Universitätsklinik Marien Hospital Herne

BACKGROUND: Radiographic contrast agents can cause a reduction in renal function that may be due to reactive oxygen species. Whether the reduction can be prevented by the administration of antioxidants is unknown. METHODS: We prospectively studied 83 patients with chronic renal insufficiency (mean [+/-SD] serum creatinine concentration, 2.4+/-1.3 mg per deciliter [216+/-116 micromol per liter]) who were undergoing computed tomography with a nonionic, low-osmolality contrast agent. Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline. RESULTS: Ten of the 83 patients (12 percent) had an increase of at least 0.5 mg per deciliter (44 micromol per liter) in the serum creatinine concentration 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidence interval, 0.02 to 0.9). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 2.5+/-1.3 to 2.1+/-1.3 mg per deciliter (220+/-118 to 186+/-112 micromol per liter) 48 hours after the administration of the contrast medium, whereas in the control group, the mean serum creatinine concentration increased nonsignificantly (P=0.18), from 2.4+/-1.3 to 2.6+/-1.5 mg per deciliter (212+/-114 to 226+/-133 micromol per liter) (P<0.001 for the comparison between groups). CONCLUSIONS: Prophylactic oral administration of the antioxidant acetylcysteine, along with hydration, prevents the reduction in renal function induced by contrast agents in patients with chronic renal insufficiency.

Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold. Furthermore, several new analysis methods are included. For example, batch annotation of TCR repertoire sequencing samples allows for annotating large datasets on-line. Using recently developed bioinformatic methods for TCR motif mining, we have built a reduced set of high-quality TCR motifs that can be used for both training TCR specificity predictors and matching against TCRs of interest. These additions enhance the versatility of the VDJdb in the task of exploring T-cell antigen specificities. The database is available at https://vdjdb.cdr3.net.

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.

Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

BACKGROUND: Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients. METHODS: Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m(2) and cisplatin 7.5 mg/m(2) (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C. RESULTS: No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2-5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0-6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days. CONCLUSIONS: PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10% of a usual systemic dose.

BACKGROUND: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear. METHODS: In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days. RESULTS: A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups. CONCLUSIONS: Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFalpha, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.

Many different systems for the assessment of pain in newborns and infants have been tested for validity, rarely for reliability but never for sensitivity or specificity. We aimed to determine whether the assessment of an analgesic demand in the lower age group during the postoperative period is possible by observational methods only. In an repetitive and sequential prospective process for identifying observationable behaviour and measurable physiological parameters as indicators of a postoperative analgesic demand, 584 newborns, infants and young children were studied (7 prospective studies, 4238 observations). Twenty-six items were selected as suggested by current literature and for reasons of economy and practicability. The factor analyses resulted in a two-factorial solution with the behavioural items loading on one factor and the physiological parameters on the other (principal component analyses). The physiological parameters blood pressure, respiratory rate and heart rate were found to be unreliable and had no discriminant power to detect an analgesic demand during the postoperative period (discriminant analyses, ROC-curves). In newborns and infants, nine observational items were identified as equally selective, reliable, sensitive and specific to the assessment of postoperative analgesic demand, whereas in young children only five items could be identified (discriminant analyses, ROC-curves). For economic reasons, these five items (crying, facial expression, posture of the trunk, posture of the legs, motor restlessness) were chosen as the basis of an additional pain scale ranging from 0=no pain to 10=maximal (Children's and Infants' Postoperative Pain Scale, CHIPPS). Its internal consistency yielded values for Cronbachs' alpha with 0.92 for toddlers and 0.96 for infants. The coefficient for interrater reliability was 0.93. The scale was validated constructively by the intravenous administration of metamizol, tramadol, nalbuphine, piritramide and ketamine (repeated measures analysis of variance). The Toddler-Preschooler Postoperative Pain Scale and CHIPPS equally identified painfree situations or analgesic demand in 87.4%. In cases with definite pain, the score of CHIPPS was never below 4 points. Seventy-one toddlers gave verbal comments on their pain intensity: in 29 painfree situations the CHIPPS score was 3.0 and in 29 painful situations it was 5.7. The values for sensitivity and specificity of CHIPPS were calculated to be 0.92-0.96 and 0.74-0.95, respectively (discriminant analyses). We conclude that it is possible to determine postoperative analgesic demand in the low age group of children by using an observational system such as CHIPPS alone.

