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Background: Acute appendicitis is one of the most common emergencies in general surgery. The gold standard treatment is surgery. Complications may occur during or after an appendectomy. In addition to age, clinically important factors for the outcome after appendicitis seems to be the comorbidities and the stage of the appendicitis at the time of the operation. Large observational data describing these facts are missing. Methods: In this retrospective multicenter observational study, all inpatients over the age of 17 years with a diagnosis of acute appendicitis in 47 hospitals of the Clinotel Hospital Group between 2010 and 2017 were included. Results: A total of 19,749 patients with acute appendicitis were operated on. The number of patients with more than five secondary diagnoses has increased from 8.4% (2010) to 14.5% (2017). The number of secondary diagnoses correlates with the ages of the patients and leads to a significantly longer hospital stay. Computer tomography (CT) has gained in importance in recent years in the diagnosis of acute appendicitis. A total of 19.9% of patients received a CT in 2017. Laparoscopic appendectomy increased from 88% in 2010 to 95% in 2017 (p < 0.001). The conversion rate did not change relevant in the study period (i.e., 2.3% in 2017). Appendicitis with perforation, abscess, or generalized peritonitis was observed in 24.8% of patients. Mortality was 0.6% during the observation period and was associated with age and the number of secondary diagnoses. The analysis is based on administrative data collected primarily for billing purposes, subject to the usual limitations of such data. This includes partially incomplete clinical data. Conclusions: Multimorbidity is increasingly present in patients with acute appendicitis. Mortality is still in an acceptably low range with no increase. A CT scan is necessary for a precise diagnosis in unclear clinical situations to avoid unnecessary operations and was performed more often at the end of the study than at the beginning.

Introduction: Quality assurance of the thyroid surgery has been an important part of the work of the endocrine surgeon. For most analyses, data from register files or studies have been used. Administrative data taken from routine data are increasingly used in quality assurance for evaluation. The aim of the study is to determine the reliability of routine data to analyse the treatment outcome and complications of thyroid surgery., Patients and Methods: In a cross-sectional study, we compared records of 121 patients with thyroid surgery for one year with the data of quality assurance of clinical routine. We determined sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of complications., Results: Screening of administrative data identified 40 specific complications; 84 by patient records. Sensitivities for the detection of complications using administrative data ranged from 31.3 to 60.0%. Specificities ranged from 97.0 to 100%; PPV were 0.77 - 1.0 and NPV were 0.56 - 1.0., Conclusion: Quality assurance of clinical routine data of the thyroid surgery shows deficiencies in sensitivity accompanied by high specificity. It is necessary to increase the validity of administrative routine data to carry out a reliable clinic quality analysis or to prepare volume-outcome relationships in clinical health service research. The parameter of hypocalcaemia shows the most limitations due to quality assurance of clinical routine data., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The COPD Patient Management European Trial (COMET) investigated the efficacy and safety of a home-based COPD disease management intervention for severe COPD patients.The study was an international open-design clinical trial in COPD patients (forced expiratory volume in 1 s <50% of predicted value) randomised 1:1 to the disease management intervention or to the usual management practices at the study centre. The disease management intervention included a self-management programme, home telemonitoring, care coordination and medical management. The primary end-point was the number of unplanned all-cause hospitalisation days in the intention-to-treat (ITT) population. Secondary end-points included acute care hospitalisation days, BODE (body mass index, airflow obstruction, dyspnoea and exercise) index and exacerbations. Safety end-points included adverse events and deaths.For the 157 (disease management) and 162 (usual management) patients eligible for ITT analyses, all-cause hospitalisation days per year (mean±sd) were 17.4±35.4 and 22.6±41.8, respectively (mean difference -5.3, 95% CI -13.7 to -3.1; p=0.16). The disease management group had fewer per-protocol acute care hospitalisation days per year (p=0.047), a lower BODE index (p=0.01) and a lower mortality rate (1.9% versus 14.2%; p<0.001), with no difference in exacerbation frequency. Patient profiles and hospitalisation practices varied substantially across countries.The COMET disease management intervention did not significantly reduce unplanned all-cause hospitalisation days, but reduced acute care hospitalisation days and mortality in severe COPD