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Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are the pathophysiological hallmark of the disease, but the role of mutation clearance after transplantation is unclear., Methods: We used highly sensitive polymerase-chain-reaction technology to analyze the dynamics of driver mutations in peripheral-blood samples from 324 patients with myelofibrosis (73% with JAK2 mutations, 23% with CALR mutations, and 4% with MPL mutations) who were undergoing transplantation after reduced-intensity conditioning. Mutations were detected before transplantation and at 30, 100, and 180 days after transplantation to measure clearance and its effect on relapse and cure. The two primary end points were relapse and disease-free survival., Results: At day 30 after transplantation, mutation clearance was found in 42% of the patients who had JAK2 mutations, 73% of those who had CALR mutations, and 54% of those who had MPL mutations; the corresponding percentages at day 100 were 63%, 82%, and 100%. The cumulative incidence of relapse at 1 year was 6% (95% confidence interval [CI], 2 to 10) among patients with mutation clearance at day 30 after transplantation and 21% (95% CI, 15 to 27) among those without mutation clearance at day 30. Disease-free and overall survival at 6 years were 61% and 74%, respectively, among patients with mutation clearance at day 30 after transplantation and 41% and 60%, respectively, among those without mutation clearance at day 30. Mutation clearance at day 30 appeared to outperform traditional donor chimerism as a measure of response; it was independently associated with a reduced risk of relapse or progression (hazard ratio, 0.36; 95% CI, 0.21 to 0.61) and appeared to overcome differences in prognosis based on the type of driver mutation ( JAK2 vs. MPL or CALR )., Conclusions: In patients with myelofibrosis, clearance of driver mutations at day 30 after transplantation appeared to influence relapse and survival, irrespective of the underlying driver mutation., (Copyright © 2025 Massachusetts Medical Society.)

Background: The optimal TBI dose for ALL patients undergoing allogeneic SCT is still not clearly defined., Methods: Single-center retrospective analysis of high-risk ALL patients in CR1 treated with 8 Gy (n = 22) or 12 Gy (n = 50) TBI in combination with fludarabine and PTCy. Median patient age in the 8 Gy TBI cohort was 63 (37-79) and 37 (18-56) in the 12 Gy TBI cohort and median follow-up time was 21 months (range 1-92)., Results: OS and LFS at 2 years after 8 Gy were 65% and 55% versus 74% and 74% after 12 Gy (p = 0.3 and p = 0.2, respectively). CIR and NRM at 2 years were 27% and 14% after 8 Gy versus 4% and 20% after 12 Gy (p = 0.004 and p = 0.4, respectively). MRD-positive (+) patients (n = 26) receiving 12 Gy (n = 19) showed better OS (p = 0.01), LFS (p = 0.009), GRFS, lower CIR (p = 0.02), and similar NRM than did MRD+ patients receiving 8 Gy (n = 7). MRD-negative (-) patients (n = 38) receiving 12 Gy (n = 27) had similar OS, LFS, GRFS, lower CIR, and higher NRM (p = 0.04) than did MRD- patients receiving 8 Gy (n = 11)., Conclusion: Our study demonstrates that 8 Gy TBI in comparison to 12 Gy TBI results in low NRM but a high relapse rate with similar OS, LFS, and GRFS. In MRD+ high-risk ALL patients, allogeneic SCT with 12 Gy TBI leads to improved OS, LFS, GRFS, and a low relapse rate. Prospective studies comparing the different treatment regimens with larger MRD patient cohorts are needed to confirm this data., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Pulmonary vein isolation (PVI) using pulsed field ablation (PFA) or cryoballoon ablation (CBA) are commonly used single-shot techniques for the treatment of patients with atrial fibrillation (AF). The number of overweight (BMI 25-30 kg/m 2 ) and obese (BMI>30 kg/m 2 ) patients undergoing PVI is increasing, but data on this patient population is limited., Methods: Consecutive AF patients with a BMI ≥25 kg/m 2 undergoing PFA- or CBA-PVI were included in this retrospective analysis. Baseline characteristics, procedural parameters and 1-year AF-freedom were retrospectively analyzed and compared for both ablation modalities., Results: Of 115 patients (66 % men, 64 years [IQR: 58-71 years], 57 % overweight and 43 % obese) PFA- was performed in 68 % and CBA-PVI in 32 %. Contrast-dye volume (PFA: 80 ml [IQR: 60 - 117 ml] vs. CBA: 130 ml [IQR: 95 - 200 ml], P =0.001) and radiation exposure (PFA: 2196 cGy·cm 2 [IQR: 1398 - 2973 cGy·cm 2 ] vs. CBA: 3239 cGy·cm 2 [IQR: 1288 - 5062 cGy·cm 2 ], P =0.009) was lower in patients undergoing PFA-PVI. Logistic regression analysis identified obesity (OR: 5.58, 95 % CI: 1.63-19.06; P =0.006) and CBA-PVI (OR: 12.93, 95 % CI: 3.51-47.68; P < 0.001) to be associated with increased radiation exposure. Both techniques were comparably safe (PFA: 4 % vs. CBA: 0 %; P =0.3). The median follow-up time was 145 days [IQR: 103 - 294 days]. AF-freedom after 1-year was similar in overweight (82 %) and obese patients (67 %) (HR: 0.61; 95 % CI: 0.29-1.28; P =0.19) as well as in PFA- and CBA-PVI patients (76 % vs. 76 %, HR: 1.37; 95 % CI: 0.63-2.99; P =0.42)., Conclusion: Overweight and obese patients undergoing PFA-PVI had lower contrast-dye volume compared to CBA-PVI. Obesity was associated with increased radiation exposure. Both techniques were comparably safe. The 1-year AF-freedom was similar in overweight and obese patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

We retrospectively analyzed high-risk ALL patients in CR1 receiving total body irradiation based conditioning regimen with ATLG (n = 74) or PTCy (n = 73) for GVHD prophylaxis. The 3-year OS and LFS were similar in both groups: 65 and 60% in the ATLG group and 64 and 67% in the PTCy group (p = 0.9 and 0.5, respectively). CIR and NRM rate at three years was 12 and 21% after PTCy and 19 and 20% after ATLG (p = 0.4 and p = 0.9, respectively). Acute GvHD grades II-IV and grades III/IV at 100 days was 46 and 19% after PTCy and 33 and 10% after ATLG (p = 0.08 and p = 0.9, respectively). Chronic GvHD of all grade at two years was higher after PTCy: 55% versus 26% (p < 0.001). Based on the propensity score matching (PSM) analysis, aGvHD grades II-IV was trending higher in the PTCy group compared to the ATLG group (p = 0.07). In contrast to the PSM analysis, on multivariate analysis the receipt of PTCy compared with ATLG was associated with a reduced CIR (p = 0.026). Our retrospective single-center analysis shows a lower incidence of acute and chronic GvHD while displaying similar LFS and OS after ATLG compared to PTCy in TBI based allogeneic stem cell transplantation for high-risk ALL., (© 2024. The Author(s).)

