CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease

Cystic fibrosis (CF) lung disease severity is largely independent on the CF transmembrane conductance regulator (CFTR) genotype, indicating the contribution of genetic modifiers. The chemokine receptors CXCR1 and CXCR2 have been found to play essential roles in the pathogenesis of CF lung disease. Here, we determine whether genetic variation of CXCR1 and CXCR2 influences CF lung disease severity. Genomic DNA of CF patients in Germany (n = 442) was analysed for common variations in CXCR1 and CXCR2 using a single-nucleotide polymorphism (SNP) tagging approach. Associations of CXCR1 and CXCR2 SNPs and haplotypes with CF lung disease severity, CXCR1 and CXCR2 expression, and neutrophil effector functions were assessed. Four SNPs in CXCR1 and three in CXCR2 strongly correlated with age-adjusted lung function in CF patients. SNPs comprising haplotypes CXCR1_Ha and CXCR2_Ha were in high linkage disequilibrium and patients heterozygous for the CXCR1-2 haplotype cluster (CXCR1-2_Ha) had lower lung function compared with patients with homozygous wild-type alleles (forced expiratory volume in 1 s ≤ 70% predicted, OR 7.24; p = 2.30 × 10(-5)). CF patients carrying CXCR1-2_Ha showed decreased CXCR1 combined with increased CXCR2 mRNA and protein expression, and displayed disturbed antibacterial effector functions. CXCR1 and CXCR2 genotypes modulate lung function and antibacterial host defence in CF lung disease.     

Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: open questions

Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patients, the anti-leukemic activity of nilotinib exceeds the efficacy of imatinib, and although long-term data for nilotinib are not available yet, the drug has recently been approved for firstline treatment of chronic phase CML in various countries. Still however, several questions concerning the optimal dose, follow-up parameters, long-term safety, and patient selection remain open. Likewise, it remains uncertain whether both Sokal low-risk and high-risk patients should receive nilotinib as frontline therapy in the future. Another question is whether nilotinib can completely eradicate CML in a subset of patients. Furthermore, it remains unclear whether and what comorbidity must be regarded as relative or absolute contra-indication for this TKI. To discuss these issues, the Austrian CML Working Group organized a series of meetings in 2010. In the current article, the outcomes from these discussions are summarized and presented together with recommendations for frontline use of TKIs in various groups of patients with CML. These recommendations should assist in daily practice as well as in the preparation and conduct of clinical trials.     

Predicting Partner HIV Testing and Counseling Following a Partner Notification Intervention

Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6-24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.     

Comparison of revision strategies for failed C2-posterior cervical pedicle screws: a biomechanical study

Study purpose

With increasing usage within challenging biomechanical constructs, failures of C2 posterior cervical pedicle screws (C2-pCPSs) will occur. The purpose of the study was therefore to investigate the biomechanical characteristics of two revision techniques after the failure of C2-pCPSs.

Materials and methods

Twelve human C2 vertebrae were tested in vitro in a biomechanical study to compare two strategies for revision screws after failure of C2-pCPSs. C2 pedicles were instrumented using unicortical 3.5-mm CPS bilaterally (Synapse/Synthes, Switzerland). Insertion accuracy was verified by fluoroscopy. C2 vertebrae were potted and fixed in an electromechanical testing machine with the screw axis coaxial to the pullout direction. Pullout testing was conducted with load and displacement data taken continuously. The peak load to failure was measured in newtons (N) and is reported as the pullout resistance (POR). After pullout, two revision strategies were tested in each vertebra. In Group-1, revision was performed with 4.0-mm C2-pCPSs. In Group-2, revision was performed with C2-pedicle bone-plastic combined with the use of a 4-mm C2-pCPSs. For the statistical analysis, the POR between screws was compared using absolute values (N) and the POR of the revision techniques normalized to that of the primary procedures (%).

Results

The POR of primary 3.5-mm CPSs was 1,140.5 ± 539.6 N for Group-1 and 1,007.7 ± 362.5 N for Group-2; the difference was not significant. In the revision setting, the POR in Group-1 was 705.8 ± 449.1 N, representing a reduction of 38.1 ± 32.9 % compared with that of primary screw fixation. For Group-2, the POR was 875.3 ± 367.9 N, representing a reduction of 13.1 ± 23.4 %. A statistical analysis showed a significantly higher POR for Group-2 compared with Group-1 (p = 0.02). Although the statistics showed a significantly reduced POR for both revision strategies compared with primary fixation (p < 0.001/p = 0.001), the loss of POR (in %) in Group-1 was significantly higher compared with the loss in Group-2 (p = 0.04).

Conclusions

Using a larger-diameter screw combined with the application of a pedicle bone-plastic, the POR can be significantly increased compared with the use of only an increased screw diameter.     

In vivo analysis of cervical kinematics after implantation of a minimally constrained cervical artificial disc replacement

Introduction

To better understand cervical kinematics following cervical disc replacement (CDR), the in vivo behavior of a minimally constrained CDR was assessed.

