Mid-term clinical and sonographic outcomes of minimally invasive acromioclavicular joint reconstruction: mini-open versus arthroscopically assisted.

INTRODUCTION: The current literature describes various operative stabilization strategies which achieve good clinical outcomes after acute acromioclavicular joint (ACJ) dislocation. The aim of this study was to compare the mid-term clinical and sonographic treatment outcomes after minimally invasive mini-open and arthroscopic reconstruction. MATERIALS AND METHODS: We conducted a retrospective two-center study of patients with acute ACJ dislocation. Surgical treatment was performed using either a mini-open approach (MIOP) or an arthroscopic technique (AR). The primary outcome parameters of this study were the sonographically measured acromioclavicular (ACD) and coracoclavicular distances (CCD). Secondary outcome parameters included the Constant-Murley score (CS), range of motion (ROM), postoperative pain scale (VAS), return to daily routine, return to sports, complications, as well as operative revisions. RESULTS: After a mean follow-up of 29 months, 30 patients were included in this study with an average age of 41.3 ± 14.8 years (MIOP) and 41.2 ± 15.4 years (AR). The sonographic ACD (MIOP 9.11 mm vs. AR 8.93 mm, p = 0.41) and CCD (MIOP 25.08 mm vs. AR 24.36 mm, p = 0.29) distances showed no statistically significant differences. Furthermore, there was no statistically significant difference when compared to the contralateral side (p = 0.42). With both techniques, patients achieved excellent clinical outcome parameters without statistically significant differences in CS (MIOP 95 vs. AR 97, p = 0.11) and VAS (MIOP 1.76 vs. AR 1.14, p = 0.18). The return to daily activity and return to sport rates did not differ. There were neither complications nor revisions in both groups. CONCLUSION: Both minimally invasive techniques for acute ACJ stabilization achieved excellent clinical and sonographic outcomes without one technique being statistically superior to the other.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells.

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.

[Safety of sedation during gastroscopy and colonoscopy in low-risk patients - results of a retrospective subgroup analysis of a registry study including over 170 000 endoscopies]. / Sicherheit der Sedierung der Gastroskopie und Koloskopie bei Niedrigrisikopatienten - Retrospektive Subgruppenanalyse der Ergebnisse einer Registerstudie von über 170 000 Endoskopien.

INTRODUCTION: Administering sedation is an established standard in gastrointestinal endoscopy, particularly in situations in which sedation is used to make the examination more comfortable for the patient (e. g., during preventive check-up examinations). It is important to have precise information about the risk of sedation-associated complications. AIMS AND METHODS: The aim of this study was to record the incidence and type of sedation-associated complications in a low-risk group of patients (ASA 1 or 2) undergoing elective diagnostic esophagogastroduodenoscopy or colonoscopy. Risk factors for the development of a sedation complication were also to be identified. Using a prospective multicenter study design, sedation-associated complications were documented in the ProSed2 study using an electronic endoscopy documentation system. RESULTS: Thirty-nine research centers took part in the study from December 2011 to June 2014. A total of 368 206 endoscopies were recorded. 177 944 of the procedures met the defined criteria for subgroup analysis (endoscopy with sedation, patient in ASA class 1 or 2, esophagogastroduodenoscopy or colonoscopy, no emergency endoscopies, no therapeutic procedures). The patients received propofol alone in 64.4 % of the sedations, or a combination of propofol and midazolam in 22.4 %. Sedation was administered by the endoscopist or endoscopy assistant in 56.5 % of cases, or by a third person in 43.5 % (anesthesist < 0.1 %, intensive-care specialist 5.7 %, nurse-administered propofol sedation 37.8 %). A total of 332 minor complications were documented (0.2 %). No major complications or deaths occurred. The following risk factors were identified for the development of sedation-associated complications: Patients in ASA class 2 and sedation with midazolam in combination with an opiate. CONCLUSIONS: These findings on sedation-associated complications show that severe complications and deaths do not occur, and that minor complications occur very rarely. Sedation can therefore be regarded as extremely safe in this group of patients. Even though this analysis did not include therapeutic colonoscopies (e. g. polypectomy), these data should lower the threshold for patients undergoing preventive check-up examinations and it should therefore be offered as a standard.

RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress.

The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here, we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN-interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability.

[Detection of early neoplasia in Barrett's oesophagus: focus attention on index endoscopy in short-segment-Barrett's oesophagus with random biopsies]. / Detektion von frühen Neoplasien im Barrett-Ösophagus: Ein Plädoyer für die Wertigkeit der Indexendoskopie und 4-Quadranten-Biopsien im Short-Segment-Barrett-Ösophagus.

