The efficacy and safety of topical rapamycin-calcitriol for facial angiofibromas in patients with tuberous sclerosis complex: a prospective, double-blind, randomized clinical trial.

BACKGROUND: The efficacy of topical rapamycin is well documented for tuberous sclerosis complex (TSC)-related facial angiofibromas (FAs). Calcitriol has been shown to lessen skin fibrosis and may be therapeutically beneficial to FAs. OBJECTIVES: To evaluate whether topical rapamycin-calcitriol combination is an effective and safe treatment for TSC-related FAs. METHODS: Fifty-two patients with TSC with FAs were enrolled in this prospective study including three 12-week periods. In period 1, either topical rapamycin 0·1% or calcitriol 0·0003% single-agent therapy vs. their combination was applied in a double-blind, left-right-randomized, split-face comparison. The primary outcome was the reduction of modified Facial Angiofibroma Severity Index (mFASI) at week 12. In period 2, the patients were reassigned to use on both cheeks the ointment that resulted in the better primary outcome in period 1. The treatment was discontinued in period 3 (week 25-36) and a follow-up mFASI was scored to evaluate the degree of recurrence. RESULTS: The mean changes in mFASI at week 12 compared with baseline were -0·92, -0·44 and -1·09 for rapamycin (P ≤ 0·001), calcitriol (P = 0·039) and rapamycin-calcitriol combination (P ≤ 0·001), respectively. Although rapamycin-calcitriol combination and rapamycin had similar statistically significant decreases of mFASI at week 12, rapamycin-calcitriol combination resulted in faster improvement in erythema, greater reduction of papule elevation and longer durability after discontinuing treatment than rapamycin alone. The treatments were well tolerated. CONCLUSIONS: This randomized clinical trial demonstrates that topical rapamycin-calcitriol combination therapy is an effective and safe regimen for TSC-related FAs. What is already known about this topic? Facial angiofibromas (FAs) cause substantial psychological distress in individuals with tuberous sclerosis complex (TSC), but invasive procedural treatments are not applicable to all patients. Topical rapamycin has been demonstrated as an effective and safe treatment regimen for TSC-related FAs. What does this study add? Compared with baseline (day 0), both topical rapamycin 0·1% and rapamycin 0·1%-calcitriol 0·0003% combination ointment achieved statistically significant reductions in modified Facial Angiofibroma Severity Index at week 12. Compared with rapamycin alone, extended use of the rapamycin-calcitriol combination regimen until week 24 showed more effectiveness in decreasing papule elevation and could maintain a longer therapeutic effect after treatment discontinuation. Linked Comment: Lee. Br J Dermatol 2020; 183:604-606.

Biomechanical study on different lengths of PFNA fixation for unstable intertrochanteric femoral fractures.

OBJECTIVE: The aim of our study was to compare the biomechanical stability of the Proximal Femoral Nail Antirotation (PFNA) (with 200 mm, 240 mm and 280 mm-long main nails) for the management of unstable intertrochanteric femoral fractures. METHODS: Tronzo-Evans Type IV and V fractures were built by applying a three-dimensional finite element model. Further, PFNA-II with 200 mm, 240 mm and 280 mm-long main nails were applied for fixation. The above model is the creation of 3 researchers designed in order to obtain average values of numerical stress. Von Mises stress distribution and medial and lateral stress peak of the femur and PFNA were compared. RESULTS: 240 mm and 280 mm PFNA medial stress peak was reduced significantly in comparison to 200 mm PFNA (p⟨0.05). However, there was no difference between 240 mm and 280 mm PFN. Also, no statistical difference was observed with any of 3 lengths in both medial and lateral stress peak for Evans Type IV and V PFNA. CONCLUSION: 240 mm and 280 mm PFNA could reduce femur fixation medial stress peak. Further, they were more efficient in comparison to the 200 mm PFNA, and their biomechanical stability was similar to that of the 280 mm nail.

[Uncommon acne-associated syndromes and their significance in understanding the pathogenesis of acne]. / Seltene Akne-assoziierte Syndrome und deren Bedeutung für das Verständnis der Pathogenese der Akne.

