing episodes, was more frequently associated with burning (P = 0·018), skin tension (P = 0·005) and itching (P = 0·027). ETR was more frequently associated with dry facial skin (P < 0·001). Flushing was reported by 66% and the site most frequently involved was the cheeks (100%). Papulopustules were evanescent in 42% and the sites most frequently involved were the cheeks (80%) and nose (67%). Of those fulfilling criteria for at least two subtypes, 66% developed ETR before PPR; 92% developed ETR before PHY; 83% developed PPR before PHY; and the majority developed cutaneous rosacea-associated features before ocular signs/symptoms. CONCLUSIONS: Significant differences exist between ETR and PPR in rosacea-associated features and in subtype associations. A small proportion of subjects with rosacea may progress between subtypes.

Endovascular treatment of aortic rupture by blunt chest trauma.

BACKGROUND: The usual treatment of blunt aortic injury (BAI) is prompt surgery. Frequently severe injuries to the brain or lungs exclude further surgical treatment. The purpose of this study is to assess the feasibility of placing endovascular stent-grafts. METHODS: From 1992 through 1999, in our primary and referral trauma center, 26 acute BAI, 21 males and 5 females, mean age 40.2+/-16.3 yrs were diagnosed. The last 4 patients underwent prospectively endovascular repair with Talent endograft. Endoprosthesis parameters were measured on three-dimensional spiral CT reconstruction. While waiting for devices, blood pressure was aggressively lowered and aortic lesions were monitored by transesophageal echography. RESULTS: Stent-graft deployment was successful in all 4 patients. There were no complications of endoleak, stent migration, paraplegia or death. Angiographic exclusion was complete in all 4 patients. CT scans at a mean follow-up of 11+/-5 months showed complete healing of the aortic wall in all patients. CONCLUSIONS: For stable acute BAI, endovascular stent-graft repair is feasible and safe, and is an effective therapeutic alternative to open surgery. Because of the normal proximal and distal wall in aortic injuries, endoluminal treatment might be the therapy of choice in the near future.

Anaesthesia for procedures in the intensive care unit.

Taking in charge severely ill patients in the intensive care environment to manage complex procedures is a performance requiring highly specific knowledge. Close collaboration between anaesthetists and intensive care specialists is likely to improve the safety and quality of medical care. Three forms of anaesthetic care should be considered in clinical practice: sedation and analgesia; monitored anaesthetic care; and general anaesthesia or conduction block anaesthesia. Even in the field of sedation and analgesia, the anaesthesiologist can offer expertise on new anaesthetic techniques like: the most recent concepts of balanced anaesthesia in terms of pharmacokinetics and dynamics, favouring the use of short-acting agents and of sedative-opioid combinations. New modes of administration and monitoring intravenous anaesthesia have been developed, with potential application in the intensive care unit. These include the use of target-controlled administration of intravenous drugs, and of electroencephalographic signals to monitor the level of sedation.

Peroxisome proliferator-activated receptor-alpha enhances lipid metabolism in a skin equivalent model.

Peroxisome proliferator-activated receptors are involved in certain cell types such as adipocytes and hepatocytes, in the control of several pathways of lipid synthesis or catabolism by regulating the gene expression level of key lipid metabolizing enzymes. As the epidermis exhibits an extensive lipid metabolism necessary for the establishment of the barrier function, we have examined the role of peroxisome proliferator-activated receptor-alpha activation in this process. Living skin equivalents were treated with Wy 14,643, a selective peroxisome proliferator- activated receptor-alpha ligand, which enhanced greatly the synthesis of membrane coating granules, the organelles specialized in the processing of stratum corneum lipids. Also, the overall stratum corneum neutral lipid content assessed by Oil red O staining was increased. A detailed analysis of the lipid species present in the reconstructed epidermis showed that peroxisome proliferator-activated receptor-alpha activation increased the synthesis of ceramides and cholesterol derivatives, thought to be essential structural components of the permeability barrier. A synergistic effect was observed on lipid synthesis when peroxisome proliferator-activated receptor-alpha and retinoid X receptor were simultaneously activated by selective ligands. Furthermore, activation of peroxisome proliferator-activated receptor-alpha led to increased mRNA expression of several key enzymes of ceramide and cholesterol metabolism. An increase of serine-palmitoyl transferase and of beta-glucocerebrosidase enzymatic activity was also demonstrated. Altogether, these results show that peroxisome proliferator-activated receptor-alpha is a key transcription factor involved in the control of the epidermal lipid barrier.

Placement of aortic endoprostheses.

Endovascular stent-grafting has found its place in the elective treatment of 60% of abdominal or thoracic aortic lesions. The morbidity and mortality rates are clearly lower than those of classical repair but the results are suboptimal with 9% residual endoleaks at 6 months. Anesthetic management with extensive monitoring even under local anesthesia remains mandatory and tends to reduce the postoperative care requirements. Future development will allow emergent endovascular treatment of ruptured aorta and further improvement will decrease the rate of late endoleaks.

Differential expression of peroxisome proliferator-activated receptor subtypes during the differentiation of human keratinocytes.

The expression of mRNA encoding peroxisome proliferator-activated receptor (PPAR) subtypes in human keratinocytes was determined by semiquantitative reverse transcriptase-polymerase chain reaction. When normal human keratinocytes were induced to differentiate by shifting the culture medium to high Ca2+ concentration, the expression of PPAR-alpha and -gamma mRNA was increased, whereas that of PPAR-delta remained unchanged. At the protein level, the expression of PPAR in cultured human keratinocytes was demonstrated by a DNA mobility shift assay and the functionality of the receptor subtypes was assessed by transactivation experiments. In epidermis reconstructed in vitro, the level of PPAR-alpha and -gamma mRNA was also associated with keratinocyte differentiation. In lesional compared with nonlesional psoriatic epidermis, the expression of PPAR-alpha and -gamma mRNA was reduced, indicating that these two subtypes are tightly linked to the epidermal differentiation process.

Midazolam-flumazenil vs. propofol in ambulatory ENT endoscopic procedures.

Two total intravenous anaesthesia techniques were compared in an open study of 80 ambulatory patients undergoing ENT endoscopic procedures randomly assigned to two groups: Group I midazolam-flumazenil n = 40, Group II propofol n = 40. The mean doses including induction were 0.75 +/- 0.31 mg kg-1 h-1 for midazolam and 171 +/- 64 micrograms kg-1 min-1 for propofol for 46.3 +/- 17.7 min and 50.3 +/- 24.8 min respectively. At the end of the procedure flumazenil 8.1 +/- 1.9 micrograms kg-1 was administered to Group I patients followed by a flumazenil continuous infusion at a minimal arousal rate (MAR) of 0.24 +/- 0.1 micrograms kg-1 min-1, and propofol discontinued in Group II patients. Baseline mean arterial pressure (MAP) and heart rate (HR) were similar in both groups and remained so during the procedure and recovery. In patients with cardiovascular disease, large variations (greater than or equal to 40% of baseline values) occurred more frequently in the propofol group whereas large variations in patients with no cardiovascular disease occurred more frequently in the midazolam group (P less than 0.05). Early recovery was more rapid after midazolam (P less than 0.05) whereas late criteria for recovery (maze and ambulation tests) were met more rapidly after propofol (P less than 0.05). It is concluded that with the midazolam-flumazenil sequence, early recovery is faster and haemodynamic stability better maintained in poor cardiovascular risk patients, whereas with propofol, street-fitness is more rapidly obtained, and haemodynamic stability better maintained in good risk patients.