Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury

The recruitment of inflammatory cells into renal tissue, mainly T cells and monocytes, is a typical feature of various renal diseases such as glomerulonephritis, thrombotic angiopathies, allograft rejection, and vasculitis. T cells predominantly infiltrate the tubulointerstitium, whereas monocytes are present in the tubulointerstitial and glomerular compartment. Because chemokines play a pivotal role in leukocyte trafficking under inflammatory conditions, this study investigated whether a differential expression of chemokines contributes to the precise coordination of leukocyte subtype trafficking in a rat model of renal microvascular endothelial injury. Renal microvascular endothelial injury was induced in rats by selective renal artery perfusion with an anti-endothelial antibody. Induction of the disease led to severe glomerular and tubulointerstitial endothelial injury with subsequent upregulation of chemokines followed by inflammatory cell recruitment. Among the analyzed chemokine mRNA, IP-10/CXCL10 (119-fold), acting via CXCR3 on activated T cells, and MCP-1/CCL2 (65-fold), acting via CCR2 on monocytes, were by far the most strongly upregulated chemokines. In situ hybridization revealed that IP-10/CXCL10 mRNA was selectively expressed by endothelial cells in the tubulointerstitial area, co-localizing with infiltrating T cells. Despite extensive damage of glomerular vasculature, no IP-10/CXCL10 expression by glomerular endothelial cells was detected. MCP-1/CCL2 mRNA in contrast was detectable in the glomerulus and the tubulointerstitium. Treatment with a neutralizing anti-IP-10/CXCL10 antibody significantly reduced the number of infiltrating tubulointerstitial T cells without affecting monocyte migration and led to an improved renal function. Our study demonstrates a role of IP-10/CXCL10 on T cell recruitment in a rat model of renal endothelial microvascular injury. Furthermore, a differential chemokine expression profile by endothelial cells in different renal compartments was found. These findings are consistent with the hypothesis that functional heterogeneity of endothelial cells from different vascular sites exists and provide an insight into the molecular mechanisms that may mediate compartment-specific T cell and monocyte recruitment in inflammatory renal disease.     

Efficacy of intra-articular bupivacaine, ropivacaine, or a combination of ropivacaine, morphine, and ketorolac on postoperative pain relief after ambulatory arthroscopic knee surgery: a randomized double-blind study

BACKGROUND: Effective pain relief is important after diagnostic and therapeutic arthroscopic knee surgery to permit early discharge and improve comfort and mobility at home. The aim of this study was to assess the efficacy of bupivacaine, ropivacaine, or a combination of ropivacaine, morphine, and ketorolac injected intra-articularly for postoperative pain relief after arthroscopic knee surgery. METHODS: Sixty-three healthy patients undergoing knee arthroscopy under local anesthesia (LA) were randomized to receive 1 of the following substances intra-articularly postoperatively: group B: 30 mL of bupivacaine (150 mg); group R: 30 mL of ropivacaine (150 mg); and group RMK: ropivacaine 150 mg, morphine 4 mg, and ketorolac 30 mg in normal saline (total volume 30 mL). Oral paracetamol 1g and tramadol 50 mg were used as rescue drugs. Postoperatively, pain was assessed at rest and movement, and side effects were recorded. The patients were asked to self-assess pain for 7 days and record analgesic consumption as well as activities of daily living (ADLs). Plasma concentration of LA was measured in another 8 patients. RESULTS: All groups had excellent analgesia at 0 and 4 hours postoperatively. Group RMK had significantly lower visual analog pain score at rest at 8 hours and during movement at 8 and 24 hours compared with the other groups (P<.05). Group RMK required less paracetamol and tramadol on day 1 (P<.05), had less sleep disturbances because of pain, more patients were ready to work on days 1 and 2 (P<.05), and were more satisfied on days 1 and 4 to 7. Postoperatively, plasma concentrations of ropivacaine and lidocaine were far below known systemic toxic concentrations in all patients. CONCLUSION: Addition of morphine and ketolorac to ropivacaine intra-articularly enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves ADLs without increasing side effects after ambulatory arthroscopic knee surgery.     