Background: Pulmonary vein isolation (PVI) has become the cornerstone treatment of atrial fibrillation (AF). While in cryoablation cell damage is caused by thermal effects, lately, pulsed field ablation (PFA) has been established as a novel non-thermal tissue-specific ablation modality for PVI. However, data comparing outcomes of patients undergoing either PFA or cryoballoon ablation (CBA) for primary PVI are sparse., Methods: Consecutive patients with AF undergoing PVI by either CBA or PFA were included in the analysis. The primary outcome was the time to AF/AT recurrence. For secondary outcomes, clinical and periprocedural parameters were compared., Results: In total, outcomes of 141 AF patients treated by PFA (94 patients) or CBA (47 patients) were compared. After 365 days, 70% of patients in the PFA group and 61% of patients in the CBA group were free from AF/AT (HR 1.35, 95% CI 0.60-3.00; p = 0.470). No deaths occurred. While symptoms alleviated in both groups, only after PFA, we observed significant improvement of left atrial volume index (PFA group baseline: 40 [31;62] ml/m 2 , PFA group follow-up: 35 [29;49] ml/m 2 ; p = 0.015), NT-pro BNP levels (PFA group baseline: 1106 ± 2479 pg/ml, PFA group follow-up: 1033 ± 1742 pg/ml; p = 0.048), and left ventricular ejection fraction (LVEF) (PFA group baseline: 55 [48;60] %, PFA group follow-up: 58 [54;63] %; p = 0.006). PVI by PFA was the only independent predictor of LVEF improvement., Conclusion: In our study, we show that CBA and PFA for PVI are of similar efficacy when it comes to AF recurrence. However, our findings suggest that PFA rather than CBA might induce left atrial reverse remodeling thereby contributing to left ventricular systolic function., (© 2024. The Author(s).)

Aims: Pulmonary vein isolation (PVI) represents the gold standard in the treatment of atrial fibrillation (AF) and the use of single-shot techniques, such as cryoballoon ablation (CBA) and pulsed field ablation (PFA) using a pentaspline catheter, has gained prominence. Recent studies hypothesize that PFA might be superior to CBA, although procedural efficacy and safety data are inconsistent. A meta-analysis was conducted to compare both energy sources for the treatment of AF., Methods and Results: A structured systematic database search and meta-analysis were performed on studies investigating outcomes, periprocedural complications, and/or procedural parameters of AF patients treated by either CBA or PFA. Eleven studies reporting data from 3805 patients were included. Pulmonary vein isolation by PFA was associated with a significantly lower recurrence of atrial fibrillation/atrial tachycardia [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.54-0.98, I 2 = 20%] and fewer periprocedural complications (OR = 0.62, 95% CI = 0.40-0.96, I 2 = 6%) compared to CBA. The lower complication rate following PFA was mainly driven by fewer phrenic nerve injuries (OR = 0.19, 95% CI = 0.08-0.43, I 2 = 0%). However, there were more cases of cardiac tamponades after PFA (OR = 2.56, 95% CI = 1.01-6.49, I 2 = 0%). Additionally, using PFA for PVI was associated with shorter total procedure times [mean difference (MD) = -9.68, 95% CI = -14.92 to -4.43 min, I 2 = 92%] and lower radiation exposure (MD = -148.07, 95% CI = -276.50 to -19.64 µGy·mI 2 = 7%)., Conclusion: Our results suggest that PFA for PVI, compared to CBA, enables shorter procedure times with lower arrhythmia recurrence and a reduced risk of periprocedural complications. Randomized controlled trials need to confirm our findings., Competing Interests: Conflict of interest: R.W. received honoraria for lectures and advisory board activities and research funding from Boston Scientific. Otherwise, there are no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: During the corona pandemic, all courses on physical activity for cancer patients were canceled. The aim of our study was to evaluate the feasibility of switching dancing classes for patients and their partners to online classes., Methods: Patients and partners from courses at four different locations who consented to the online course offer were asked to fill in a pseudonymous questionnaire on access to the training, technical challenges, acceptance and well-being (1-item visual analog scale from 1 to 10) before and after the training., Results: Sixty-five participants returned the questionnaire (39 patients and 23 partners). Fifty-eight (89.2%) had danced before, and forty-eight (73.8%) had visited at least one course of ballroom dancing for cancer patients before. The first access to the online platform was difficult for 39 participants (60%). Most participants (57; 87.7%) enjoyed the online classes, but 53 (81.5%) rated them as less fun than the real classes as direct contact was missing. Well-being increased significantly after the lesson and remained improved for several days., Conclusion: Transforming a dancing class is feasible for participants with digital experience and goes along with technical difficulties. It is a substitute for real classes if mandatory and improves well-being.

The objective of this study was to compare 18 F-PSMA-1007 PET/CT and 18 F-fluorocholine PET/CT for the localization of prostate cancer (PCa) biochemical recurrence. Methods: This prospective, open-label, randomized, crossover multicenter study included PCa patients with prior definitive therapy and suspected PCa recurrence. All men underwent both 18 F-PSMA-1007 PET/CT and 18 F-fluorocholine PET/CT (102 received 18 F-PSMA-1007 PET/CT first and 88 received 18 F-fluorocholine PET/CT first). All images were assessed independently by 3 readers masked to all clinical information using a 3-point qualitative scale (0 = no recurrence, 1 = undetermined, and 2 = recurrence). Patients were monitored for approximately 6 mo. An independent panel with a urologist, radiologist, and nuclear physician reviewed all clinical data, including imaging and response to therapy, but were masked regarding PET/CT information; acting in consensus, they determined a patient-based and region-based composite standard of truth for PCa lesions. The "correct detection rates" for PCa lesions on a patient basis for each radiopharmaceutical were compared for the 3 readers individually and for the "average reader." Secondary objectives included determining whether PET/CT findings affected diagnostic thinking (impact of a test result on posttest vs. pretest probability of a correct diagnosis), therapeutic decision making (description and quantification of impact of diagnostic information gained with both radiopharmaceuticals on patient management), and adequacy of management changes. Results: A total of 190 patients were included. The primary endpoint was met. The overall correct detection rates were 0.82 for 18 F-PSMA-1007 and 0.65 for 18 F-fluorocholine ( P  < 0.0001) when undetermined findings were considered positive for malignancy and 0.77 and 0.57, respectively ( P  < 0.0001), when undetermined findings were considered negative for malignancy. A change in diagnostic thinking due to PET/CT was reported in 149 patients; 18 F-PSMA-1007 contributed more than 18 F-fluorocholine in 93 of these patients. In 122 patients, PET/CT led to an adequate diagnosis that benefited the patient; 18 F-PSMA-1007 contributed more than 18 F-fluorocholine in 88 of these patients. Conclusion: 18 F-PSMA-1007 PET/CT is superior to 18 F-fluorocholine PET/CT for the localization of PCa recurrence. Decision making was more beneficial when based on 18 F-PSMA-1007 PET/CT results., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Due to the corona, pandemic classes with physical activity for cancer patients were postponed. For an ongoing program with ballroom dancing classes for patients and their partners, the training was switched to a digital format., Methods: We evaluated the training by structured written interviews of the trainers including an open report part concerning the development and realization of the project, the teaching and training concept and their experiences as trainers., Results: 5 trainers reported data from 6 different classes including 65 participants. All in all, digital dance training is feasible and a substantial part of the participants of former face-to-face training took part. Yet, digital training imposes some restrictions to the movements taught and the interactions with and between the participants. Trainers have to invest time in a new conception of the training and additional time in guiding participants with lower experience in technical issues., Conclusion: Participants in virtual training rooms need more support and social interactions in digital training are less and different from ballroom lessons and trainers which puts more strain on trainers to motivate cancer patients., (© 2022. The Author(s).)