patients., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Background: This study is aimed to evaluate the effect of inspiratory muscle training (IMT) added to rehabilitation in patients with chronic obstructive pulmonary disease (COPD) who remain hypercapnic and use non-invasive ventilation after successful weaning., Methods: Patients received rehabilitation and were randomized to inspiratory muscle or sham training for 4 weeks. The primary outcome was distance walked within 6 min. Secondary outcomes were inspiratory muscle strength, endurance, lung function, and blood gas levels., Results: Twenty-nine patients participated in this study. Walking distance of the sham group increased from 93 ± 52 m at baseline to 196 ± 85 m at week 4 (p = 0.019, 95% CI: 11-196 m). Patients in the IMT group significantly improved their walking distance from 94 ± 32 to 290 ± 75 m (p < 0.0001 [107-286 m]; p = 0.04 [3-186 m] for between-group comparison). Patients in the IMT group increased their maximal inspiratory pressure from -35 ± 8 to -55 ± 11 cmH 2 O (p = 0.001; -6 to -33 cmH 2 O), while the increase in the sham group failed to reach significance (-29 ± 10 to -37 ± 13 cmH 2 O [-22 to 6 cmH 2 O]). Inspiratory power increased from 9.6 ± 5.4 to 20.7 ± 9.7 joules/min (2.6-19.5 joules/min, p = 0.003) in the IMT group, while no significant change occurred in the sham group (7.6 ± 4.2 joules/min at study entry and 11.1 ± 6.9 joules/min [-5.2-12.3 joules/min] at study end)., Conclusions: Rehabilitation of successfully weaned patients with COPD and persistent hypercapnia significantly improves functional exercise capacity. Additional IMT significantly enhances functional exercise capacity and increases respiratory muscle strength and power., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Dysregulation of c-Jun N -terminal kinase (JNK) activation promoted DNA damage response bypass and tumorigenesis in our model of hydrogen peroxide-associated ulcerative colitis (UC) and in patients with quiescent UC (QUC), UC-related dysplasia, and UC-related carcinoma (UC-CRC), thereby adapting to oxidative stress. In the UC model, we have observed features of oncogenic transformation: increased proliferation, undetected DNA damage, and apoptosis resistance. Here, we show that Chk1 was downregulated but activated in the acute and quiescent chronic phases. In both phases, Chk1 was linked to DNA damage response bypass by suppressing JNK activation following oxidative stress, promoting cell cycle progression despite DNA damage. Simultaneously, activated Chk1 was bound to chromatin. This triggered histone acetylation and the binding of histone acetyltransferases and transcription factors to chromatin. Thus, chromatin-immobilized activated Chk1 executed a dual function by suppressing DNA damage response and simultaneously inducing chromatin modulation. This caused undetected DNA damage and increased cellular proliferation through failure to transmit the appropriate DNA damage signal. Findings in vitro were corroborated by chromatin accumulation of activated Chk1, Ac-H3, Ac-H4, and c-Jun in active UC (AUC) in vivo. Targeting chromatin-bound Chk1, GCN5, PCAF, and p300/CBP could be a novel therapeutic strategy to prevent UC-related tumor progression.

Cathepsin X (CTSX, also called cathepsin Z/P) is a cysteine protease that still plays an unknown role in human cancer. It has been shown to bind cell surface heparin sulphate proteoglycans and integrins, indicating possible functions of CTSX in cellular adhesion, phagocytosis, and immune response. Our previous studies have shown an association between Helicobacter pylori (H. pylori) infection, a strong up-regulation of CTSX, and development of gastric cancer. In this study, yeast two-hybrid analysis revealed that RPLP0, a ribosomal protein P0, interacts with the human CTSX protein in gastric cancer. The CTSX/RPLP0 interaction was confirmed by co-immunoprecipitation assays. In addition, co-localization studies in cancer cell line N87 and gastric cancer tissue samples were performed. Laserscan microscopy revealed a shuttling of RPLP0 (and CTSX) from cytoplasm to the nucleus after CTSX knockdown. Down-regulation of RPLP0 resulted in G1 arrest of gastric cancer cells, whereas knockdown of CTSX led to G1 arrest and apoptosis after 48 h. Knockdown of both proteins caused increased apoptosis. RPLP0 deficiency could suppress cell growth and cell cycle progression by down-regulating CDK2. It was further demonstrated that RPLP0 affected p21 expression, but did not change the expression of Cyclin E. Down-regulation of both proteins at least through CDK2 suggests an anti-apoptotic effect on gastric cancer cells and opens up new possibilities for apoptotic immune modulation and gastric cancer therapy., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