Acne is an intriguing model for the study of interactions between hormones, innate immunity, inflammation and wound healing (scarring). The manifestations and involvement of acne in different systemic diseases and some rare syndromes demonstrate its multifaceted nature. Synovitis-Acne-Pustulosis-Hyperostosis-Osteitis (SAPHO) and Pyogenic Arthritis-Pyoderma gangrenosum-Acne (PAPA) syndromes, both regarded as autoinflammatory diseases, highlight the attributes of inflammation in acne. While SAPHO syndrome can be used to explore the pathogenic role of Propionibacterium acnes in acne, PAPA syndrome and Apert syndrome can help understand the genetic influence on acne. The genetic defects in the gain-of-function of FGFR2 mutations in Apert syndrome and acne nevus of Munro lend further support to the hypothesis that the interaction of forkhead box class O (FoxOs)-mediated transcriptional regulation with androgen receptor transactivation and insulin/insulin like growth factor-1(IGF-1)-signaling is crucial in acne pathogenesis. Novel biologics, such as tumor necrosis factor (TNF) blockers and IL-1 inhibitors, appear promising in opposing the inflammation associated with SAPHO and PAPA syndromes, but it remains to seen if they can also improve severe acne particularly in the long term.

Acne-associated syndromes: models for better understanding of acne pathogenesis.

Acne, one of the most common skin disorders, is also a cardinal component of many systemic diseases or syndromes. Their association illustrates the nature of these diseases and is indicative of the pathogenesis of acne. Congenital adrenal hyperplasia (CAH) and seborrhoea-acne-hirsutism-androgenetic alopecia (SAHA) syndrome highlight the role of androgen steroids, while polycystic ovary (PCO) and hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndromes indicate insulin resistance in acne. Apert syndrome with increased fibroblast growth factor receptor 2 (FGFR2) signalling results in follicular hyperkeratinization and sebaceous gland hypertrophy in acne. Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) and pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndromes highlight the attributes of inflammation to acne formation. Advances in the understanding of the manifestation and molecular mechanisms of these syndromes will help to clarify acne pathogenesis and develop novel therapeutic modalities.

Direct observation of dispersive Kondo resonance peaks in a heavy-fermion system.

Ce 4d-4f resonant angle-resolved photoemission spectroscopy was carried out to study the electronic structure of strongly correlated Ce 4f electrons in a quasi-two-dimensional nonmagnetic heavy-fermion system CeCoGe1.2Si0.8. For the first time, dispersive coherent peaks of an f state crossing the Fermi level, the so-called Kondo resonance, are directly observed together with the hybridized conduction band. Moreover, the experimental band dispersion is quantitatively in good agreement with a simple hybridization-band picture based on the periodic Anderson model. The obtained physical quantities, i.e., coherent temperature, Kondo temperature, and mass enhancement, are comparable to the results of thermodynamic measurements. These results manifest an itinerant nature of Ce 4f electrons in heavy-fermion systems and clarify their microscopic hybridization mechanism.

Force assessment of the stimulated arm flexors: quantification of contractile properties.

The primary objective was to develop equipment and evaluate protocols for non-invasive assessment of contractile properties of human arm flexors. The research design consisted of a non-randomized control trial, with repeated measures. Data from six males and two females were gathered in a clinical research laboratory. The elbow flexor torque following motor point or direct nerve stimulation was measured in response to single pulses or short trains of electrical pulses. Length--tension relationships were determined; comparative data were obtained at the identified optimal muscle lengths. Twitch waveforms and peak torques following either type of stimulation were reproducible (within 10%). Peak torques following a 4-pulse small interpulse interval stimulation were nearly identical for motor-point activation and direct nerve stimulation (15.2+/- 6.6Nm for motor point stimulation; 14.5 +/- 6.6Nm for nerve stimulation). Average perceived pain indexes associated with 4-pulse stimuli were slightly higher following nerve stimulation (782 for nerve versus 6.23 for motor-point, n=8). A reliable methodology (motor-point stimulation) has been identified to perform stimulated force assessment of human arm flexors.

C-H and C-C bond activation of primary amines through dehydrogenation and transimination.

[structure: see text]. Dehydrogenation and subsequent transimination of primary amines offer a new pathway for C-H bond activation, ortho-alkylation, and C-C bond activation to afford a variety of ketones in the reaction of 1-alkene by a cocatalyt system of Rh(I) and 2-amino-3-picoline.