In the past, it was thought that physical rest was relevant for recovery of patients with prostate cancer; however, more recently there has been a paradigm shift towards physical activity parallel to oncological treatment. Diagnosis and treatment of prostate cancer are associated with limitations at various levels and side effects [9], which in the course of therapy can be a potentially therapy-limiting factor associated with dose reduction, delay or even discontinuation of therapy with negative consequences for outcome and median survival. The current study situation on the topic of physical activity in prostate cancer includes various studies with differentiated physical activity interventions and treatment time points. The studies measured physiological and psychological parameters such as physical performance, incontinence, quality of life, and fatigue. Further studies also show a positive influence of exercise therapy on the prevention of long-term complications [11, 14-16]. Various international guidelines recommend physical activity during ongoing oncological therapy [5]., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Resonant inelastic X-ray scattering in the XUV-regime has been implemented at BESSY II, pushing for a few-meV bandwidth in inelastic X-ray scattering at transition metal M-edges, rare earth N-edges and the K-edges of light elements up to carbon with full polarization control. The new dedicated low-energy beamline UE112-PGM1 has been designed to provide 1 µm vertical and 20 µm horizontal beam dimensions that serve together with sub-micrometre solid-state sample positioning as the source point for a high-resolution plane grating spectrometer and a high-transmission Rowland spectrometer for rapid overview spectra. The design and commissioning results of the beamline and high-resolution spectrometer are presented. Helium autoionization spectra demonstrate a resolving power of the beamline better than 10 000 at 64 eV with a 300 lines mm -1 grating while the measured resolving power of the spectrometer in the relevant energy range is 3000 to 6000., (open access.)

8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Physical activity has a high importance for cancer patients. The present study aimed to evaluate the influence of ballroom dancing on fatigue, body image, self-efficacy, and functional exercise capacity for patients with cancer. We collected data among participants of a regular dance training program for cancer patients with a questionnaire including the Body Image Scale (BIS), Brief Fatigue inventory (BFI), Short Scale for Measuring General Self-efficacy Beliefs (ASKU), and the 6-min walking test (6-MWT). 66 participants took part in the study, and among them, 39 participants also engaged in the 6-MWT: dance experience and the weeks of dance training were significantly associated with a higher walking distance in the 6-MWT. Participants with dance experience showed higher self-efficacy scores than participants without. Participants rated the influence of dancing on partnership positively. However, the dance training had no significant effects on fatigue or body image. Ballroom dancing may improve functional exercise capacity, and dance experience may be associated with a high self-efficacy and active lifestyle, which can be beneficial for cancer patients during and after treatment. Further studies are needed to assess the influence of ballroom dancing more deeply on physical activity and fitness and to learn more on impact on the partnership. As ballroom dancing seems to improve physical activity and wellbeing and can promote intimacy between partners, this intervention has the potential to support cancer survivors in various levels.

1,3-Benzo-thia-zin-4-ones (BTZs) are a promising new class of anti-tuberculosis drug candidates, some of which have reached clinical trials. The title compound, the benzamide derivative [2-chloro-3-nitro-5-(tri-fluoro-meth-yl)phen-yl](piper-id-in-1-yl)methanone, C 13 H 12 ClF 3 N 2 O 3 , occurs as a side product as a result of competitive reaction pathways in the nucleophilic attack during the synthesis of the BTZ 8-nitro-2-(piperidin-1-yl)-6-(tri-fluoro-meth-yl)-1,3-benzo-thia-zin-4-one, following the original synthetic route, whereby the corresponding benzoyl iso-thio-cyanate is reacted with piperidine as secondary amine. In the title compound, the nitro group and the nearly planar amide group are significantly twisted out of the plane of the benzene ring. The piperidine ring adopts a chair conformation. The tri-fluoro-methyl group exhibits slight rotational disorder with a refined ratio of occupancies of 0.972 (2):0.028 (2). There is structural evidence for inter-molecular weak C-H⋯O hydrogen bonds., (© Eckhardt et al. 2020.)

Background: Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti-inflammatory drugs failed to show distinct cachexia-inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia., Methods: A transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell-mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro-inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care., Results: We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss., Conclusions: Myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs., (© 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Data on patients' needs with respect to physicians' ethical behavior and virtues are important but not available in most cases., Patients and Methods: In an iterative process together with patients' representatives, we developed a standardized questionnaire which was distributed to the representatives of the Women's Self-Help after Cancer in Germany. We started with the classical ethical virtues and clustered them to characteristics. The patients' representatives were asked to rate in different communications settings., Results: One hundred eighty-six patients' representatives took part in the survey. For four communication situations (first communication on symptoms, diagnosis of cancer, choice of therapy, doubts on therapy), competence was rated as very important by 80-89% and as important by 6-7%; honesty as very important by 78-89% and as important by 5-12%; respect as very important by 66-71% and as important by 19-21%; and patience as very important by 55-68% and as important by 6-24%. Compassion was rated as less important, with only 24-31% rating it as very important and another 26-32% as important. Additional desires expressed by the participants were physicians having more time (9.1%) and a better relationship between physician and patient (7.0%)., Conclusion: Competence, honesty, respect, and patience are important characteristics which should be focused on in communication training of medical students and physicians. In spite of compassion being rated as less important, training on compassion/empathy might help doctors to improve coping with the continuous confrontation with complications, progress, suffering, and death of their patients.

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

According to the information-seeking behaviors of patients, booklets which can be downloaded from the Internet for free are an important source of information notably for patients with cancer. This study investigated whether information booklets for patients with cancer available at German websites are in accordance with the formal and content criteria of evidence-based information. We compared and compiled both content and formal criteria by matching different national and international standards for written patient information using a merged instrument. A catalog with a total of 16 items within 4 categories (quality of the publication, quality of information, quality of information representation, and transparency) was created. Patient information booklets for the most frequent tumor types were collected from the Internet. A total of 52 different patient booklets were downloaded and assessed. Overall, no booklet fulfilled all criteria. The quality of the publications was evaluated with an average value of 1.67 while the quality of the information had a mean value of 1.45, and the quality of information presentation had a similar rating (1.39). The transparency criteria were evaluated as lowest with an average of 1.07. In summary, German booklets for cancer patients have some shortcomings concerning formal and content criteria for evidence-based patient information. The applied requirement catalog is suitable for wide use and may help in quality assurance of health information. It may be used as part of an obligatory external evaluation, which could help improving the quality of health information.

