Description: Background: KLF6-SV1 ( SV1 ), the major splice variant of KLF6 , antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis, and to elucidate its mechanism of action. Results: In HCV-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with more features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6 -depleted mice developed bigger tumors compared to the Klf6 fl(+/+) control mice. Nine months after DEN, SV1 transgenic-mice with Klf6 -depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 over-expression and Klf6 depletion. Parallel results were obtained by viral SV1-transduction- and depletion of Klf6 through adenovirus-Cre infection of primary Klf6 fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Co-IP studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6 . Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. Conclusion: Increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene. (H EPATOLOGY 2012.)

Description: Background: A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease-specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. Methods: We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). Results: Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88% -- 100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. Conclusions: Healthy persons' and patients' decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer.

Description: Background: Acute Otitis Media (AOM) is an important and common disease of childhood. Bacteria isolated from cases of clinically problematic AOM in German children were identified and characterized Methods: In a prospective non-interventional study in German children between 3 months and less than 60 months of age with Ear, Nose and Throat Specialist --confirmed AOM, middle ear fluid was obtained by tympanocentesis (when clinically indicated) or by careful sampling of otorrhea through/at an existing perforation. Results: In 100 children with severe AOM, Haemophilus influenzae was identified in 21% (18/21, 85.7% were non-typeable [NTHi]), Streptococcus pneumoniae in 10%, S. pyogenes in 13% and Moraxella catarrhalis in 1%. H. influenzae was the most frequently identified pathogen in children from 12 months of age. H. influenzae and S. pneumoniae were equally prevalent in children aged 3--11 months, but S. pyogenes was most frequently isolated in this age group. NTHi AOM disease appeared prevalent in all ages. Conclusions: NTHi, S. pneumoniae and S. pyogenes are implicated as important causes of complicated AOM in children in Germany. NTHi disease appears prevalent in all ages. The impact of vaccination to prevent NTHi and S. pneumoniae AOM may be substantial in this population and is worth investigating.

Description: ABSTRACT Riffle-pool sequences are a common feature of gravel-bed rivers. However, mechanisms of their generation and maintenance are still not fully understood. In this study a monitoring approach similar to the one of Andrews (1979 and 1982) is employed. It focuses on analysing cross-sectional and longitudinal channel geometry of a large floodplain river (Vereinigte Mulde, Sachsen-Anhalt, Germany) with a high temporal and spatial resolution, in order to conclude from stage-dependant morphometric changes to riffle and pool maintaining processes. In accordance with Richards (1976a), Andrews (1979 and 1982) among others, pool cross sections of the Mulde River are narrow and riffle cross sections are wide suggesting that they should rather be addressed as two general types of channel cross-sections than solely as bedforms. At high flows, riffles and pools in the study reaches changed in length and height but not in position. Pools were scoured and riffles aggraded, a development which was reversed during receding flows below the threshold of 0.4·Q bf (40% bankfull discharge). An index for the longitudinal amplitude of riffle-pool sequences, the bed undulation intensity or bedform amplitude, is introduced and proved to be highly significant as a form parameter, its first derivative as a process parameter. The process of pool scour and riffle fill is addressed as bedform maintenance or bedform accentuation. It is indicated by increasing longitudinal bed amplitudes. According to the observed dynamics of bed amplitudes, maintenance of riffle-pool sequences lags behind discharge peaks. Maximum bed amplitudes may be reached with a delay of several days after peak discharges. Increasing bed undulation intensity is interpreted to indicate bed mobility. Post-flood decrease of the bed undulation intensity indicates a retrograde phase when transport from pools to riffles has ceased and bed mobility is restricted to riffle tails and heads of pools. This type of transport behaviour is referred to as disconnected mobility. The comparison of two river reaches, one with undisturbed sediment supply, the other with sediment deficit, suggests that high bed undulation intensity values at low flows indicate sediment deficit and potentially channel degrading conditions. It is more generally hypothesised that channel bed undulations constitute a major component of form roughness and that increased bed amplitudes are an important feature of channel bed adjustment to sediment deficit be it temporally during late floods or permanently due to a supply limitation of bedload. Copyright © 2011 John Wiley & Sons, Ltd.

Description: Measurements of trace metal ratios in foraminiferal calcite are routinely used to reconstruct paleoceanographic conditions. Analyses using solution-based inductively coupled plasma mass spectrometry (ICP-MS) require dissolution of the entire foraminifer shell. The potential exists for contamination from adherent clays, mineralized coatings, and other diagenetic components that confound the biogenic trace metal signal. We present results from a cleaning experiment on fossil specimens of the planktic foraminifer Orbulina universa that were cracked into several shell fragments and subjected to different cleaning protocols. We use LA-ICP-MS depth profiling to evaluate the effects of reductive, oxidative, and chelating (DTPA) cleaning protocols on shell Mg/Ca and Ba/Ca ratios. Using the natural pattern of intrashell Mg/Ca heterogeneity exhibited by O. universa , we demonstrate that reductive and oxidative cleaning can dissolve shell calcite from available surfaces, although intrashell Mg/Ca minima and maxima are unaffected. High-resolution depth profiles can be used to identify areas of heterogeneous intrashell Ba/Ca, which can be excluded from computations of whole-shell Ba/Ca. The size and density of shell pores plays a major role in the degree of contamination from sedimentary material. We demonstrate an approach for computing whole-shell Me/Ca ratios from LA-ICP-MS depth profiles that accounts for potential contamination and diagenetic overprinting.

