We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p.V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 micro moles/mg/min vs. 1,678.7 +/- SD 527.2 micro moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS.

This study assessed defect depth and volume resulting from root instrumentation using a KaVo Sonic-flex Lux 2000 L sonic scaler with a slim scaling tip (Perio-Tip no. 8) in vitro. Combinations of the following working parameters were analyzed: lateral forces of 0.5 N, 1 N, and 2 N; tip angulations of 0 degree, 45 degrees, and 90 degrees; and instrumentation time of 10 s, 20 s, 40 s, and 80 s. Defects were quantified using a three-dimensional optical laser scanner. Instrumentation time had an almost linear impact on defect depth and volume. Although lateral force (beta-weight 0.55 +/- 0.062) had a greater influence on defect volume than tip angulation (beta-weight 0.29 +/- 0.062), their effects on defect depth were similar (beta-weight 0.43 +/- 0.052 and 0.50 +/- 0.052, respectively). The combination of force and angulation showed synergistic effects resulting in a wide range of defect depths (21.9 +/- 0.96 microns to 174 +/- 28.8 microns, at 40 s) and volumes (0.056 +/- 0.019 mm3 to 0.68 +/- 0.10 mm3 at 40 s). Severe root damage (> 50 microns/40 s) did not occur at any combination of 0.5 N lateral force and/or 0 degree tip angulation. By adjusting lateral force and tip angulation, the efficacy of the assessed sonic scaler may be adapted to various clinical needs.

The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.

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The results of this study suggest that pPTT might be an interesting surrogate marker of pulmonary hemodynamic and vascular alterations in PH and PF. Further studies are warranted to evaluate the possible influence of other variables on pPTT.

Background and Aims: Although the efficacy and safety of omalizumab (OMA) in uncontrolled severe allergic asthma has been demonstrated in several randomised controlled trials (RCTs), information on the treatment in a practice-related setting is limited. Thus, the purpose of this prospective multi-centre study (XCLUSIVE) was to investigate the efficacy, compliance and utilisation of OMA therapy in real-life clinical practice in Germany. Methods: One hundred ninety-five asthmatic patients initiated on antiImmunoglobulin E (IgE) IgE treatment were followed-up for 6 months. Forced expiratory volume in 1 s (FEV1), exacerbation rate, days of absence, asthma symptoms [Asthma Control Questionnaire (ACQ)], a Global Evaluation of Treatment Effectiveness (GETE) and medication use were assessed. Results: Measured outcome variables improved after a 16-week treatment period with OMA (FEV1 +13.7% predicted P < 0.05, exacerbation rate -74.9% P < 0.0001, days of absence -92.1% P < 0.001, ACQ -43.7% P < 0.0001). Investigators evaluated the effectiveness of OMA by GETE in 78.8% as excellent or good (responder), and in 12.6%/8.6% as moderate/poor or worse (non-responder). Responders demonstrated better improvement of FEV1, exacerbation rate, days of absence, ACQ and reduction of oral corticosteroids compared with non-responders. Conclusion: Results of effectiveness strongly suggest that the efficacy demonstrated in RCTs can be transposed to a clinical practice-related setting.Please cite this paper as: Schumann C, Kropf C, Wibmer T, Rüdiger S, Stoiber KM, Thielen A, Rottbauer W and Kroegel C. Omalizumab in patients with severe asthma: the XCLUSIVE study. Clin Respir J 2012; 6: 215-227.

Increased gingival crevicular fluid flow during gingivitis affects pellicle formation and increased plasma proteins in the pellicle may modify bacterial attachment and early dental plaque composition.