Nitro-substituted 1,3-benzothiazinones (nitro-BTZs) are mechanism-based covalent inhibitors of Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose-2'-oxidase (DprE1) with strong antimycobacterial properties. We prepared a number of oxidized and reduced forms of nitro-BTZs to probe the mechanism of inactivation of the enzyme and to identify opportunities for further chemistry. The kinetics of inactivation of DprE1 was examined using an enzymatic assay that monitored reaction progress up to 100 min, permitting compound ranking according to k inact /K i values. The side-chain at the 2-position and heteroatom identity at the 1-position of the BTZs were found to be important for inhibitory activity. We obtained crystal structures with several compounds covalently bound. The data suggest that steps upstream from the covalent end-points are likely the key determinants of potency and reactivity. The results of protein mass spectrometry using a 7-chloro-nitro-BTZ suggest that nucleophilic reactions at the 7-position do not operate and support a previously proposed mechanism in which BTZ activation by a reduced flavin intermediate is required. Unexpectedly, a hydroxylamino-BTZ showed time-dependent inhibition and mass spectrometry corroborated that this hydroxylamino-BTZ is a mechanism-based suicide inhibitor of DprE1. With this BTZ derivative, we propose a new covalent mechanism of inhibition of DprE1 that takes advantage of the oxidation cycle of the enzyme.

The present study aimed to evaluate the feasibility of ballroom dancing for patients with cancer and their partners, and develop a simple method for assessing its effects on the patients' well-being. A total of 11 pairs (14 patients and 8 healthy partners) participated. Participation was open, and there were no restrictions in terms of the type of cancer, treatment or comorbidities. An anonymous standardized questionnaire allowing participants to rate their well-being on a visual analogue scale (VAS) from 1 to 10 was used. This rating was repeated at defined time points over 1 week. No adverse events occurred during the study, and the teaching methods appeared to be feasible for the patients. The well-being of all patients remained stable or increased during the class, and returned to the initial level within the following days. A total of 3 patients with a low well-being rating prior to class experienced a strong improvement during the class, which continued until the last day of observation for 2 patients. These results confirm the effectiveness of a VAS-based method for the evaluation of ballroom dancing in patients with different types of cancer undergoing different treatments, and its positive effect on the patients' well-being.

Background: Physical activity has positive effects on cancer patients. Dancing addresses diverse bio-psycho-social aspects. Our aim was to assess the evidence on ballroom dancing and to develop the setting for a pilot project., Methods: We performed a systematic review, extracted the data and designed a pilot training based on standard curricula. We included cancer patients during or after therapy. Training duration was 90 min with one regular pause and individual pauses as needed., Results: We retrieved two systematic reviews and six controlled studies. Types of dancing varied. Only one study used ballroom dancing. Dance training might improve well-being, physical fitness, fatigue and coping during and after therapy. Yet, evidence is scarce and data to derive the effect size are lacking; 27 patients and their partners took part in the pilot training. Patients and partners needed more time to learn the steps than is planned in regular ballroom classes. Participants were very satisfied with the adaptation of the training to their physical strength and estimated the training in a sheltered group. No side effects occurred. In spite of a high rate of participants reporting fatigue, 90 min of physical activity with only a few minutes of rest were manageable for all participants., Conclusion: Ballroom dancing may offer benefits for patients with respect to quality of life. Cancer patients prefer sheltered training setting and curricula of regular ballroom classes must be adapted for cancer patients. Strict curricula might reduce motivation and adherence and exclude patients with lower or variable fitness.

Blazed gratings are of dedicated interest for the monochromatization of synchrotron radiation when a high photon flux is required, such as, for example, in resonant inelastic X-ray scattering experiments or when the use of laminar gratings is excluded due to too high flux densities and expected damage, for example at free-electron laser beamlines. Their availability became a bottleneck since the decommissioning of the grating manufacture facility at Carl Zeiss in Oberkochen. To resolve this situation a new technological laboratory was established at the Helmholtz Zentrum Berlin, including instrumentation from Carl Zeiss. Besides the upgraded ZEISS equipment, an advanced grating production line has been developed, including a new ultra-precise ruling machine, ion etching technology as well as laser interference lithography. While the old ZEISS ruling machine GTM-6 allows ruling for a grating length up to 170 mm, the new GTM-24 will have the capacity for 600 mm (24 inch) gratings with groove densities between 50 lines mm -1 and 1200 lines mm -1 . A new ion etching machine with a scanning radiofrequency excited ion beam (HF) source allows gratings to be etched into substrates of up to 500 mm length. For a final at-wavelength characterization, a new reflectometer at a new Optics beamline at the BESSY-II storage ring is under operation. This paper reports on the status of the grating fabrication, the measured quality of fabricated items by ex situ and in situ metrology, and future development goals.

An increasing number of patients and relatives use the Internet to get additional or initial information about their disease. The aim of the study was to reevaluate the Internet usage among German cancer patients. Using a standardized questionnaire, we did an anonymous survey on patients attending a series of lectures on complementary medicine in 2014. We received 255 questionnaires. Nearly 80 % of the participants stated that they used the Internet to read up information about health or medicine issues. There was no significant difference regarding gender, age, or status (patient, current treatment/former treatment; relatives). Most users use the Internet in order to get additional information after a consultation with a physician (82.2 %). Important qualities from the view of the patient are a trustable source (65.3 %), information from experts (59.6 %), and actual information (52.8 %). There is an increasing number of patients in Germany looking for information in the Internet mostly in the intention of getting additional information. Yet, as the quality of information is heterogeneous, false information may lead to distrust in the doctor or wrong decision-making. Accordingly, organizations working on improving quality of cancer care should engage in conveying comprehensive and actual information adapted to the needs of patients. Physicians should know trustful websites for referral of patients.