BACKGROUND: Detecting early neoplasias in Barrett's oesophagus (BE) is challenging. Recent publications have been focusing on improving the detection of such lesions during Barrett's surveillance. However in a recently published Danish register study calculating the risk for cancer-development in BE two-thirds of the diagnosed tumors were identified during the first examination or in the first year. This means that index endoscopy might be more effective than surveillance in detecting early neoplasia in BE. METHODS: In the period from January 2010 to April 2011, all patients who consecutively presented with a diagnosis of early neoplastic changes in BE were recorded prospectively. ANALYSIS: The analysis included data for 121 patients. In patients with short-segment BE (SSBE), neoplasia was only diagnosed in 6 % of cases in the surveillance examination, compared with 44 % of cases in long-segment BE (LSBE). The neoplastic lesion was identified visually in 43 patients (36 %) during the external EGD. Type II tumours were detected in 40 % (39/98) and were correctly assessed as neoplastic in 25 % of cases (24/98). CONCLUSIONS: 1. in patients with SSBE almost all early tumours are diagnosed by index endoscopy and not by Barrett's surveillance; 2. around 40 % of all early neoplasias are endoscopically invisible and are only diagnosed using four-quadrant biopsies; 3. the macroscopic tumour type has a substantial influence on the detection rate for neoplasia. If efforts to increase the detection rate for early neoplasia in BE are focused solely on the Barrett's surveillance method, then only a minority of patients - 20 % in the present group - will benefit from the measure. German clinical trials register, DRKS00 004 168.

Endoscopic management for patients with serrated polyposis syndrome is feasible and effective: a prospective observational study at a tertiary centre.

BACKGROUND AND STUDY AIMS: Serrated polyposis syndrome is a rare condition in which multiple serrated lesions develop all over the colon, which is thought to be associated with an increased risk for the development of cancer. The aim of this study was to investigate the feasibility of endoscopic treatment and standardised surveillance in patients with this increasingly recognised syndrome. METHODS: From September 2010 to November 2013, consecutive patients were included in a prospective study. All patients underwent chromoendoscopy at first presentation and during surveillance. Follow-up examinations were carried out at 3 month intervals until complete clearance was achieved. Afterwards, patients entered a standardised surveillance protocol with a chromoendoscopic colonoscopy annually. RESULTS: Altogether 100 colonoscopies were carried out in 28 patients, with endoscopic resection of 436 lesions. Total clearance was accomplished in 27 patients (96.0 %) after 2.5 colonoscopies (range 1 - 8). Histology revealed 359 hyperplastic polyps (82.3 %), 37 sessile serrated adenomas (8.5 %), 36 low-grade adenomas (8.3 %), and one patient with advanced colorectal cancer. Twelve patients (42.8 %) had serrated polyps > 10 mm in size. During the surveillance period, 86 additional lesions were detected and resected. The mean follow-up period was 21.5 months (range 2 - 39 months). No interval carcinoma was detected during the surveillance. CONCLUSIONS: The present study indicates that endoscopic management in patients who meet the diagnostic criteria for serrated polyposis syndrome is feasible and safe. In particular, the incidence of colorectal cancer in this cohort was lower in comparison with previous studies.

[Challenges and limits for endoscopic resection of oesophageal and oesophagogastric cancer]. / Wann ist eine endoskopische Resektion einer Neoplasie im Ösophagus und der Kardia indiziert?

There is good evidence for the safety and efficacy of endoscopic treatment for early neoplasia in Barrett's oesophagus and in oesophageal squamous epithelium within defined margins, and this form of therapy is therefore the treatment of choice. With a low morbidity rate, it offers patients a good quality of life with preservation of the organ. The mortality risk is minimal. The decisive element for success is early diagnosis. Oesophageal resection and radiotherapy/chemotherapy are nowadays reserve procedures in the treatment of early oesophageal carcinoma and should only be used in patients in whom the tumour shows defined histological risk factors or endoscopic therapy has failed. Discussion is currently taking place on whether the criteria used to indicate endoscopic therapy for early Barrett's adenocarcinoma can be expanded to include lesions with superficial submucosal infiltration and no additional histological risk factors.

DMAP1 is an essential regulator of ATM activity and function.

The hereditary autosomal recessive disease ataxia telangiectasia (A-T) is caused by mutation in the DNA damage kinase ATM. ATM's main function is to orchestrate DNA repair, thereby maintaining genomic stability. ATM activity is increased in response to several stimuli, including ionising radiation (IR) and hypotonic stress. DNMT1-associated protein 1 (DMAP1) is a member of the TIP60-p400 histone acetyl transferase (HAT) complex, which acetylates histone H4 at lysine 16 (H4K16) to affect chromatin relaxation and modulate ATM activation. Here we demonstrate that DMAP1 is required for both modes of ATM activation. Knockdown of DMAP1 impaired IR-induced ATM activation and consequently resulted in radiosensitivity and impaired the G2/M checkpoint. Moreover, DMAP1 was also required for efficient ATM signalling in response to hypotonic stress. Overexpression of DMAP1 increased IR-induced ATM substrate phosphorylation, suggesting that DMAP1 function is rate limiting for ATM signalling. DMAP1 associated with TIP60-dependent HAT activity, and depletion of DMAP1 reduced H4K16 acetylation in response to DNA damage. Treatment with histone deacetylase inhibitors rescued IR-induced ATM signalling in Dmap1-depleted cells. These results suggest that DMAP1 is a critical regulator of ATM activity and function.

ATM signalling and cancer.

ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data, ATM alterations have been revealed both in the germline as a predisposing factor for cancer and as somatic changes in tumours themselves. Here we review these findings, as well as advances in the understanding of ATM signalling mechanisms in cancer and ATM inhibition as a strategy for cancer treatment.

Limits on spin-dependent WIMP-nucleon cross sections from 225 live days of XENON100 data.

We present new experimental constraints on the elastic, spin-dependent WIMP-nucleon cross section using recent data from the XENON100 experiment, operated in the Laboratori Nazionali del Gran Sasso in Italy. An analysis of 224.6 live days×34 kg of exposure acquired during 2011 and 2012 revealed no excess signal due to axial-vector WIMP interactions with 129Xe and 131Xe nuclei. This leads to the most stringent upper limits on WIMP-neutron cross sections for WIMP masses above 6 GeV/c², with a minimum cross section of 3.5×10(-40) cm² at a WIMP mass of 45 GeV/c², at 90% confidence level.

[Esophageal precancerous lesions: early diagnosis, treatment, and preservation of quality of life]. / Präkanzerosen im Ösophagus: Früherkennung, sichere Behandlung und Erhalt der Lebensqualität.

Modern high-resolution video endoscopes allow detailed examination of the esophageal mucosa and diagnosis of early neoplastic changes in the gastrointestinal tract. Whereas Barrett's esophagus is a precancerous condition that can develop into adenocarcinoma, there is no defined precancerous lesion for squamous cell carcinoma. Various diseases are associated with the development of esophageal squamous cell carcinoma. Chromoendoscopy has become an established method in the diagnostic work-up for better visualization of early neoplasia. If Barrett's esophagus is present, acetic acid spraying or virtual chromoendoscopy can be used to accentuate the display of superficial gyriform structures in the mucosa. The gold standard for detecting squamous cell carcinoma is still the use of Lugol solution. When early neoplasia is suspected, diagnostic endoscopic resection should be performed. This allows precise histological assessment of the tumor. Early diagnosis of neoplastic changes in the esophagus provides patients not only with the option of curative therapy but also with a good quality of life through preservation of the esophagus.

[How safe is sedation in gastrointestinal endoscopy? A multicentre analysis of 388,404 endoscopies and analysis of data from prospective registries of complications managed by members of the Working Group of Leading Hospital Gastroenterologists (ALGK)]. / Wie sicher ist die Sedierung in der gastrointestinalen Endoskopie? Eine multizentrische Auswertung von 388 404 Endoskopien und Auswertung der Daten aus prospektiv geführten Komplikationsregistern von Mitgliedern der Arbeitsgemeinschaft leitender Gastroenterologen im Krankenhaus (ALGK).

BACKGROUND: Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. METHODS: Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). RESULTS: Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty-one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class ≥ 3. CONCLUSIONS: Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class ≥ 3.

Are intracranial pressure wave amplitudes measurable through lumbar puncture?

OBJECTIVE: The aim of this study was to investigate whether pulsations measured in the brain correspond to those measured in lumbar space, and subsequently whether lumbar punctures could replace invasive recordings. METHODS: In ten patients with normal pressure hydrocephalus, simultaneous recordings of the intracranial pressure (ICP; intraparenchymal) and lumbar pressure (LP; cerebrospinal fluid pressure) were performed. During registration, pressure was altered between resting pressure and 45 mmHg using an infusion test. Data were analyzed regarding pulsations (i.e., amplitudes). Also, the pressure sensors were compared in a bench test. RESULTS: The correlation between intracranial and lumbar amplitudes was 0.98. At resting pressure, and moderately elevated ICP, intracranial pulse amplitudes exceeded that of lumbar space with about 0.9 mmHg. At the highest ICP, the difference changed to -0.2 mmHg. The bench test showed that the agreement of sensor readings was good at resting pressure, but reduced at higher amplitudes. CONCLUSIONS: Compared to intracranial registrations, amplitudes measured through lumbar puncture were slightly attenuated. The bench test showed that differences were not attributable to dissimilarities of the sensor systems. A lumbar pressure amplitude measurement is an alternative to ICP recording, but the thresholds for what should be interpreted as elevated amplitudes need to be adjusted.

Dark matter results from 225 live days of XENON100 data.

We report on a search for particle dark matter with the XENON100 experiment, operated at the Laboratori Nazionali del Gran Sasso for 13 months during 2011 and 2012. XENON100 features an ultralow electromagnetic background of (5.3 ± 0.6) × 10(-3) events/(keV(ee) × kg × day) in the energy region of interest. A blind analysis of 224.6 live days × 34 kg exposure has yielded no evidence for dark matter interactions. The two candidate events observed in the predefined nuclear recoil energy range of 6.6-30.5 keV(nr) are consistent with the background expectation of (1.0 ± 0.2) events. A profile likelihood analysis using a 6.6-43.3 keV(nr) energy range sets the most stringent limit on the spin-independent elastic weakly interacting massive particle-nucleon scattering cross section for weakly interacting massive particle masses above 8 GeV/c(2), with a minimum of 2 × 10(-45) cm(2) at 55 GeV/c(2) and 90% confidence level.