Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

Background and purpose:

The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK₁) receptor. We investigated whether ECE-1 regulates NK₁ receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium.

Experimental approach:

We examined ECE-1 expression, SP trafficking and NK₁ receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats.

Key results:

HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca²⁺ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK₁ receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization.

Conclusions and implications:

By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK₁ receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.     

Development of a femoral non-union model in the mouse

OBJECTIVES: Advancements in our knowledge of fracture healing have occurred in large part by the understanding of this process on a microscopic level. The ability to develop experimental non-union models in animals will assist in the investigation of this problem and are likely to lead to novel treatments. We report on a technique for developing experimental non-unions in mice. METHODS: Femoral fractures were created in 48 CD1 mice, 24 mice underwent standard closed femoral fractures, and 24 mice underwent creation of a femoral non-union through an open osteotomy and fracture devascularisation method. All fractures were subsequently rodded. Histological examinations of the fractures were then conducted at eight time points post-operatively. RESULTS: The control group showed normal fracture healing with histological evidence of bony fracture bridging by 28 days and mature bony remodelling at 63 days. The non-union group showed delayed fracture healing at all time points and no evidence of bony healing at 63 days. CONCLUSION: This is the first report of a reliable method to develop fracture non-union in mice. We believe this technique will be critical to further the investigation of fracture non-union in normal mice and provides the great advantage of using the plethora of transgenic and knockout mouse models to analyse non-union at the cell and molecular level.     

Body mass, fat distribution and blood pressure in Southern Italian children: results of the ARCA project

OBJECTIVE: To investigate the association between the degree of adiposity, assessed using the international reference values for body mass index (BMI) of the International Obesity Task Force (IOTF), the fat distribution pattern and the blood pressure (BP) profile in children. METHODS: Anthropometric indices and blood pressure were measured in 3923 children aged 6-11 years in southern Italy. RESULTS: The prevalence of overweight and obesity (by IOTF references) and pediatric hypertension was, respectively: 27, 21 and 10% for boys; 25, 21 and 14% for girls. Body mass index and waist z-scores were the strongest determinants of BP by regression analysis. Overweight and obesity were associated with a greater tendency for central fat deposition and higher BP (waist, cm; boys: 59.2+/-6.0, 69.5+/-7.9, 79.0+/-9.7; girls: 58.8+/-6.5, 68.2+/-7.4, 75.3+/-8.9; SBP/DBP, mmHg; boys: 94/60+/-12/9, 99/62+/-13/8, 103/64+/-15/10; girls: 93/59+/-12/9, 99/62+/-14/9, 101/63+/-14/9; normal weight, overweight and obese, respectively; P<0.0001; M+/-SD), and a higher risk of hypertension (overweight: RR=2.33; 95% CI 1.76-3.08; obesity: RR=3.69; 95% CI 2.78-4.90), independent of age, physical activity, birth weight, parental adiposity and education. Among normal weight children, 99% had waist <85th percentile and 93% were normotensive. CONCLUSIONS: Overweight and obese children, identified according to the IOTF growth charts, are characterized by a central fat distribution pattern and higher BP.     

Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors

High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with ‘high’ or ‘low’ HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.     

Infliximab efficacy in nail psoriasis. A retrospective study in 48 patients

Background Nail psoriasis occurs in up to half of psoriatic patients and can lead to significant physical impairment and pain. To date, patients and clinicians are actually dissatisfied by current therapeutic approaches. Objective Our main aim is to evaluate Infliximab efficacy in nail psoriasis. Methods We performed an open‐label and uncontrolled retrospective study considering all psoriatic patients presenting recalcitrant nail involvement and receiving Infliximab in our Department during the period between January 2008 and March 2009. We calculated nail psoriasis severity index (NAPSI) score at 0, 14, 22 and 38 weeks and percentage of patients achieving NAPSI‐50,‐75,‐90 at 14, 22 and 38 weeks. Results We observed a rapid nail improvement in most cases after 22 weeks of Infliximab therapy, but a complete nail clearing was reached in only five (10.4%) patients. We don’t have a follow‐up longer than 38 weeks to assess long‐term efficacy of this treatment in nail psoriasis. Conclusions Infliximab, in our experience, has proved to be effective in reducing nail lesions and, in some cases, even clearing them. Our data demonstrate long‐term efficacy of this biological agent in nail psoriasis.     

Unicornuate uterus with a rudimentary horn and ovarian dysgerminoma. A case report

BACKGROUND: Several documented cases of endometrial and cervical carcinoma arising in unicornuate uteri have been described; however, ovarian malignancy occurring in conjunction with this müllerian anomaly has not been reported. CASE: An 18-year-old woman had a unicornuate uterus, noncommunicating rudimentary horn and homogeneous, solid, right ovarian mass found to be a dysgerminoma at surgery. CONCLUSION: Müllerian anomalies are unlikely to predispose women to ovarian malignancies. However, it is essential to keep in mind that women with such anomalies, though presenting at a young age, could still have cervical, uterine or even ovarian malignancies.