Methods

Radiographic analysis of 19 patients undergoing a 1-level CDR from C4–5 to C6–7 (DISCOVER, Depuy-Spine, USA) was performed. Neutral–lateral and flexion–extension radiographs obtained at preop, postop and late follow-up were analyzed for segmental angle and global angle (GA C2–7). Flexion–extension range of motion was analyzed using validated quantitative motion analysis software (QMA®, Medical Metrics, USA). The FSU motion parameters measured at the index and adjacent levels were angular range of motion (ROM), translation and center of rotation (COR). Translation and COR were normalized to the AP dimension of the inferior endplate of the caudal vertebra. All motion parameters, including COR, were compared with normative reference data.

Results

The average patient age was 43.5 ± 7.3 years. The mean follow-up was 15.3 ± 7.2 months. C2–7 ROM was 35.9° ± 15.7° at preop and 45.4° ± 13.6° at follow-up (?p < .01). Based on the QMA at follow-up, angular ROM at the CDR level measured 9.8° ± 5.9° and translation was 10.1 ± 7.8 %. Individuals with higher ROM at the CDR level had increased translation at that level (p < .001, r = 0.97), increased translation and ROM at the supra-adjacent level (p < .001, r = .8; p = .005, r = .6). There was a strong interrelation between angular ROM and translation at the supra-adjacent level (p < .001, r = .9) and caudal-adjacent level (p < .001, r = .9). The location of the COR at the CDR- and supra-adjacent levels was significantly different for the COR-X (p < .001). Notably, the COR-Y at the CDR level was significantly correlated with the extent of CDR-level translation (p = .02, r = .6). Shell angle, which may be influenced by implant size and positioning had no impact on angular ROM but was correlated with COR-X (p = .05, r = ?.6) and COR-Y (p = .04, r = ?.5).

Conclusion

The COR is an important parameter for assessing the ability of non-constrained CDRs to replicate the normal kinematics of a FSU. CDR size and location, both of which can impact shell angle, may influence the amount of translation by affecting the location of the COR. Future research is needed to show how much translation is beneficial concerning clinical outcomes and facet loading.     

Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is an inherited condition that leads to respiratory failure and is the third most common indication for adult bilateral lung transplantation (LuTX). In contrast to other lung diseases, the immune system of CF patients is up‐regulated and we therefore hypothesized that these patients would benefit from induction therapy. In the current study, we investigated the impact of antithymocyte globulin (ATG) induction therapy in CF patients after LuTX. One hundred and forty six patients who underwent LuTX for CF at our centre between January 1999 and December 2010 were included in the study and retrospectively analysed. They were divided into two groups according to the immunosuppressive protocol: group‐A (n = 103) with and group‐B (n = 43) without induction therapy on top of the basic calcineurin inhibitor based triple immunosuppression with mycophenolate mofetil and steroids. Perioperative survival was significantly better in the ATG group, a benefit sustained for the entire follow‐up. ATG induction resulted in a significantly lower incidence of acute rejections without an increase in infectious complications. Taken together, our results indicate that ATG induction therapy confers a significant survival benefit in CF patients undergoing LuTX and reduces rejection. We advocate the use of induction therapy in this patient cohort.     

Polypropylene meshes coated with a polysaccharide based bioadhesive for intra-abdominal mesh fixation in a rabbit model

Background

In this study, we evaluate a new bioadhesive for intra-abdominal onlay mesh fixation of a polypropylene–polyvinylchloride graft.

Methods

Three pieces of a commercially available polypropylene/polyvinylfluoride mesh, each 3 × 3 cm in size, and three pieces of the same mesh coated with a polysaccharide bioadhesive were fixated to the surface of the anterior abdominal wall of 30 New Zealand white rabbits. The fixation was performed either by using four transabdominal Prolene^® 4/0 sutures, four spiral tacks (Protack 5 mm Tyco), or cyanoacrylate glue (Glubran^® GEM, Viareggio, Italy). Each mesh position and the according kind of fixation were randomized before implantation. The animals were sacrificed 12 weeks postoperatively. After determining the extent of intra-abdominal adhesions, the meshes were excised en bloc with the anterior abdominal wall for tensile strength measurements and histological analysis.

Results

All meshes coated with the bioadhesive adhered to the intact peritoneum without extra fixation. Irrespective of the fixation technique coated meshes led to more and stronger adhesions. Mesh shrinkage by scarring was increased in coated meshes fixed with glue and low in uncoated meshes fixed with tacks. Testing the tensile strength, coated meshes fixed with transfascial sutures achieved the best results (16.14 ± 6.1 N), whereas coated meshes fixed with glue showed the lowest strength (10.39 ± 4.81 N). The foreign body reaction was considerably more distinctive using coated mesh. The mesh ingrowth was not influenced by this reaction.

Conclusions

All meshes coated with the new bioadhesive were self-adhesive in that way; they stayed in position when attached to the peritoneum. Although this may facilitate intra-operative mesh fixation, the bioadhesive displayed several disadvantages, such as stronger adhesions and an increased shrinkage of the implant. The tensile strength was not influenced by the use of the bioadhesive. At present, we see no major advantage for polysaccharide bioadhesive applied in this study.