Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema

Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca(2+) signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo two-photon imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca(2+) spikes and that deletion of Aqp4 reduces these signals. The Ca(2+) signals are partly dependent on activation of P2 purinergic receptors, which was judged from the effects of appropriate antagonists applied to cortical slices. Supporting the involvement of purinergic signaling, osmotic stress was found to induce ATP release from cultured astrocytes in an AQP4-dependent manner. Our results suggest that AQP4 not only serves as an influx route for water but also is critical for initiating downstream signaling events that may affect and potentially exacerbate the pathological outcome in clinical conditions associated with brain edema.     

Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier

Expression of the water channel aquaporin-4 (AQP4) at the blood-brain interface is dependent upon the dystrophin associated protein complex. Here we investigated whether deletion of the Aqp4 gene affects the molecular composition of this protein scaffold and the integrity of the blood-brain barrier. High-resolution immunogold cytochemistry revealed that perivascular expression of α-syntrophin was reduced by 60% in Aqp4(-/-) mice. Additionally, perivascular AQP4 expression was reduced by 88% in α-syn(-/-) mice, in accordance with earlier reports. Immunofluorescence showed that Aqp4 deletion also caused a modest reduction in perivascular dystrophin, whereas β-dystroglycan labeling was unaltered. Perivascular microglia were devoid of AQP4 immunoreactivity. Deletion of Aqp4 did not alter the ultrastructure of capillary endothelial cells, the expression of tight junction proteins (claudin-5, occludin, and zonula occludens 1), or the vascular permeability to horseradish peroxidase and Evans blue albumin dye. We conclude that Aqp4 deletion reduces the expression of perivascular glial scaffolding proteins without affecting the endothelial barrier. Our data also indicate that AQP4 and α-syntrophin are mutually dependent upon each other for proper perivascular expression.     

Long-term outcome after intestinal resection for Crohn's disease

Objective. To assess the need for intestinal repeat resection for recurrence of Crohn's disease in patients observed for more than 20 years after the first resection. Material and methods. Data were gathered retrospectively from the medical records of 53 (28 F) consecutive patients with Crohn's disease from May 1954 to December 2002. Median age at first intestinal resection was 24.5 (range 13–65) years, and median observation time thereafter was 26.5 (20.1–48.6) years. Disease location and behaviour were defined according to the Vienna classification. Results. The 53 patients had an average 2.7 and a median 2 intestinal resections. Out of 144 intestinal resections (77.1%) 111 were performed during the first three operations; no alterations in distribution of ileal, ileocolic and colic resections were found. From the first to the third operation there was an increase in penetrating disease from 15% to 39% (p=0.046) concomitant with a decrease in stricturing disease from 72% to 44% (p=0.048) of the patients. There was also a corresponding decrease in ileocolic disease from 45% to 5% (p=0.003) and a tendency towards an increase in ileal disease from 38% to 67%. One patient died (1.8%) from rectosigmoid perforation after the third resectional operation. Six patients needed reoperation (11.3%) for ileus, anastomotic bleeding, rectosigmoidal perforation and abdominal pain. Thirty-four patients (64.2%) needed intestinal repeat resection (median 8.3 years) during 25.3 years after the first repeat resection. Conclusions. This study indicates a diminution of Crohn's disease activity with time, as demonstrated by no need for intestinal repeat resection more than 25 years after the first resection.     

A comparison of general and ambulance specific stressors: predictors of job satisfaction and health problems in a nationwide one-year follow-up study of Norwegian ambulance personnel

Objectives  

To address the relative importance of general job-related stressors, ambulance specific stressors and individual characteristics in relation to job satisfaction and health complaints (emotional exhaustion, psychological distress and musculoskeletal pain) among ambulance personnel.     

High tacrolimus clearance – a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single‐center cohort study

Patients with high tacrolimus clearance are more likely to experience transient under‐immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1‐year post‐transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1‐year post‐transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11–2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18–3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.     

Reduced risk of head and neck second primary tumors after radiotherapy

Background and purpose

With radiotherapy of primary tumors of the head and neck, a significant dose reaches the surrounding mucosa. The field cancerization and second field tumor theories state that premalignant lesions are present in the mucosa even at the time of primary tumor treatment. We tested the hypothesis that exposure to irradiation stabilizes subclinical premalignant lesions. This would reduce the rate of second primary tumors in the upper aerodigestive tract (UADT).

Materials and methods

The cohort consisted of 346 patients treated for small localized squamous cell carcinoma of the oral cavity (T1-2, N0, and M0). The rate of UADT second primary tumors was compared between 247 patients exposed to radiation (case subjects) and 99 patients unexposed to radiation (control subjects).

Results

Median time to UADT second primary tumor was 8.6 years for irradiated patients and 3.9 years for controls (p = 0.007). Through the first 5 years after the treatment of the primary tumor, the relative risk of developing a new UADT tumor for irradiated patients compared to controls was 0.12 (p < 0.001). After 5 years the risk increased for irradiated cases. A corresponding change in risk was not found for controls.

Conclusions

A slower rate of second primary tumors was seen within UADT mucosa exposed to irradiation. This could suggest a preventive effect by radiation on malignant transformation of subclinical premalignant foci.