Maxillary Sinus Augmentation Using Prehydrated Corticocancellous Porcine Bone: Hystomorphometric Evaluation after 6 Months

Background: Insufficient alveolar bone height often prevents the placement of standard dental implants in the posterior part of edentulous maxilla. In order to increase adequately the vertical dimension of the reabsorbed alveolar process, a sinus lift procedure is often necessary. The aim of this study was to evaluate histologic results of a prehydrated corticocancellous porcine bone used in maxillary sinus augmentation. Methods: Patients (age 18–70 years) with a residual bone height requiring a maxillary sinus augmentation procedure to place dental implants were eligible for this study. All patients were treated with the same surgical technique consisting of sinus floor augmentation via a lateral approach. The space obtained by elevation of the mucosa wall was grafted with prehydrated and collagenated corticocancellous porcine bone. Biopsies were harvested 6 months after the augmentation procedures. Results: Twenty‐four patients were enrolled. The mean percentage of new formed bone was 43.9 ± 18.6% (range 7.5–100%), whereas the mean percentage of residual graft material was 14.2 ± 13.6% (range 0–41.9%). The new bone/residual graft material ratio in the maxillary sinuses was 3.1. The mean soft tissues percentage was 41.8 ± 22.7% (range 0–92.5%). Conclusion: The present study suggested that porcine bone showed excellent osteoconductive properties and could be used successfully for sinus augmentation. Moreover, the porcine bone showed a high percentage of reabsorption after 6 months; this might be because of the presence of collagen and the porosity of the graft material.     

Fatigue properties of bone cement: Comparison of mixing techniques

A four-point bending test was made on 54 specimens of CMW, Simplex P, and Zimmer LVC bone cements. The samples were cyclically loaded at a stress level of 20 MPa at a frequency of 4 Hz. The different cements were mixed either by hand or mechanically with or without a 0.15-bar vacuum. Mechanical mixing in a vacuum improved all three cements, and was the best of all the tested mixing techniques. Simplex P showed the best fatigue properties regardless of mixing technique.     

Incisional hernia after surgery for colorectal cancer: a population-based register study

Background

Our knowledge on the incidence of incisional hernia and risk factors for developing incisional hernia following surgery for colorectal cancer is far from complete.

Methods

All procedures registered in the Swedish Colorectal Cancer Register (SCRCR) 2007–2013 were identified. Patients with comorbid disease diagnoses, registered at admissions and visits prior to the procedure and relevant to this study, were obtained from the National Patient Register (NPR). These diagnoses included cardiovascular disease, connective tissue disorders, liver cirrhosis, renal failure, diabetes, chronic obstructive lung disease and chronic inflammatory conditions. Data on occurrence of incisional hernias were obtained by combining data from the SCRCR and the NPR (International Classification of Diseases code).

Results

During 2007–2013, 39,984 procedures were registered in the SCRCR. After excluding laparoscopic procedures, procedures repeated on the same patient, procedures with concomitant liver resection and procedures without laparotomy, 28,913 cases remained for analysis. Five years after surgery, the cumulative incidence of incisional hernia was 5.3%. In multivariate proportional hazard analysis, significantly increased risk for incisional hernia was found for the male gender (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.21–1.62), operation time exceeding 180 min (HR 1.25, CI 1.08–1.45), body mass index (BMI) >?30 (HR 1.78, CI 1.51–2.09), age <?70 years (HR 1.34, CI 1.16–1.56) and postoperative wound complication (HR 2.09, CI 1.70–2.58).

Discussion

Men, patients younger than 70 years and patients with BMI?>?30 face a higher risk for incisional hernia. The risk is also increased in cases where the procedure takes longer than 3 h or where postoperative wound complications occur. These patients will benefit from measures aimed at preventing the development of incisional hernia.

     

Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)‐Mediated Therapy Resistance in Head and Neck Cancer Patients

Survivin (BIRC5) is an acknowledged cancer therapy‐resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation‐induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin‐based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients.