High-Brightness Continuous-Wave Electron Beams from Superconducting Radio-Frequency Photoemission Gun.

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK_{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10 nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

Impact of preoperative hemoglobin and CRP levels on cancer-specific survival in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder: results of a single-center study.

PURPOSE: Different blood parameters have shown to be associated with patient's oncological outcome. There is only limited knowledge about the prognostic relevance of routine blood parameters in patients undergoing radical cystectomy for transitional cell carcinoma (TCC). Therefore, we retrospectively analyzed the influence of preoperative C-reactive protein (CRP) and hemoglobin (Hb) levels on overall survival (OS) and cancer-specific survival (CSS). MATERIALS AND METHODS: Preoperative CRP and Hb levels were available in 664 patients who underwent RC due to TCC from 2004 to 2013 at our institution. More men than women (77 vs. 23 %) underwent surgery with a median age of 70 years (35-97). Median follow-up time was 24 months (max. 108). Outcome was analyzed using Kaplan-Meier method, log-rank test, and Cox regression models. RESULTS: Median CRP level was 0.5 mg/dl (0.1-28.3), and median Hb level was 13.4 g/dl (6.7-17.9). Patients with CRP value above the median died significantly earlier due to their disease than those with CRP below the median (median CSS 19 vs. 70 months; p < 0.001). Patients with preoperative Hb level below the median had significantly worse outcome than those with Hb level above the median (median CSS 25 vs. 78 months; p < 0.001). In multivariate analysis, CRP and Hb levels were independent prognostic parameters regarding CSS/OS (CRP p = 0.016/p = 0.004; Hb p = 0.006/p = 0.004, respectively). CONCLUSIONS: In our single-center study, preoperative CRP and Hb levels were found to be independent prognostic factors, indicating impaired outcome in patients undergoing RC for TCC. These findings could be used for individual risk stratification and optimization of therapeutic strategies.

[Common and not so common nerve entrapment syndromes: diagnostics, clinical aspects and therapy]. / Häufige und nicht so häufige Engpasssyndrome : Diagnostik, Klinik, Therapie.

Altogether, nerve entrapment syndromes have a very high incidence. Neurological deficits attributable to a focal peripheral nerve lesion lead to the clinical diagnosis. Frequently, pain is the dominant symptom but is often not confined to the nerve supply area. Electroneurography, electromyography, and more recently also neurosonography are the most important diagnostic tools. In most patients surgical therapy is necessary, which should be carried out in a timely manner. The entrapment syndromes discussed are suprascapular nerve entrapment, carpal tunnel syndrome, cubital tunnel syndrome, meralgia paraesthetica, thoracic outlet syndrome and anterior interosseous nerve syndrome.

A new concept for early recovery after surgery for patients undergoing radical cystectomy for bladder cancer: results of a prospective randomized study.

PURPOSE: Early recovery after surgery concepts have gained wide acceptance in various surgical specialties. However, limited data are available for radical cystectomy. A new early recovery after surgery concept was compared to a more conservative regimen in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: A total of 101 consecutive patients were prospectively randomized to early recovery after surgery (62) or a conservative regimen (39) (intended randomization ratio was 2 early recovery after surgery-to-1 conservative regimen). Primary end points were differences in quality of life, and secondary end points included postoperative morbidity, demand for analgesics, time spent in the intermediate care unit, mobility and number of gastrointestinal events during hospital stay. RESULTS: Quality of life parameters, as measured by the EORTC (European Organization for the Research and Treatment of Cancer) Quality of Life questionnaire QLQ-30 did not change significantly between postoperative days 3 and 7 and at discharge from hospital in the conservative regimen group, whereas a significant improvement was observed in the early recovery after surgery group. Postoperative morbidity was lower in the early recovery after surgery group in terms of wound healing disorders (p = 0.006), fever (p = 0.004) and thrombosis (p = 0.027). The demand for analgesics was significantly lower in the early recovery after surgery group. The amount of food consumed in relation to the amount of food offered was significantly higher for the early recovery after surgery group as early as day 3 (p = 0.02). Time spent in the intermediate care unit was significantly shorter for the early recovery after surgery group (p <0.001). There were no significant differences between the groups with respect to gastrointestinal events. The main limitations of this study were the lack of long-term data as well as the single center approach. CONCLUSIONS: Early recovery after surgery of patients who underwent radical cystectomy appears to have significant benefits compared to a conservative regimen in terms of postoperative morbidity, quality of life, use of analgesics and time spent in the intermediate care unit.

Feasibility of radical cystectomy in exclusive spinal and/or epidural anaesthesia.

PURPOSE: Muscle invasive bladder cancer can be found predominantly in elderly people with a high likelihood of suffering from concomitant diseases; especially in these patients, the risks associated with general anaesthesia during radical cystectomy can be the limiting factor of performing an otherwise indicated radical operation. To overcome this limitation, we analysed the feasibility of performing radical cystectomy in exclusive spinal and/or epidural anaesthesia. METHODS: Between March and June 2010, nine patients underwent radical cystectomy in exclusive spinal and/or epidural anaesthesia. These patients were either not willing or unfit to undergo radical cystectomy in general anaesthesia. A continent urinary diversion (ileum neobladder) and an ileum-conduit were performed in five patients and four patients, respectively. The feasibility of radical cystectomy in regional anaesthesia was tested using a variety of parameters. RESULTS: All nine procedures could be performed under strict regional anaesthesia. Mean operation time was 206 min (range 146-265 min), mean intraoperative blood loss was 622 ml (range 200-1,500 ml), mean postoperative time at intermediate care was 1 day (range 0-3 days) and mean length of hospital stay was 21.8 days (range 17-26 days). Analgesics of the WHO class I, II and III were applied for 5.7, 1.2 and 2.8 days mean, respectively. CONCLUSION: Performance of radical cystectomy in exclusive spinal and/or epidural anaesthesia is feasible and can be considered particularly in those patients who would be otherwise unfit to undergo radical cystectomy in general anaesthesia. This new operative and anaesthesiological concept could also play an important role in new fast track regimens.

BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families.

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

Enzyme-based glucose delivery as a high content screening tool in yeast-based whole-cell biocatalysis.

The influence of glucose release on growth and biotransformation of yeasts was examined by using the medium EnBase® Flo in shake flasks. The medium contains a polysaccharide acting as substrate, which is degraded to glucose by the addition of an enzyme. In the present paper, this medium was adapted for the cultivation of yeasts by increasing the complex components (booster) and the enzyme concentrations to guarantee a higher glucose release rate. Important changes were an increase of the complex component booster to 10-15% and an increased glucose release by increasing the enzyme content to 15 U L(-1). The 20 yeasts investigated in the present work showed an improvement of growth and biomass production when cultivated with the EnBase medium in comparison to yeast extract dextrose (YED) medium. Values of optical densities (OD(600)) of approximately 40 AU (corresponding to over 60 g L(-1) wet cell weight) were achieved for all 20 yeast strains tested. During the following screening of the yeasts in whole-cell biotransformation, an improvement of the conversion for 19 out of the 20 yeasts cultivated with the EnBase Flo medium could be observed. The biomass from the EnBase Flo cultivation showed a higher conversion activity in the reduction of 2-butanone to (R/S)-2-butanol. The enantioselectivity (ee) of 15 yeast strains showed an improvement by using the EnBase medium. The number of yeasts with an ee >97% increased from zero with YED to six with EnBase medium. Thus, the use of a glucose release cultivation strategy in the screening process for transformation approaches provides significant benefits compared to standard batch approaches.

Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.

Sonic hedgehog, Patched and Gli are components of a mammalian signalling pathway that has been conserved during evolution and which has a central role in the control of pattern formation and cellular proliferation during development. Here we identify the human Suppressor-of-Fused (SUFUH) complementary DNA and show that the gene product interacts physically with the transcriptional effector GLI-1, can sequester GLI-1 in the cytoplasm, but can also interact with GLI-1 on DNA. Functionally, SUFUH inhibits transcriptional activation by GLI-1, as well as osteogenic differentiation in response to signalling from Sonic hedgehog. Localization of GLI-1 is influenced by the presence of a nuclear-export signal, and GLI-1 becomes constitutively nuclear when this signal is mutated or nuclear export is inhibited. These results show that SUFUH is a conserved negative regulator of GLI-1 signalling that may affect nuclear-cytoplasmic shuttling of GLI-1 or the activity of GLI-1 in the nucleus and thereby modulate cellular responses.

Generation of a zinc and rhodium containing metallomacrocycle by rearrangement of a six-coordinate precursor complex.

Two pentadentate N3,P2 ligands coordinate zinc(ii) by their N3 pocket. Four free phosphine donors allow the coordination of four AuCl moieties leading to a pentanuclear ZnAu4 complex. In contrast, the attempt to use the phosphines for chelating coordination of two Rh(CO)Cl units results in a well-organized rearrangement that ends up with the formation of a metallomacrocycle in high yields.

Prospective evaluation of 4-D contrast-enhanced-ultrasound (CEUS) imaging in bladder tumors.

PURPOSE: The evaluation of the potential clinical benefit of four-dimensional ultrasound (4D-US) in the assessment of bladder cancer (BC). MATERIAL AND METHODS: 20 patients with indication for cystoscopy for suspicion of bladder cancer were prospectively included in this study. All patients underwent two-dimensional ultrasound (2D-US), contrast enhanced ultrasound (CEUS) and real-time four-dimensional ultrasound (4D-US). All acquisitions were compared to each other in regard to image quality. This assessment was done using a 6 point scale (1 = best). All patients underwent subsequently cystoscopy with resection of the tumor (TURB), due a histopathological analysis was possible. RESULTS: All examinations were performed successfully and no patient had to be excluded from the study. Patients acceptance of 4D-US was consistently good. No adverse events occurred. Image quality of real time 4D-US (score: 1.27±0.46) was significantly superior (p < 0.001) to both, conventional 2D-US (score: 2.33±0.62) and also to 2D-CEUS (score: 2.00±0.53). In terms of tumor detection no superiority was evident for 4D-US compared to 2D-US or in utilization of CEUS (sensitivity = 0.89; specificity = 1.00; positive predictive value = 1.00; negative predictive value = 0.50; AUC = 0.944; (95% CI: 07.43-0.998)). CONCLUSION: The assessment of bladder cancer using real time 4D-US is feasible and improves the image quality and therefore also the precise anatomical consistency of intravesical tumor masses.

Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling.

We reviewed the natural history and assessed the SMN2 copy number of 66 patients with infantile spinal muscular atrophy (SMA) type I born between 2000 and 2005 in Germany whose diagnosis was confirmed by a homozygous SMN1 deletion in the first 6 months of life. After excluding patients who had received valproic acid, the median/mean age at disease endpoint was 6.1/7.3 months (range 0.0-34.0). Four (6.1%) patients with one SMN2 copy had severe SMA type '0' with joint contractures and respiratory distress from birth. Median/mean age at onset (months) in 57 (86.3%) patients with two SMN2 copies was 1.2/1.3, and 3.5/3.4 in 5 (7.6%) patients with three SMN2 copies. Median/mean age at disease endpoint was 6.5/7.8 months (range 0.5-30) in patients with two SMN2 copies. All patients with three SMN2 copies were still alive at 10-55 months, two of them under permanent ventilation. Our data are relevant for prognostication and genetic counselling. The observed clinical variability, especially in the group with two SMN2 copies, might be important for clinical trials in SMA I where a possible control group could be defined as follows: age at onset within 4-5 months, age at genetic diagnosis <6 months, two SMN2 copies present, head control in less than 10%, no respiratory distress from birth, disease endpoint either age at death or age at permanent ventilation.

Airborne lead and other elements derived from local fires in the himalayas.

The combustion of wood and yak dung for heating and cooking in a populated Nepal Himalayan valley contributes significantly to the ambient airborne concentrations of lead, copper, aluminum, magnesium, and elemental and organic carbon. A comparison of the concentrations of these elements in fresh snow with corresponding values in air suggests that the pollution aerosol is confined to the valley, with pristine air aloft.

Congenital heart disease is a feature of severe infantile spinal muscular atrophy.

OBJECTIVE: Homozygous deletions/mutations of the SMN1 gene cause infantile spinal muscular atrophy (SMA). The presence of at least one SMN2 gene copy is required for normal embryogenesis. Lack of SMN protein results in degeneration of motor neurons, while extraneuronal manifestations have been regarded as a chance association with SMA. We report on heart defects in the subgroup of congenital SMA type I patients. METHODS: Data were recruited from 65 unselected SMA I patients whose diagnosis had been confirmed genetically within the first 6 months of age. SMN2 copy numbers were analysed retrospectively and correlated with clinical findings including heart malformations. RESULTS: Four (6%) patients had one copy of SMN2, 56 (86%) had two and five (8%) had three SMN2 copies. Three out of four (75%) patients with a single SMN2 copy had congenital SMA with haemodynamically relevant atrial or ventricular septal defects. CONCLUSIONS: Previous case reports of SMA I patients with congenital heart defects did not clarify whether the cardiac malformations were coincidental. Given the respective incidences of congenitally lethal SMA with a single SMN2 copy and of cardiac septal defects in humans, a chance association of both conditions would occur in less than one out of 50 million individuals. Our findings suggest that the SMN protein is relevant for normal cardiogenesis.

[Active surveillance of prostate cancer : An update]. / Active Surveillance beim Prostatakarzinom : Ein Update.

Prostate cancer is a heterogeneous disease. In cases of low-risk prostate cancer, active surveillance represents an attractive alternative treatment. Significant complications of a definitive treatment can therefore be delayed or completely avoided. Despite strict inclusion criteria for active surveillance, the diagnosis of low-risk prostate cancer can be inaccurate and there is therefore a risk of missing the optimal point in time for definitive treatment. Multimodal diagnostics and continuous aftercare are therefore crucial.

[Current controversies in the treatment of localized prostate cancer]. / Aktuelle Kontroversen in der Therapie des lokal begrenzten Prostatakarzinoms.

In the prostate-specific antigen (PSA) era, most prostate cancers (PCa) are diagnosed in a localized stage and a plethora of therapeutic options are warranted in different clinical settings and disease stages of localized PCa. In the current narrative review, we give an overview of the current controversies in the therapeutic landscape of localized PCa and focus on organ-sparing approaches, percutaneous radiotherapy, brachytherapy as well as retropubic and robot-assisted prostatectomy by summarizing studies that have been published within the last two years.

Risks and benefits of pelvic lymphadenectomy in octogenarians undergoing radical cystectomy due to urothelial carcinoma of the bladder.

OBJECTIVES: According to current guidelines, radical cystectomy (RC) should be combined with an extended pelvic lymphadenectomy (PLND) as therapeutic and staging instrument. Objective of this study was to analyze the influence of PLND on survival rates and complication rates in a selected group of elderly patients with a minimum age of 80 years. MATERIALS AND METHODS: In this single-center retrospective analysis, we evaluated 102 patients who underwent RC due to UCB from 2004 to 2015 at our institution. In 74 patients (73%), RC was combined with PLND; in 28 cases (27%), RC was performed without PLND. Impact of PLND on cancer specific survival (CSS), overall survival (OS) and progression-free survival (PFS) was analyzed using log-rank test and COX regression model. RESULTS: In univariate analysis of the data, we were not able to show a significant impact of PLND on CSS (p = 0.606), OS (p = 0.979) or PFS (p = 0.883). Also in multivariate analysis of the data, we were not able to identify PLND as an independent prognostic parameter on survival rates of patients undergoing RC, neither for CSS (p = 0.912) nor OS (p = 0.618) or PFS (p = 0.900). CONCLUSIONS: Our small and single-center study was not able to demonstrate a significant independent influence of PLND on CSS, OS and PFS in octogenarians undergoing RC due to UCB. There is no doubt that RC should usually be combined with PLND, but the results of this small data set with a selected patient cohort indicate that RC without PLND might be an option in selected cases of elderly patients.

Is there evidence for a close connection between side of intravesical tumor location and ipsilateral lymphatic spread in lymph node-positive bladder cancer patients at radical cystectomy? Results of the PROMETRICS 2011 database.

PURPOSE: To evaluate the possible association between bladder tumor location and the laterality of positive lymph nodes (LN) in a prospectively collected multi-institutional radical cystectomy (RC) series. METHODS: The study population included 148 node-positive bladder cancer (BC) patients undergoing RC and pelvic lymph node dissection in 2011 without neoadjuvant chemotherapy and without distant metastasis. Tumor location was classified as right, left or bilateral and compared to the laterality of positive pelvic LN. A logistic regression model was used to identify predictors of ipsilaterality of lymphatic spread. Using multivariate Cox regression analyses (median follow-up: 25 months), the effect of the laterality of positive LN on cancer-specific mortality (CSM) was estimated. RESULTS: Overall, median 18.5 LN [interquartile range (IQR), 11-27] were removed and 3 LN (IQR 1-5) were positive. There was concordance of tumor location and laterality of positive LN in 82% [95% confidence interval (CI), 76-89]. Patients with unilateral tumors (n = 78) harbored exclusively ipsilateral positive LN in 67% (95% CI 56-77). No criteria were found to predict ipsilateral positive LN in patients with unilateral tumors. CSM after 3 years in patients with ipsilateral, contralateral, and bilateral LN metastasis was 41, 67, and 100%, respectively (p = 0.042). However, no significant effect of the laterality of positive pelvic LN on CSM could be confirmed in multivariate analyses. CONCLUSIONS: Our prospective cohort showed a concordance of tumor location and laterality of LN metastasis in BC at RC without any predictive criteria and without any influence on CSM. It is debatable, whether these findings may contribute to a more individualized patient management.

Expression of calcitonin receptor-like receptor in human vascular tumours.

BACKGROUND: Vascular tumours such as Kaposi's sarcoma and capillary haemangioma are characterised by abnormal vascularisation and proliferation of endothelial cells or neoplastic cells. Adrenomedullin, a potent vasodilative peptide, and its receptor, calcitonin receptor-like receptor (CRLR), play an important part in angiogenesis. AIM: To establish whether this system also plays a part in vascular diseases, showing abnormal proliferation such as vascular tumours. METHODS: CRLR expression was investigated in several specimens of Kaposi's sarcoma and other vascular tumours, using immunohistochemical analysis with a previously described CRLR-specific polyclonal antibody and reverse transcriptase-polymerase chain reaction. RESULTS: Intense and specific CRLR-immunoreactive staining of neoplastic cells was observed in all specimens, which was of greater intensity than similar staining of adjacent normal endothelium. CONCLUSIONS: CRLR is expressed in vascular tumours and, with adrenomedullin, may have a role in neoplastic vascular growth.

Ectopic expression of carcinoembryonic antigen by a melanoma cell leads to changes in the transcription of two additional cell adhesion molecules.

Ectopic expression of carcinoembryonic antigen (CEA) by the melanoma cell line Mel Wei led to alterations in cell morphology and to changes in the expression of two melanoma-associated cell adhesion molecules, neural cell adhesion molecule and MUC18. The normally flat, triangular cells developed neurite-like extensions and exhibited a less organized growth pattern. When compared to untransfected Mel Wei cells or to those transfected with an irrelevant cDNA, two independent CEA transfectants showed a decrease in the expression of neural cell adhesion molecule and an increase in the expression of MUC18. These changes, which are characteristic of the metastatic phenotype in melanomas, were observed at the cell surface and at the level of mRNA and were independent of adherent growth. Steady-state levels of neural cell adhesion molecule mRNA were reduced in CEA-expressing cells by approximately 5-fold, while MUC18 mRNA showed an 8-fold increase. No significant differences in the expression of intercellular adhesion molecule-1 or beta-2 microglobulin were observed between Mel Wei and CEA-Mel Wei. These data indicate that changes in the expression of a single cell adhesion molecule such as CEA can lead to alterations in the expression of unrelated cell adhesion molecules and may contribute to the general derangement of adhesive interactions observed frequently in tumor cells.

Biochemical characterization and tissue distribution of the Cora antigen, a cell surface glycoprotein differentially expressed on malignant and benign gastrointestinal epithelia.

A monoclonal antibody designated Cora was isolated which discriminates between malignant and benign colon epithelium. It identifies a novel, variably glycosylated membrane glycoprotein. Expression of the Cora antigen was shown to be characteristic for gastrointestinal carcinomas (100% of tested colorectal carcinomas, 70% of tested gastric carcinomas) but could not be detected on normal gastrointestinal tissues using histochemical methods on frozen tissue sections. An extensive survey of normal tissues revealed that the Cora antigen has a very restricted distribution pattern, being detected only on alveoli of the lung, granulocytes, and bone marrow. Polyacrylamide gel electrophoresis of immunoprecipitates prepared from [35S]methionine, 125I, or [3H]glucosamine labeled colon carcinoma cell lines showed that the Cora antigen consists of a group of glycoproteins ranging in apparent molecular weight from 75,000 to 95,000. Following treatment with neuraminidase, the apparent molecular weights were reduced (65,000 to 85,000) but the size heterogeneity remained. Culturing the cells in the presence of tunicamycin, which inhibits N-linked glycosylation, removed this heterogeneity and under these conditions monoclonal antibody Cora precipitated a major band with an apparent molecular weight of 33,000. Because this monoclonal antibody can distinguish between normal and malignant gastrointestinal epithelia, expression of the Cora antigen may be associated with the process of malignant transformation in this tissue.