The production of hydrogen peroxide (H2 O2 ) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2 O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c-Jun N-terminal Kinases (JNK) that induces p21(WAF1) . Moreover, caspases circumvented the G1/S and intra-S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2 O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2 O2 -exposed HCEC cells (C-cell cultures) was associated with (i) increased phospho-p46 JNK, (ii) decreased total JNK and phospho-p54 JNK and (iii) p21(WAF1) down-regulation. Altered JNK activation and p21(WAF1) down-regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2 O2 exposure. This may cause increased proliferation of C-cell cultures, a defining initiating feature in the inflammation-carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non-apoptotic function of caspases, causing checkpoint adaptation in C-cell cultures. Additionally, loss of cell-contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell-contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2 O2 -induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21(WAF1) , c-Fos, c-Jun/phospho-c-Jun, ATF2/phospho-ATF2, β-catenin/TCF4-signalling, c-Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression., (© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress-based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21(WAF1) , but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21(WAF1) protein expression, suggesting p21(WAF1) transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2-binding sequence in the p21(WAF1) promoter. p-ATF2 was found to interact with p-c-Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21(WAF1) downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4-dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti-cancer therapies., (© 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H2 O2 ). A population of HCEC survived H2 O2 -induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21(WAF1) and γ-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of γ-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G1 -phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non-apoptotic function by promoting cells through G1 - and S-phase by overriding the G1 /S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G2 /M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via γ-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX. As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo., (© 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Besides the well-understood DNA damage response via establishment of G(2) checkpoint arrest, novel studies focus on the recovery from arrest by checkpoint override to monitor cell cycle re-entry. The aim of this study was to investigate the role of Chk1 in the recovery from G(2) checkpoint arrest in HCT116 (human colorectal cancer) wt, p53(-/-) and p21(-/-) cell lines following H(2) O(2) treatment. Firstly, DNA damage caused G(2) checkpoint activation via Chk1. Secondly, overriding G(2) checkpoint led to (i) mitotic slippage, cell cycle re-entry in G(1) and subsequent G(1) arrest associated with senescence or (ii) premature mitotic entry in the absence of p53/p21(WAF1) causing mitotic catastrophe. We revealed subtle differences in the initial Chk1-involved G(2) arrest with respect to p53/p21(WAF1) : absence of either protein led to late G(2) arrest instead of the classic G(2) arrest during checkpoint initiation, and this impacted the release back into the cell cycle. Thus, G(2) arrest correlated with downstream senescence, but late G(2) arrest led to mitotic catastrophe, although both cell cycle re-entries were linked to upstream Chk1 signalling. Chk1 knockdown deciphered that Chk1 defines long-term DNA damage responses causing cell cycle re-entry. We propose that recovery from oxidative DNA damage-induced G(2) arrest requires Chk1. It works as cutting edge and navigates cells to senescence or mitotic catastrophe. The decision, however, seems to depend on p53/p21(WAF1) . The general relevance of Chk1 as an important determinant of recovery from G(2) checkpoint arrest was verified in HT29 colorectal cancer cells., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Leiomyomas are benign neoplasms arising from smooth muscle cells. We describe the case of a 17-year-old boy admitted with progressive severe obstructive voiding symptoms. Retrograde urethrography showed a bulbous urethral stricture which was resected with primary urethral anastomosis. Histopathological examination confirmed the very rare case of a leiomyoma of the urethra. In patients with urethral stricture, leiomyoma should be included in the diagnostic considerations.

Cranford, Boose, & Moore (1990a) reported that many elderly persons exhibit problems in perceiving the apparent location of fused auditory images in a sound localization task involving the Precedence Effect (PE). In the earlier study, differences in peripheral hearing sensitivity between young and elderly subjects were not controlled. In the present study, four groups of young and elderly subjects, matched with respect to age and the presence or absence of sensorineural hearing loss, were examined to determine the effects of these two factors on performance with the PE task. Although significantly poorer performances on the PE task were found to be associated with both increased age and hearing loss, additional tentative evidence was obtained that the presence of hearing loss may have a relatively greater detrimental effect on the performance of at least some elderly subjects than it does on younger persons.