Polychlorinated biphenyl (PCB) levels were determined in the faeces of three Antarctic Peninsula penguin species to assess viability as a non-invasive approach for sampling PCBs in Antarctic biota. These determinations were complemented with stable isotope and porphyrins assessments, and together this methodology determined the role of diet and metabolic disruption in penguins. Up to 60% of the collected faecal samples evidenced low molecular weight PCBs, of which, the more volatile compounds were predominant, in agreement with previous results. The highest PCB levels were reported in the gentoo penguin (Pygoscelis papua; 35.3ngg -1 wet weight average), followed by the chinstrap (Pygoscelis antarctica; 6.4ngg -1 wet weight average) and Adélie penguins (Pygoscelis adeliae; 12.9ngg -1 wet weight average). Stable isotope analyses (δ 15 N and δ 13 C) demonstrated that gentoo feeding and foraging habits differed from those of Adélie and chinstrap penguins. A strong positive correlation was found between PCB concentrations and δ 15 N, indicating the role of diet on the observed pollutant levels. Porphyrins metabolite levels were also directly correlated with PCB concentrations. These results suggest that PCB levels impair the health of Antarctic penguins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The aim of our study was to investigate the relationship between information needs and cancer patients' perceptions of the impact of the disease, self-efficacy, and locus of control. Using a standardized questionnaire, we obtained data from patients who attended a series of lectures. The questionnaire included questions on their information needs, sources of information, satisfaction with information, and short questionnaires on self-efficacy, perception of the disease, and locus of control of reinforcement. Data was obtained from 185 patients. Our results showed that the sources of information that were most often used were physicians (84 %), print media (68 %), and the Internet (59 %); online fora (7.5 %), non-medical practitioners (9.7 %), and telephone-based counseling (8.6 %) were only used by a minority. Patients with a high perception of their own control over the disease more often used any source of information available to them and were more often interested in acquiring additional information. Higher self-efficacy was significantly associated with the need for information on all topics. Patients with a higher external locus of control significantly more often used sources of information and had significantly more need for additional information. By contrast, there were no associations with an internal locus of control. Neither external nor internal locus of control showed any associations with satisfaction with information. Information needs seem to be higher in patients with a high external locus of control and low self-efficacy. Physicians, other professionals, and institutions that provide information may take these relationships into consideration for tailoring their services to patients.

For photon energies of 1 - 5 keV, blazed gratings with multilayer coating are ideally suited for the suppression of stray and higher orders light in grating monochromators. We developed and characterized a blazed 2000 lines/mm grating coated with a 20 period Cr/C- multilayer. The multilayer d-spacing of 7.3 nm has been adapted to the line distance of 500 nm and the blaze angle of 0.84° in order to provide highest efficiency in the photon energy range between 1.5 keV and 3 keV. Efficiency of the multilayer grating as well as the reflectance of a witness multilayer which were coated simultaneously have been measured. An efficiency of 35% was measured at 2 keV while a maximum efficiency of 55% was achieved at 4 keV. In addition, a strong suppression of higher orders was observed which makes blazed multilayer gratings a favorable dispersing element also for the low X-ray energy range.

Background: Endocrine therapy is a mainstay of prostate cancer therapy. Given that few data exist on patient physician communication with regard to this field of therapy and adherence, we conducted a survey of patient members of a German support organization., Patients and Methods: We developed a structured questionnaire that was tested in a pilot version and then programmed as an online questionnaire., Results: The questionnaire was completed by 694 patients. While 58 % of participants rated the information they received as comprehensive, 42 % did not. Fifty-one percentage stated that they were informed of side effects in detail, and 35 % received information on supportive treatments available in the event of side effects. Patients with higher education more often reported receiving information on side effects (p = 0.036) as well as alternatives for treatment (p = 0.001). Only 13 % stated that their questions were answered in detail, with 43 % receiving no answers or only non-detailed answers. Additional information was sought by 82 %, mostly from the Internet (67 %) and patient support groups (66 %). Seventy-six percentage experienced side effects that imposed limitations on their daily activities. Of those patients with side effects, 60 % reported that their physicians did not react to their complaints. There is a significant association between side effects in general and depression in particular and non-adherence (p < 0.01 and p = 0.002, respectively). In contrast, better information on side effects is associated with better adherence (p < 0001)., Conclusion: In order to improve adherence, detailed information on side effects and comprehensive supportive care is most important. Physicians should not rely on written information but should rather mainly engage in direct communication.

Background: Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals., Objective: To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys., Design: Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB. Protein and calorie intakes were compared to UCD treatment guidelines, average nutrient intakes of a healthy US population based on the National Health and Nutrition Examination Survey (NHANES) and Recommended Daily Allowances (RDA)., Results: In adults, mean protein intake was higher than UCD recommendations but lower than RDA and NHANES values, while calorie intake was lower than UCD recommendations, RDA and NHANES. In pediatric subjects, prescribed protein intake was higher than UCD guidelines, similar to RDA, and lower than NHANES data for all age groups, while calorie intake was at the lower end of the recommended UCD range and close to RDA and NHANES data. In pediatric subjects height, weight, and body mass index (BMI) Z-scores were within normal range (- 2 to 2)., Conclusions: Pediatric patients treated with phenylbutyrate derivatives exhibited normal height and weight. Protein and calorie intakes in adult and pediatric UCD subjects differed from UCD dietary guidelines, suggesting that these guidelines may need to be reconsidered.

Purpose: A high percentage of cancer patients use complementary and alternative medicine (CAM). The aim of our study was to learn more about the association of CAM usage, information needs, perceived impact of disease, locus of control and self-efficacy of cancer patients., Methods: We asked patients attending a series of lectures on CAM using a standardized questionnaire which integrated questions on information needs, CAM and validated short questionnaires on self-efficacy, perception of the disease and locus of control of reinforcement., Results: One hundred and eighty-five patients answered the questionnaire, from whom 45 % used CAM. Sixty percentage disclosed using CAM to the general practitioner and 57 % to the oncologist. Physicians and nurses, print media and the Internet are the most important source of information on CAM (used by 20-25 % each). Impact on neither daily life, perceived personal control nor coherence was associated with CAM usage, disclosure to physicians or sources of information. There also was no association between CAM usage and self-efficacy. In contrast, there was a significant association between CAM user rate and a high external locus of control., Conclusion: While CAM usage is agreed upon by many physicians due to the idea that it helps patients to become active and feel more in control of the disease, our data are in favor of the contrary. A strong perception of external locus of control seems to be a driver of CAM usage. Physicians should be aware of this association when counseling on CAM.

Introduction: Cancer patients generally have a great need for disease-related information. They prefer to be informed personally by the attending doctor. Yet, they also use other sources, mostly from medical laypersons or public media. The goal of our survey was to obtain insight into information patients get and their requirements regarding information., Methods and Participants: Using a standardized questionnaire, we conducted a survey on 226 patients and 32 relatives, who attended meetings providing information for cancer patients., Results: Patients were generally content or highly content with the information they got. The direct consultation with the doctor is the most important source of information especially for older patients. Information by other patients and self-help groups rank second, followed by internet and online chats, which both are of minor importance for patients older than 60 years. From the patients' point of view, sources of information should be individualized and comprehensive, provided by experts and allowing for questions. Patients prefer one constant person for communication. Remarkably, empathic communication was not rated as important. Age and gender are not associated with these preferences for these characteristics of sources of information., Discussion: Patients' and relatives' desire for an individualized, comprehensive counseling with high expertise provided by one person points to the limits of resources of the health system. The importance of additional information material will rise accordingly. This material should be tailored to the needs of diverse patient groups., (© Georg Thieme Verlag KG Stuttgart · New York.)

