TNFα From Classically Activated Macrophages Accentuates Epithelial to Mesenchymal Transition in Obliterative Bronchiolitis

Bronchiolitis obliterans syndrome is characterized by fibrotic obliteration of small airways which severely impairs graft function and survival after lung transplantation. Bronchial epithelial cells from the transplanted lung can undergo epithelial to mesenchymal transition and this can be accentuated by activated macrophages. Macrophages demonstrate significant plasticity and change phenotype in response to their microenvironment. In this study we aimed to identify secretory products from macrophages that might be therapeutic targets for limiting the inflammatory accentuation of epithelial to mesenchymal transition in bronchiolitis obliterans syndrome. TNFα, IL‐1β and IL‐8 are elevated in bronchoalveolar lavage from lung transplant patients prior to diagnosis of bronchiolitis obliterans syndrome. Classically activated macrophages secrete more TNFα and IL‐1β than alternatively activated macrophages and dramatically accentuate TGF‐β1‐driven epithelial to mesenchymal transition in bronchial epithelial cells isolated from lung transplant patients. Blocking TNFα, but not IL‐1β, inhibits the accentuation of epithelial to mesenchymal transition. In a pilot unblinded therapeutic intervention in five patients with progressive bronchiolitis obliterans syndrome, anti‐TNFα treatment improved forced expiratory volume in 1 second and 6‐min walk distances in four patients. Our data identify TNFα as a potential new therapeutic target in bronchiolitis obliterans syndrome deserving of a randomized placebo controlled clinical trial.     

Beta-blockers for the treatment of problematic hemangiomas

OBJECTIVE:

To examine treatment indications, efficacy and side effects of oral beta-blockers for the treatment of problematic hemangiomas.

METHODS:

A retrospective review of patients with hemangiomas presenting to the Alberta Children’s Hospital Vascular Birthmark Clinic (Calgary, Alberta) between 2009 and 2011 was conducted. The subset of patients treated with oral beta-blockers was further characterized, investigating indication for treatment, response to treatment, time to resolution of indication, duration of treatment, occurrence of rebound growth and side effects of therapy.

RESULTS:

Between 2009 and 2011, 311 new patients with hemangiomas were seen, of whom 105 were treated with oral beta-blockers. Forty-five patients completed beta-blocker treatment while the remainder continue to receive therapy. Indications for treatment were either functional concerns (68.6%) or disfigurement (31.4%). Functional concerns included ulceration (29.5%), periocular location with potential for visual interference (28.6%), airway interference (4.8%), PHACES syndrome (3.8%), auditory interference (0.95%) and visceral location with congestive heart failure (0.95%). The median age at beta-blocker initiation was 3.3 months; median duration of therapy was 10.6 months; and median maximal treatment dose was 1.5 mg/kg/day for propranolol and 1.6 mg/kg/day for atenolol. Ninety-nine patients (94.3%) responded to therapy with size reduction, colour changes, softened texture and/or healing of ulceration. Rebound growth requiring an additional course of therapy was observed in 23 patients. Side effects from beta-blockers included cool extremities (26.7%), irritability (17.1%), lower gastrointestinal upset (14.3%), emesis (11.4%), hypotension (10.5%), poor feeding (7.6%), lethargy (4.8%), bronchospasm (0.95%) and rash (0.95%). Side effects did not result in complete discontinuation of beta-blocker treatment in any case; however, they prompted a switch to a different beta-blocker preparation in some cases. Resolution of the primary indication, requiring a median time of three months, occurred in 87 individuals (82.9%).

CONCLUSIONS:

Treatment of infantile hemangiomas with oral beta-blocker therapy is highly effective and well tolerated, with more than 94% of patients demonstrating a response to treatment and 90% showing resolution of the primary functional indication for treatment.     

Nerve cross-sectional area in extremes of age

Introduction: Nerve cross-sectional area reference values have been reported for many nerves, but there have been few studies in pediatric and geriatric populations. This study was conducted to determine the influence of age on nerve cross-sectional area. Methods: Thirty-two children (3 months to 16 years) and 20 geriatric adults (67–92 years) without known neurologic conditions underwent bilateral ultrasound to measure the area of the following nerves: median at the wrist and forearm; ulnar at the wrist and elbow; radial in the spiral groove; sciatic in the distal thigh; fibular at the knee; tibial at the knee and ankle; and sural at the ankle. Results: In general, nerve cross-sectional area increased with age. Nerve size correlated most closely with age, but a correlation was also seen with body mass index. Conclusions: Nerve cross-sectional area increases with age, which is important to note when using ultrasound to evaluate children and geriatric patients. Muscle Nerve 47: 890–893, 2013     

Validity and reliability of nerve and muscle ultrasound

Introduction: Nerve and muscle ultrasound has been studied in several conditions, but validity and reliability have not been assessed systematically. Methods: Nerve cross‐sectional area and muscle thickness were measured ultrasonographically at several sites in 4 cadavers, which were then dissected, and actual measurements were obtained. To assess intrarater and interrater reliability, between 3 and 5 ultrasonographers, with varying experience levels, made repeated measurements on healthy volunteers. Results: Correlation coefficients for nerve and muscle validity were >0.968 (P < 0.001), and for intrarater reliability were >0.901 (P < 0.001) for still and real‐time images. Correlation coefficients for interrater reliability were more varied, but for still images they were all significant at the P < 0.001 (0.542–0.998) level, and for real‐time images they were significant at the P < 0.05 level for half the sites (0.243–0.981). Conclusion: Overall, nerve and muscle ultrasound is a valid and reliable diagnostic imaging technique. Muscle Nerve, 2013