Description: Background: Treatment-naive patients newly diagnosed with HIV occasionally present with low viral RNA of

Description: Background: With the advent of percutaneous coronary intervention, specifically the bare metal stent and subsequently, the drug-eluting stent, the scope of interventional cardiology has greatly increased. Aspirin, in combination with a thienopyridine is the present-day cornerstone of oral antiplatelet therapy after coronary artery stent placement. Continuing this chronic antiplatelet therapy, to mitigate a perioperative major adverse cardiac event, can be challenging and remains controversial in patients with a coronary artery stent undergoing non-cardiac surgery. We describe here the rationale for and successful use of an alternate approach to formulating local institutional management protocols for patients with a coronary artery stent, undergoing an elective surgical procedure.DiscussionA recent systematic review identified 11 clinical practice guidelines for the perioperative management of antiplatelet therapy in patients with a coronary stent who need non-cardiac surgery. However, there is significant variance and inadequacy with these current applicable professional society guidelines. Moreover, persistently variable success has been experienced in translating even well-grounded national clinical guidelines into local practice, including in the perioperative setting. Under the auspices of a broadly multidisciplinary institutional task force and applying the Consensus-Oriented Decision-Making model, we created two evidence-informed and local expert opinion-supported standardized clinical assessment and management plans for the preoperative management of antiplatelet therapy in patients with a coronary artery stent.SummaryPatient care can be optimized via evidence-based, yet locally developed and reiterative standardized clinical assessment and management plans for patients with coronary artery stents undergoing surgical procedures. Such standardized clinical assessment and management plans can result in greater consistency in care, providing a positive feedback loop in which the care plan itself can be continuously reevaluated, improved, and brought up to date with the most recent available data and knowledge.

Description: Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently over-expressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all 8 ccRCC lines tested and was the 7th most over-expressed gene in a meta-analysis of 5 ccRCC expression datasets. MCT4-silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intratumoral heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Description: Background: Varied and fragmented care plans undertaken by different practitioners currently expose surgical patients to lapses in expected care, increase the chance for operational mistakes and accidents, and often result in unnecessary care. The Perioperative Surgical Home has thus been proposed by the American Society of Anesthesiologists and other stakeholders as an innovative, patient-centered, surgical continuity of care model that incorporates shared decision making. Topics central to the debate about an anesthesiology-based Perioperative Surgical Home include: holding the gains made in anesthesia-related patient safety; impacting surgical morbidity and mortality, including failure-to-rescue; achieving healthcare outcome metrics; assimilating comparative effectiveness research into the model; establishing necessary audit and data collection; a comparison with the hospitalist model of perioperative care; the perspective of the surgeon; the benefits of the Perioperative Surgical Home to the specialty of anesthesiology; and its associated healthcare economic advantages.DiscussionImproving surgical morbidity and mortality mandates a more comprehensive and integrated approach to the management of surgical patients. In their expanded capacity as the surgical patient's "perioperativist," anesthesiologists can play a key role in compliance with broader set of process measures, thus becoming a more vital and valuable provider from the patient, administrator, and payer perspective. The robust perioperative databases created within the Perioperative Surgical Home present new opportunities for health services and population-level research. The Perioperative Surgical Home is not intended to replace the surgeon's patient care responsibility, but rather leverage the abilities of the entire perioperative care team in the service of the patient. To achieve this goal, it will be necessary to expand the core knowledge, skills, and experience of anesthesiologists. Anesthesiologists will need to view becoming perioperative physicians as an expansion of the specialty, rather than an abdication of their traditional intraoperative role. The Perioperative Surgical Home will need to create strategic added value for a health system and payers. This added value will strengthen the position of anesthesiologists as they navigate and negotiate in the face of finite, if not decreasing fiscal resources.SummaryBroadening the anesthesiologist's scope of practice via the Perioperative Surgical Home may promote standardization and improve clinical outcomes and decrease resource utilization by providing greater patient-centered continuity of care throughout the preoperative, intraoperative, and postoperative periods.

Description: We report on the calibration of the one-dimensional hydrodynamic lake model DYRESM to simulate the water temperature conditions of the pre-alpine Lake Ammersee (South-east Germany) which is representative of deep and large lakes in this region. Special focus is given to the calibration in order to reproduce the correct thermal distribution and stratification including the time of onset and duration of summer stratification. To ensure the application of the model to investigate the impact of climate change on lakes, an analysis of the model sensitivity under stepwise modification of meteorological input parameters (air temperature, wind speed, precipitation, global radiation, cloud cover, vapor pressure, and tributary water temperature) was conducted. The total mean error of the calibration results is –0.23 °C, the root mean square error amounts to 1.012 °C. All characteristics of the annual stratification cycle were reproduced accurately by the model. Additionally, the simulated deviations for all applied modifications of the input parameters for the sensitivity analysis can be differentiated in the high temporal resolution of monthly values for each specific depth. The smallest applied alteration to each modified input parameter caused a maximum deviation in the simulation results of at least 0.26 °C. The most sensitive reactions of the model can be observed through modifications of the input parameters air temperature and wind speed. Hence the results show that further investigations at Lake Ammersee, such as coupling the hydrodynamic model with chemo-dynamic models to assess the impact of changing climate on biochemical conditions within lakes, can be carried out using DYRESM. Copyright © 2012 John Wiley & Sons, Ltd.