Rationale and Objectives: The aim of the present study was to characterize the kinetics of two nanoparticle-based contrast agents for preclinical imaging, Exitron nano 6000 and Exitron nano 12000, and the iodinated agent eXIA 160 in both healthy mice and in a mouse model of hepatocellular carcinoma (HCC). Semiautomatic segmentation of liver lesions for estimation of total tumor load of the liver was evaluated in HCC mice., Materials and Methods: The normal time course of contrast enhancement was assessed in 15 healthy C57BL/6 mice. Imaging of tumor spread in the liver was evaluated in 15 mice harboring a transgenic HCC model (ASV-B mice). Automatic segmentation of liver lesions for determination of total tumor burden of the liver was tested in three additional ASV-B mice before and after an experimental therapy., Results: In healthy mice, clearance of the contrast agent from blood was completed within 3-4 hours for eXIA 160 and Exitron nano 6000, whereas complete blood clearance of Exitron nano 12000 required about 24 hours. eXIA 160 provided maximum liver contrast at 1 hour post injection (p.i.) followed by a continuous decline. Enhancement of liver contrast with Exitron nano 6000 and Exitron nano 12000 reached a plateau at about 4 hours p.i., which lasted until the end of the measurements at 96 hours p.i. Maximum contrast enhancement of the liver was not statistically different between Exitron nano 6000 and Exitron nano 12000, but was about three times lower for eXIA 160 (P < .05). Visually Exitron nano 12000 provided the best liver-to-tumor contrast. Semiautomatic liver and tumor segmentation was feasible after the administration of Exitron nano 12000 but did not work properly for the other two contrast agents., Conclusions: Both nanoparticle-based contrast agents provided stronger and longer lasting contrast enhancement of healthy liver parenchyma. Exitron nano 12000 allowed automatic segmentation of tumor lesions for estimation of the total tumor load in the liver., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

Lowland meadow irrigation used to be widespread in Central Europe, but has largely been abandoned during the 20th century. As a result of agri-environment schemes and nature conservation efforts, meadow irrigation is now being re-established in some European regions. In the absence of natural flood events, irrigation is expected to favour fauna typical of lowland wet meadows. We analysed the effects of traditional flood irrigation on diversity, densities and species composition of three invertebrate indicator taxa in lowland meadows in Germany. Unexpectedly, alpha diversity (species richness and Simpson diversity) and beta diversity (multivariate homogeneity of group dispersions) of orthopterans, carabids, and spiders were not significantly different between irrigated and non-irrigated meadows. However, spider densities were significantly higher in irrigated meadows. Furthermore, irrigation and elevated humidity affected species composition and shifted assemblages towards moisture-dependent species. The number of species of conservation concern, however, did not differ between irrigated and non-irrigated meadows. More variable and intensive (higher duration and/or frequency) flooding regimes might provide stronger conservation benefits, additional species and enhance habitat heterogeneity on a landscape scale.

Fifty-five biota samples from the Coast of Concepcion (Chile) were analyzed for PBDEs, emerging brominated FRs, halogenated norbornenes and naturally-occurring MeO-PBDEs. PBDEs, MeO-PBDEs and halogenated norbornenes were detected at concentration levels ranging from 11 to 170, nd to 118 and nd to 5.8 ng/g lw, respectively. However, emerging brominated FRs such as decabromodiphenylethane (DBDPE), hexabromobenzene (HBB) and pentabromoethylbenzene (PBEB) were not detected in any sample. Bioaccumulation and bioconcentration processes were evaluated for the different families of compounds. Biomagnification factors (BMFs) were calculated, and some PBDE congeners (BDE-28, BDE-183 and BDE-209) as well as MeO-PBDEs presented BMF>1, being values of the naturally occurring MeO-PBDEs higher than those obtained for PBDEs. As regards halogenated norbornenes, BMF<1 were found., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We developed a model for evaluating the environmental risk of persistent organic pollutants (POPs) to aquatic organisms. The model is based on fuzzy theory and uses information provided by international experts through a questionnaire. It has been tested in two case studies for a particular type of POPs: brominated flame retardants (BFRs). The first case study is related to the EU-funded AQUATERRA project, with sampling campaigns carried out in two Ebro tributaries in Spain (the Cinca and Vero Rivers). The second one, named the BROMACUA project, assessed different aquatic ecosystems in Chile (San Vicente Bay) and Colombia (Santa Marta Marsh). In both projects, the BFRs under study were polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD). However, the model can be extrapolated to other POPs and to different aquatic ecosystems to provide useful results for decision-makers., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In the present study the occurrence of emerging hydrophobic organic pollutants in sediment samples from South America (Chile and Colombia) was investigated for the first time. Nineteen Chilean and thirteen Colombian sediment samples were analyzed in order to determine their content of brominated flame retardants (BFRs) (including PBDEs and emerging BFRs) as well as UV filters (UV-F). Samples were collected from neighboring aquatic ecosystems highly urbanized and industrialized in Colombia (Magdalena River area) and Chile (Biobio region). Different analytical procedures were applied depending on the selected analytes, based on chromatographic and mass spectrometric methodologies (GC-MS and LC-MS-MS). In general, concentration levels of both BFRs (up to 2.43 and 143ngg(-1) dw of PBDEs in Chile and Colombia, respectively) and UV-F (nd-2.96 and nd-54.4ngg(-1) dw in Chile and Colombia, respectively) were in the low range of published data, and the contribution of BFRs was higher than that of UV-F for almost all the sampled sediments., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The Lenga Estuary is one of the most industrialized sites in south central Chile where the historic operation of chlor-alkali plants resulted in large quantities of mercury (Hg) being deposited into the estuary. This historical contamination may still represent a risk to the biota in the estuary. To investigate this four macroinvertebrates, Neotrypaea uncinata (ghostshrimp), Elminius kingii (barnacle), Hemigrapsus crenulatus (shore crab) and Perinereis gualpensis (ragworm) were collected seasonally from three different sites in the Lenga Estuary and one in a reference estuary (Tubul Estuary), and analyzed for Hg and stable isotopes (δ(15)N and δ(13)C). Mercury concentrations in Lenga sediments ranged from 0.4 ± 0.1 to 13 ± 3 mg/kg, while those in Tubul sediments ranged from 0.02 ± 0.01 to 0.07 ± 0.09 mg/kg. Total Hg concentrations of invertebrates were significantly different between estuaries (p<0.05), but not by species or season for each estuary (p>0.05). In contrast, organic Hg concentrations were different by species and season with shore crab muscle tissues exhibiting the greatest percent difference. Site-specific relationships demonstrated that total Hg concentrations in ragworm best reflected the total Hg sediment mercury concentrations. Signatures of δ(13)C were correlated to the organic Hg % rather than total Hg. This suggests that organic Hg concentrations in these species were related to the carbon sources., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: This paper analyses the presence of polychlorinated biphenyls (PCBs) in escaped: farmed and wild salmons in southern Chile, analysing their concentrations and congener profiles in two species (Oncorhynchus kisutch and Oncorhynchus mykiss)., Methods: Muscle samples from both farmed and escaped fish of two species, O. mykiss (rainbow trout) and O. kisutch (coho salmon), were analysed for PCBs (42 congeners). To differentiate between the wild salmon and the salmon that have escaped from fish farms, the astaxanthin content in the muscular tissue was analysed with a high-performance liquid chromatography -diode array detector method. PCBs were measured by gas chromatography with an electron capture detector., Results: The levels of astaxanthin can be used to differentiate between farmed, escaped and wild-borne salmons with statistically different concentrations. When comparing the total PCB concentrations for both trout and salmon samples, it can be determined that a separate analysis for farmed, escaped and wild-borne fish more accurately describes the real differences in the concentrations; these differences are hidden when separate analyses are not performed. The congener profiles are similar in both trout and coho salmon, where the tri-, tetra- and penta-CB congeners are the most abundant., Conclusion: This study is the first report of PCBs in wild-borne, farmed and escaped salmons for the Southern Hemisphere, considering that Chile is actually one of the principal world producers of salmon.

Background: Schizophrenia is a severe mental illness associated with hallucinations, delusions, apathy, poor social functioning, and impaired cognition. Researchers and funders have been hesitant to focus efforts on treatment preferences of patients with schizophrenia because of the perceived cognitive burden that research methods, such as conjoint analysis, place on them., Objective: The objective of this study was to test if patients diagnosed with schizophrenia were able to complete a choice-based conjoint analysis (often referred to as discrete-choice experiments) and to test if meaningful trade-offs were being made., Methods: German outpatients diagnosed with schizophrenia were eligible to participate in this study if they were aged 18-65 years, had received treatment for at least 1 year and were not experiencing acute symptoms. Conjoint analysis tasks were based on six attributes, each with two levels, which were identified via a literature review and focus groups. A psychologist in a professional interview facility presented each respondent with the eight tasks with little explanation. All interviews were recorded, transcribed, and analyzed to verify that respondents understood the tasks. Preferences were assessed using logistic regression, with a correction for clustering., Results: We found evidence that the 21 patients diagnosed with schizophrenia participating in the study could complete conjoint analysis tasks in a meaningful way. Patients not only related to the scenarios presented in conjoint tasks, but explicitly stated that they used their own preferences to judge which scenarios were better. Statistical analysis confirmed all hypotheses about the attributes (i.e. all attributes had the expected sign). Having a supportive physician, not feeling slowed, and improvements in stressful situations (p < 0.01) were the most important attributes., Conclusions: We found that patients diagnosed with schizophrenia can complete conjoint analysis tasks, that they base their decisions on their own preferences, and that patients make trade-offs between attributes.

A series of tetrahydro-1 H-1,4-diazepines 4a-c, dihydro-1 H-1,4-diazepine 5 and pyrido diazepines 8 and 10 was prepared. Originated form dehydroacetic acid (DHA) and aromatic aldehydes cinnamoyl compounds 3a-c were obtained and converted with ethylenediamine to give tetrahydro-1H-1,4-diazepines 4a-c. For the synthesis of pyrido[1,2-d][1,4]diazepines 8 and 10 a new snythetic approach is described. Compounds 4b and 5 were investigated concerning their affinity to different benzodiazepine receptor subtypes. The determined IC50 values for 5 are 1.5 microM and 1.1 microM at 10 microM respectively.

A number of publications on publication bias or selected outcomes reporting have led critics to doubt that the pharmaceutical industry is able to remain objective in its research activities. This paper discusses the prerequisites for objective research and to what extent these are met by research projects conducted by the pharmaceutical industry. Problems with meeting objectivity criteria on the part of the pharmaceutical industry will be highlighted, distinguishing between industrial research activities themselves (i.e., studies) and the publication of data resulting from such research. The aim of the discussion is to illustrate how and which research-guiding conditions can ensure that sponsors indeed meet the criteria for objective research.

Background: While there is an increasing emphasis on patient empowerment and shared decision-making, subjective values for attributes associated with their treatment still need to be measured and considered. This contribution seeks to define properties of an ideal drug treatment of individuals concerned with Attention-Deficit/Hyperactivity Disorder (ADHD). Because of the lack of information on patient needs in the decision-makers assessment of health services, the individuals' preferences often play a subordinate role at present. Discrete Choice Experiments offer strategies for eliciting subjective values and making them accessible for physicians and other health care professionals., Methods: The evidence comes from a Discrete Choice Experiments (DCE) performed in 2007. After reviewing the literature about preferences of ADHS we conducted a qualitative study with four focus groups consisting of five to eleven ADHS-patients each. In order to achieve content validity, we aimed at collecting all relevant factors for an ideal ADHS treatment. In a subsequent quantitative study phase (n = 219), data was collected in an online or paper-pencil self-completed questionnaire. It included sociodemographic data, health status and patients' preferences of therapy characteristics using direct measurement (23 items on a five-point Likert-scale) as well as a Discrete-Choice-Experiment (DCE, six factors in a fold-over design)., Results: Those concerned were capable of clearly defining success criteria and expectations. In the direct assessment and the DCE, respondents attached special significance to the improvement of their social situation and emotional state (relative importance 40%). Another essential factor was the desire for drugs with a long-lasting effect over the day (relative importance 18%). Other criteria, such as flexibility and discretion, were less important to the respondents (6% and 9%, respectively)., Conclusion: Results point out that ADHD patients and their family members have clear ideas of their needs. This is especially important against the backdrop of present discussions in the healthcare sector on the relevance of patient reported outcomes (PROs) and shared decision-making. The combination of the methods used in this study offer promising strategies to elicit subjective values and making them accessible for health care professionals in a manner that drives health choices.

Objectives: Schizophrenia imposes a great burden on society, and while evaluation should play an important role in informing society's efforts to alleviate these burdens, it is unclear what "endpoints" should be chosen as the objective of such analyses. The objectives of the study were to elicit endpoints directly from patients with schizophrenia, to ascertain whether patients are sufficiently cognoscente to express what endpoints are and are not important to them and to rank the relevant endpoints., Methods: We applied principles of patient-centered health technology assessment to identify and value endpoints from the patient's perspective. Focus groups were conducted to elicit endpoints, using interpretive phenomalogical analysis (IPA) to guide the collection, analysis and interpretation of data. Patient interviews were subsequently used to elicit patient preference over endpoints. Respondents were presented with cards outlining the endpoints and asked to remove irrelevant cards. They where then asked to identify and rank their five most relevant endpoints in order of importance. Interviews were recorded for the purposed of triangulation, and data was analyzed using descriptive statistics. Patients were recruited from five geographically diverse cities in Germany. Eligibility required a diagnosis of schizophrenia by a physician and treatment with an antipsychotic medication for at least one year. Respondents were excluded if they were experiencing an acute episode., Results: Thirteen endpoints emerged as important from the focus groups spanning side-effects, functional status, processes of care and clinical outcomes. Respondents could clearly identify relevant and irrelevant endpoints, and rank which factors were important to them. Triangulation between field notes of the ranking exercise and recordings confirmed that rankings were not arbitrary, but justified from the respondents' point of view., Conclusions: Patients with schizophrenia can express preferences over endpoints. Our results show that qualitative methods such as IPA can be used to identify factors, but ranking exercises provide a more robust method for ranking the importance of endpoints. Future research involving patients with schizophrenia ranking outcomes is needed to identify variations across patients and methods such as conjoint analysis could prove beneficial in identifying acceptable tradeoffs across endpoints.

The goal of this study was to find the most favorable injection interval of norethisterone enanthate (NETE) plus testosterone undecanoate (TU) in terms of gonadotropin, sperm suppression, and prostatic effects. Fifty normal men were randomly assigned to receive NETE 200 mg plus TU 1000 mg every 8 wk (n = 10), every 12 wk (n = 10), every 6 wk for 12 wk and then every 12 wk (n = 10), and every 6 wk for 12 wk and thereafter TU 1000 mg plus placebo every 12 wk (n = 10), and placebo plus placebo every 6 wk for 12 wk and then every 12 wk (n = 10) for 48 wk. Semen analyses, blood drawings, physical examinations, and prostate ultrasounds were performed throughout the study. Of the men in the 8-wk injection group, 90% (nine of 10) achieved azoospermia, compared with 37.5% (three of eight) in the 12-wk injection group (P = 0.019). TU plus placebo injected every 12 wk did not maintain sperm suppression. Prostate volumes did not change significantly in either group. In conclusion, these data suggest that the combined administration of NETE and TU at 8-wk intervals represents an effective hormonal contraceptive regimen.

Objective: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression., Method: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND)., Results: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35)., Conclusion: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Introduction: Dehydroleucodine (DhL), a sesquiterpene lactone isolated from Artemisia douglasiana Besser, prevents gastroduodenal damage elicited by necrosis-inducing agents such as absolute ethanol. Changes in the number of mast cells or evidence of activation of the cells for mediator release have been observed in a wide spectrum of disease processes involving the gastrointestinal tract. In the present study we examined the effects of DhL on duodenal mast cell population and their histamine content, with the goal of throwing more light on the mechanism of action of the drug., Materials and Methods: Male Rockland mice (n = 30) were divided into two groups and administered orally with 0.4% carboxymethylcellulose (CMC; control group) or DhL in 0.4% CMC, 40 mg/kg body weight (DhL group). The animals were killed 60 min after dosing and their duodena were removed. Mucosal and submucosal mast cells were studied by light and electron microscopy, and the duodenal histamine content was measured by high-performance liquid chromatography., Results: DhL increased the number of mast cells in the submucosal layer. This was related to an increase in the tissue histamine levels (from 324 +/- 19.14 to 1,284 +/- 20 pg/mg tissue, in controls and DhL-treated, respectively). The mast cells in the submucosa from the control group showed a cytoplasm containing a predominant population of homogenously dense granules, and the DhL-treated group exhibited swollen granules showing different degrees of particulation. The mucosal mast cell population showed no modifications in response to the cytoprotective agent., Conclusions: DhL induces (1) a selective increase in the number of mast cells in the submucosal layer and (2) changes in the distribution and appearance of their secretory granules. These findings, probably associated with the higher histamine levels after DhL treatment, could be involved in the cytoprotective action of the lactone, previously reported by us., (Copyright 2003 S. Karger AG, Basel)

Environmental chemicals may be involved in the etiology of breast cancers. Many studies have addressed the association between cancer in humans and agricultural pesticide exposure. Organophosphorous pesticides have been used extensively to control mosquito plagues. Parathion and malathion are organophosphorous pesticides extensively used to control a wide range of sucking and chewing pests of field crops, fruits, and vegetables. They have many structural similarities with naturally occurring compounds, and their primary target of action in insects is the nervous system; they inhibit the release of the enzyme acetylcholinesterase at the synaptic junction. Eserine, parathion, and malathion are cholinesterase inhibitors responsible for the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses. Atropine, a parasympatholytic alkaloid, is used as an antidote to acetylcholinesterase inhibitors. The aim of this study was to examine whether pesticides were able to induce malignant transformation of the rat mammary gland and to determine whether alterations induced by these substances increase the cholinergic activation influencing such transformation. These results showed that eserine, parathion, and malathion increased cell proliferation of terminal end buds of the 44-day-old mammary gland of rats, followed by formation of 8.6, 14.3, and 24.3% of mammary carcinomas, respectively, after about 28 months. At the same time, acetylcholinesterase activity decreased in the serum of these animals from 9.78 +/- 0.78 U/mL in the control animals to 3.05 +/- 0.06 U/mL; 2.57 +/- 0.15 U/mL; and 3.88 +/- 0.44 U/mL in the eserine-, parathion-, and malathion-treated groups, respectively. However, atropine alone induced a significant (p < 0.05) decrease in the acetylcholinesterase activity from the control value of 9.78 +/- 0.78 to 4.38 +/- 0.10 for atropine alone, to 1.32 +/- 0.06 for atropine in combination with eserine, and 2.39 +/- 0.29 for atropine with malathion, and there was no mammary tumor formation. These results indicate that organophosphorous pesticides induce changes in the epithelium of mammary gland influencing the process of carcinogenesis, and such alterations occur at the level of nervous system by increasing the cholinergic stimulation.

Three cases of esophageal Crohn's disease (CD) are described, each with dysphagia and/or odynophagia caused by esophageal ulceration. All three patients had associated ileocolitis. One patient followed for a prolonged period responded to treatment with sulfasalazine and prednisone. A computer search back to 1967 produced 72 additional cases of esophageal CD. Among these 75 patients (total), who were, on average, 34 years old, esophageal disease was the presenting disease symptom in 41 patients (55%). The diagnosis was difficult in 13 patients, in whom no distal bowel disease was detected at the time of initial esophageal presentation. The most common presentation was dysphagia associated with aphthous or deeper ulcerations (52 patients). In 11 of these patients, oral aphthous ulcerations were also present. Esophageal stenosis or fistulas to surrounding structures were present in 27 patients and led to surgery in 17 patients. Most of the unfavourable outcomes were in this group of 27 patients with esophageal complications, including five deaths. Fourteen additional patients required surgery for CD of other areas. Responses of uncomplicated ulcerative disease of the esophagus tended to be favourable if the medical regimen included prednisone. Clinical patterns of esophageal CD were divided into three categories: ulcerative, stenosing and asymptomatic (acute disease in children).