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

RATIONALE: Obstructive sleep apnea (OSA) is linked to increased cardiovascular risk, but the impact of mild forms of OSA and their treatment on cardiovascular outcomes remains controversial. OBJECTIVES: To prospectively investigate cardiovascular outcomes in treated versus untreated patients with OSA. METHODS: Consecutive sleep laboratory patients with all degrees of OSA were included. Endpoints were nonfatal (myocardial infarction, stroke, and acute coronary syndrome requiring revascularization procedures) and fatal (death from myocardial infarction or stroke) cardiovascular events. MEASUREMENTS AND MAIN RESULTS: Comparison of event-free survival rates in treated versus untreated patients (Kaplan-Meier estimates, log-rank test). Of 449 patients enrolled (age, 56.0 +/- 10.5 years; body mass index, 30.8 +/- 5.4 kg/m(2)), 364 patients received OSA treatment, and 85 patients remained untreated. Median follow-up was 72.0 months (range, 1-156). Mean apnea-hypopnea index before treatment was 30.9 +/- 21.8/hour in treated and 15.3 +/- 13.0/hour in untreated patients, but there were no differences in cardiovascular comorbidities or risk factors. In patients with mild-moderate OSA (n = 288), events were more frequent in untreated patients (estimated event-free survival at 10 yr, 51.8 vs. 80.3% [P < 0.001]; absolute risk reduction, 28.5%; number needed to treat to prevent one event/10 yr, 3.5). After adjustment for age, gender, cardiovascular risk factors, and comorbidities at baseline, OSA treatment was an independent predictor for events (hazard ratio, 0.36; 95% confidence interval, 0.21-0.62; P < 0.001). CONCLUSIONS: OSA treatment was associated with a cardiovascular risk reduction of 64% independent from age and preexisting cardiovascular comorbidities. OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA.

Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients. Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

This manuscript describes the use of ultrasound elastography, with the exception of liver applications, and represents an update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography.

Malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences for health outcomes and quality of life. The aim of the present paper is to describe current approaches and evidence regarding malnutrition treatment and to highlight relevant knowledge gaps that need to be addressed. Recently published guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) provide a summary of the available evidence and highlight the wide range of different measures that can be taken-from the identification and elimination of potential causes to enteral and parenteral nutrition-depending on the patient's abilities and needs. However, more than half of the recommendations therein are based on expert consensus because of a lack of evidence, and only three are concern patient-centred outcomes. Future research should further clarify the etiology of malnutrition and identify the most relevant causes in order to prevent malnutrition. Based on limited and partly conflicting evidence and the limitations of existing studies, it remains unclear which interventions are most effective in which patient groups, and if specific situations, diseases or etiologies of malnutrition require specific approaches. Patient-relevant outcomes such as functionality and quality of life need more attention, and research methodology should be harmonised to allow for the comparability of studies.

Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient's conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient's preferences - his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.Please see related article: http://www.biomedcentral.com/1741-7015/12/222.

Post-stroke dysphagia (PSD) is present in more than 50% of acute stroke patients, increases the risk of complications, in particular aspiration pneumonia, malnutrition and dehydration, and is linked to poor outcome and mortality. The aim of this guideline is to assist all members of the multidisciplinary team in their management of patients with PSD. These guidelines were developed based on the European Stroke Organisation (ESO) standard operating procedure and followed the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. An interdisciplinary working group identified 20 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence and wrote evidence-based recommendations. Expert opinion was provided if not enough evidence was available to provide recommendations based on the GRADE approach. We found moderate quality of evidence to recommend dysphagia screening in all stroke patients to prevent post-stroke pneumonia and to early mortality and low quality of evidence to suggest dysphagia assessment in stroke patients having been identified at being at risk of PSD. We found low to moderate quality of evidence for a variety of treatment options to improve swallowing physiology and swallowing safety. These options include dietary interventions, behavioural swallowing treatment including acupuncture, nutritional interventions, oral health care, different pharmacological agents and different types of neurostimulation treatment. Some of the studied interventions also had an impact on other clinical endpoints such as feedings status or pneumonia. Overall, further randomized trials are needed to improve the quality of evidence for the treatment of PSD.

PURPOSE: Based on our first experiences with real-time elastography in the field of prostate diagnostics we evaluate its usefulness for biopsy guidance for prostate cancer detection. MATERIALS AND METHODS: After imaging with conventional B-mode ultrasound in conjunction with real-time elastography 404 men underwent systematic sextant biopsy. RESULTS: Overall prostate cancer was found in 151 of 404 cases (37.4%). In 127 of 151 cases (84.1%), prostate cancer was detected using real-time elastography as an additional diagnostic feature. CONCLUSIONS: The results show that it is possible to detect prostate cancer with a high degree of sensitivity using real-time elastography in conjunction with conventional diagnostic methods for guided prostate biopsies.

Olfactory receptors (ORs) are expressed not only in the sensory neurons of the olfactory epithelium, where they detect volatile substances, but also in various other tissues where their potential functions are largely unknown. Here, we report the physiological characterization of human OR51E2, also named prostate-specific G-protein-coupled receptor (PSGR) due to its reported up-regulation in prostate cancer. We identified androstenone derivatives as ligands for the recombinant receptor. PSGR can also be activated with the odorant β-ionone. Activation of the endogenous receptor in prostate cancer cells by the identified ligands evoked an intracellular Ca2+ increase. Exposure to β-ionone resulted in the activation of members of the MAPK family and inhibition of cell proliferation. Our data give support to the hypothesis that because PSGR signaling could reduce growth of prostate cancer cells, specific receptor ligands might therefore be potential candidates for prostate cancer treatment. Olfactory receptors (ORs) are expressed not only in the sensory neurons of the olfactory epithelium, where they detect volatile substances, but also in various other tissues where their potential functions are largely unknown. Here, we report the physiological characterization of human OR51E2, also named prostate-specific G-protein-coupled receptor (PSGR) due to its reported up-regulation in prostate cancer. We identified androstenone derivatives as ligands for the recombinant receptor. PSGR can also be activated with the odorant β-ionone. Activation of the endogenous receptor in prostate cancer cells by the identified ligands evoked an intracellular Ca2+ increase. Exposure to β-ionone resulted in the activation of members of the MAPK family and inhibition of cell proliferation. Our data give support to the hypothesis that because PSGR signaling could reduce growth of prostate cancer cells, specific receptor ligands might therefore be potential candidates for prostate cancer treatment. Excessive signaling by G-protein-coupled receptors (GPCRs) 3The abbreviations used are: GPCRG-protein-coupled receptorPSGRprostate-specific G-protein-coupled receptorPSAprostate-specific antigenORolfactory receptorCKcytokeratinMAPmitogen-activated proteinMAPKMAP kinaseSAPKstress-activated protein kinaseJNKc-Jun NH2-terminal kinasesiRNAsmall interfering RNADHTdihydrotestosteroneRTreverse transcriptionADT1,4,6-androstatriene-3,17-dioneGFPgreen fluorescent protein. such as endothelin A receptor (1Godara G. Cannon G.W. Cannon Jr., G.M. Bies R.R. Nelson J.B. Pflug B.R. Prostate. 2005; 65: 27-34Crossref PubMed Scopus (32) Google Scholar), bradykinin 1 receptor (2Taub J.S. Guo R. Leeb-Lundberg L.M. Madden J.F. Daaka Y. Cancer Res. 2003; 63: 2037-2041PubMed Google Scholar), follicle-stimulating hormone receptor (3Ben-Josef E. Yang S.Y. Ji T.H. Bidart J.M. Garde S.V. Chopra D.P. Porter A.T. Tang D.G. J. Urol. 1999; 161: 970-976Crossref PubMed Scopus (114) Google Scholar), and thrombin receptor (4Chay C.H. Cooper C.R. Gendernalik J.D. Dhanasekaran S.M. Chinnaiyan A.M. Rubin M.A. Schmaier A.H. Pienta K.J. Urology. 2002; 60: 760-765Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 5Cooper C.R. Chay C.H. Gendernalik J.D. Lee H.L. Bhatia J. Taichman R.S. McCauley L.K. Keller E.T. Pienta K.J. Cancer. 2003; 97: 739-747Crossref PubMed Scopus (156) Google Scholar) is known to occur in prostate cancers due to strong overexpression of the respective receptors. Activation of some of these GPCRs results in androgen-independent androgen receptor activation, thus promoting the transition of prostate cancer cells from an androgen-dependent to an androgen-independent state (6Dai J. Shen R. Sumitomo M. Stahl R. Navarro D. Gershengorn M.C. Nanus D.M. Clin. Cancer Res. 2002; 8: 2399-2405PubMed Google Scholar, 7Lee L.F. Guan J. Qiu Y. Kung H.J. Mol. Cell. Biol. 2001; 21: 8385-8397Crossref PubMed Scopus (169) Google Scholar). G-protein-coupled receptor prostate-specific G-protein-coupled receptor prostate-specific antigen olfactory receptor cytokeratin mitogen-activated protein MAP kinase stress-activated protein kinase c-Jun NH2-terminal kinase small interfering RNA dihydrotestosterone reverse transcription 1,4,6-androstatriene-3,17-dione green fluorescent protein. The prostate-specific G-protein-coupled receptor (PSGR) is a class A GPCR that was initially identified as a prostate-specific tumor biomarker (8Wang J. Weng J. Cai Y. Penland R. Liu M. Ittmann M. Prostate. 2006; 66: 847-857Crossref PubMed Scopus (45) Google Scholar, 9Weng J. Wang J. Cai Y. Stafford L.J. Mitchell D. Ittmann M. Liu M. Int. J. Cancer. 2005; 113: 811-818Crossref PubMed Scopus (51) Google Scholar, 10Xu L.L. Stackhouse B.G. Florence K. Zhang W. Shanmugam N. Sesterhenn I.A. Zou Z. Srikantan V. Augustus M. Roschke V. Carter K. McLeod D.G. Moul J.W. Soppett D. Srivastava S. Cancer Res. 2000; 60: 6568-6572PubMed Google Scholar). It is specifically expressed in prostate epithelial cells, and its expression increases significantly in human prostate intraepithelial neoplasia and prostate tumors, suggesting that PSGR may play an important role in early prostate cancer development and progression (9Weng J. Wang J. Cai Y. Stafford L.J. Mitchell D. Ittmann M. Liu M. Int. J. Cancer. 2005; 113: 811-818Crossref PubMed Scopus (51) Google Scholar, 11Xu L.L. Sun C. Petrovics G. Makarem M. Furusato B. Zhang W. Sesterhenn I.A. McLeod D.G. Sun L. Moul J.W. Srivastava S. Prostate Cancer Prostatic. Dis. 2006; 9: 56-61Crossref PubMed Scopus (36) Google Scholar). Although expression of the human PSGR was found to be prostate-specific (10Xu L.L. Stackhouse B.G. Florence K. Zhang W. Shanmugam N. Sesterhenn I.A. Zou Z. Srikantan V. Augustus M. Roschke V. Carter K. McLeod D.G. Moul J.W. Soppett D. Srivastava S. Cancer Res. 2000; 60: 6568-6572PubMed Google Scholar, 12Yuan T.T. Toy P. McClary J.A. Lin R.J. Miyamoto N.G. Kretschmer P.J. Gene. 2001; 278: 41-51Crossref PubMed Scopus (46) Google Scholar), mRNA can also be detected in the olfactory zone and the medulla oblongata of the human brain (12Yuan T.T. Toy P. McClary J.A. Lin R.J. Miyamoto N.G. Kretschmer P.J. Gene. 2001; 278: 41-51Crossref PubMed Scopus (46) Google Scholar). Human PSGR shares 93% amino acid homology to the respective mouse and rat homologues, which are also expressed in the brain (12Yuan T.T. Toy P. McClary J.A. Lin R.J. Miyamoto N.G. Kretschmer P.J. Gene. 2001; 278: 41-51Crossref PubMed Scopus (46) Google Scholar). Interestingly, PSGR has numerous sequence motifs in common with the large superfamily of olfactory receptors (ORs), which build the largest class of human GPCRs and allow the recognition of a wide range of structurally diverse molecules in the nasal epithelium (13Buck L. Axel R. Cell. 1991; 65: 175-187Abstract Full Text PDF PubMed Scopus (3695) Google Scholar, 14Firestein S. Sci. STKE. 2004; 2004: pe15PubMed Google Scholar, 15Malnic B. Godfrey P.A. Buck L.B. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 2584-2589Crossref PubMed Scopus (415) Google Scholar). Recently, also the steroid hormones androstenone and androstadienone were identified as OR ligands (16Keller A. Zhuang H. Chi Q. Vosshall L.B. Matsunami H. Nature. 2007; 449: 468-472Crossref PubMed Scopus (466) Google Scholar). In addition to their role in the sensory neurons of the nose, ORs have been found in different tissues throughout the body (17Feldmesser E. Olender T. Khen M. Yanai I. Ophir R. Lancet D. BMC Genomics. 2006; 7: 121Crossref PubMed Scopus (194) Google Scholar, 18Zhang X. De la Cruz O. Pinto J.M. Nicolae D. Firestein S. Gilad Y. Genome Biol. 2007; 8: R86Crossref PubMed Scopus (130) Google Scholar). Their function(s) in these extranasal locations are questionable except for in a few cases where functional studies have been performed in spermatozoa (19Fukuda N. Yomogida K. Okabe M. Touhara K. J. Cell Sci. 2004; 117: 5835-5845Crossref PubMed Scopus (177) Google Scholar, 20Spehr M. Gisselmann G. Poplawski A. Riffell J.A. Wetzel C.H. Zimmer R.K. Hatt H. Science. 2003; 299: 2054-2058Crossref PubMed Scopus (596) Google Scholar) and in enterochromaffin cells of the gastrointestinal tract (21Braun T. Voland P. Kunz L. Prinz C. Gratzl M. Gastroenterology. 2007; 132: 1890-1901Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Here, we report the identification of steroid ligands of heterologously expressed PSGR and investigate the functional relevance of PSGR expression in prostate tissue. Steroid hormones elicited rapid Ca2+ responses in the LNCaP prostate cancer cell line and in primary human prostate epithelial cells. Moreover, activated PSGR causes phosphorylation of p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) mitogen-activated protein kinases (MAPKs), resulting in reduced proliferation rates in prostate cancer cells. Reagents for cell culture use were purchased from Invitrogen, unless stated otherwise. HEK293 cells were maintained under standard conditions in minimum Eagle's medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin and streptomycin, and 2 mml-glutamine. LNCaP cells were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum and 100 units/ml penicillin and streptomycin. PC-3 cells were maintained in Ham's F12/RPMI 1640 (1:1) supplemented with 10% fetal bovine serum and 100 units/ml penicillin and streptomycin. HEK293 cell transfections with the PSGR-containing plasmid were performed using a standard calcium phosphate precipitation technique; for siRNA experiments, LNCaP cells were transiently transfected with either targeted or scrambled siRNAs using Exgen 500 (Fermentas). 2 days after transfection, the growth medium was removed and replaced with standard Ringer solution. Prostate cancer epithelial cells were isolated from freshly collected prostate tissue, which was obtained from radical prostatectomy specimens (adenocarcinoma of the prostate pT2c, pN0, Gleason score 4 + 4) after written consent. The tissue pieces were minced to 1-mm3 pieces and digested for 30 min at 37 °C in Ringer solution containing 0.1% trypsin-EDTA. The tissue was dissociated by trituration and washed, and single cell suspensions were prepared by centrifugation of the remaining tissue pieces. Cells were seeded in the serum-free keratinocyte medium, supplemented with 50 ng/ml human recombinant epidermal growth factor 1–53 and 50 mg/ml bovine pituitary extract and kept at 37 °C in a humidified incubator with 5% CO2. When they reached 70–80% confluence, the cells were trypsinized and subcultured either in Petri dishes for Ca2+-imaging experiments or in 96-well plates for cell proliferation. Cell morphology was checked with Zeiss Axioskop 2 microscope and viewed with ×20 magnification. The following primary antibodies were used: (a) rabbit polyclonal antibodies against p44/42 MAPK and against phosphorylated p44/42 MAPK (New England Biolabs); (b) rabbit polyclonal antibodies against p38 MAPK and phosphorylated p38 MAPK (New England Biolabs); (c) rabbit polyclonal antibodies against SAPK/JNK and phosphorylated SAPK/JNK (New England Biolabs); and (d) rabbit polyclonal against PSGR (Abcam). Secondary goat anti-rabbit antibodies conjugated to horseradish peroxidase (Bio-Rad) or Alexa Fluor 546 or Alexa Fluor 488 (Invitrogen) were used. LNCaP cells were treated with 500 mm β-ionone for the indicated times, harvested, pelleted, and homogenized in lysis buffer (50 mm Tris HCl, pH 7.4, 150 mm NaCl, 1 mm EDTA, 1% Triton X-100) with protease inhibitors (Roche Applied Science Complete® protease inhibitor mixture). Sample aliquots of the cells were mixed with Laemmli buffer (30% glycerol, 3% SDS, 125 mm Tris/Cl, pH 6.8), resolved by 10% SDS-PAGE, and transferred to nitrocellulose membrane (Protran; Schleicher & Schuell). The nitrocellulose membranes were stained with Ponceau S (Sigma), blocked with TBST (150 mm NaCl, 50 mm Tris-Cl, Tween 20, pH 7.4) containing 5% nonfat dried milk (Bio-Rad), and incubated with primary antibodies diluted in 3% dry milk in TBST. After washing and incubation with horseradish peroxidase-coupled secondary antibodies, detection was performed with ECL plus or ECL Advance (Amersham Biosciences) on Hyperfilm ECL (Amersham Biosciences). Cells were incubated (45 min/37 °C) in Ringer solution containing 3 mm Fura-2-AM (Molecular Probes). After removal of extracellular Fura-2, cells were washed with extracellular solution. For the inhibitor experiments, cells were treated with Ca2+ was performed as using a Zeiss microscope for were from of and were Exposure to was using a used were a of T. and J. Steroid hormones were purchased from and for potential activation of PSGR were in at experiments in HEK293 cells and for activation of LNCaP cells as ligands to Ca2+ responses in different experiments they not Ca2+ in was as the at the of in HEK293 cells. Human PSGR was from human by using specific that the and for the plasmid was by PSGR targeted and scrambled siRNA were with siRNA were by and the to the The siRNA sequence of PSGR was the to were and The following scrambled of the siRNA sequence was used as and LNCaP cells and primary human prostate epithelial cells were in 96-well plates at a of After at 37 °C with 5% cells were treated with different of β-ionone dihydrotestosterone or with a of β-ionone and 100 and cells were with β-ionone and of inhibitors for p38 and Cell proliferation was after 3 and days using the cell proliferation RNA of human olfactory epithelium, LNCaP and human primary prostate cells was isolated with digested with and with of mRNA with was by using reverse (Invitrogen) and was performed with 2 of and specific for PSGR prostate-specific antigen androgen cytokeratin and cytokeratin The were for 1 investigate the of PSGR in prostate tissue, we to a for G-protein-coupled receptor. We therefore transiently expressed PSGR in HEK293 cells and its by the cell responses to a of using Ca2+ to the we used to for GPCRs M. Gisselmann G. Poplawski A. Riffell J.A. Wetzel C.H. Zimmer R.K. Hatt H. Science. 2003; 299: 2054-2058Crossref PubMed Scopus (596) Google Scholar, A. Zhang W. J. Hatt H. 2006; PubMed Scopus Google Scholar, C.H. M. C. M. Gisselmann G. Hatt H. J. 1999; PubMed Google Scholar). In the used for a of 100 steroid hormones from different we identified as ligands was at different for activation of PSGR and found to as a in the range The of an at with at at 4 and which are in and were for PSGR ligands of the at of the steroid were the of the at in the of the to PSGR single substances, which were and found to be were and were in a of mm in HEK293 cells and not Ca2+ responses and PSGR has sequence of an olfactory receptor and because ORs can be activated by ligands with different receptor we the transiently expressed PSGR in HEK293 cells with a of odorant using Ca2+ 100 and which was used to for ORs M. Gisselmann G. Poplawski A. Riffell J.A. Wetzel C.H. Zimmer R.K. Hatt H. Science. 2003; 299: 2054-2058Crossref PubMed Scopus (596) Google Scholar, A. Zhang W. J. Hatt H. 2006; PubMed Scopus Google Scholar, C.H. M. C. M. Gisselmann G. Hatt H. J. 1999; PubMed Google Scholar). the we found β-ionone to be an in elicited Ca2+ responses at as as of the were as single and not in Ca2+ in HEK293 cells. In HEK293 cells, β-ionone not Ca2+ We that the of expressed PSGR to β-ionone can be by the structurally which not expressed PSGR and we PSGR is expressed in prostate epithelial cells. The prostate of epithelium in a The epithelium is of different a that a and is for the development of the epithelial cells, and the which is for the of and other of the C. J.M. Clin. Sci. 2005; PubMed Scopus Google Scholar). The of androgen-dependent cells, which and the androgen receptor C. J.M. Clin. Sci. 2005; PubMed Scopus Google Scholar), as as PSGR (10Xu L.L. Stackhouse B.G. Florence K. Zhang W. Shanmugam N. Sesterhenn I.A. Zou Z. Srikantan V. Augustus M. Roschke V. Carter K. McLeod D.G. Moul J.W. Soppett D. Srivastava S. Cancer Res. 2000; 60: 6568-6572PubMed Google Scholar). We human prostate epithelial cells from freshly collected prostate tissue, obtained from a radical prostatectomy we the LNCaP cell which is from a prostate cancer and was also to PSGR (10Xu L.L. Stackhouse B.G. Florence K. Zhang W. Shanmugam N. Sesterhenn I.A. Zou Z. Srikantan V. Augustus M. Roschke V. Carter K. McLeod D.G. Moul J.W. Soppett D. Srivastava S. Cancer Res. 2000; 60: 6568-6572PubMed Google Scholar). that primary to the LNCaP cell expression of the prostate epithelial cell and androgen receptor Moreover, cell PSGR prostate cancer cell not PSGR protein can be detected in LNCaP prostate cells, but not in HEK293 cells as by LNCaP cells to the of β-ionone with an in the intracellular calcium which could be by the of the specific inhibitor the of not an in the calcium and The of β-ionone not an in the intracellular calcium in PC-3 cells, which were not to PSGR and The primary cell culture the morphology of prostate epithelial cells the PSGR and β-ionone to prostate cancer cells elicited a in the intracellular Ca2+ to the Ca2+ responses in the LNCaP cell these results that PSGR is expressed in primary prostate epithelial cells and can be activated by the identified that the Ca2+ is not or by androgen receptor activation, we performed Ca2+ in the of the androgen receptor inhibitor which not the or the of the Moreover, that are known to the androgen and but not the heterologously expressed elicited Ca2+ increases in LNCaP cells increases in intracellular Ca2+ at in the range that have been identified as PSGR ligands in HEK293 cells were to an in the intracellular Ca2+ in LNCaP cells, at or 4 in not Ca2+ We to that of prostate cells with β-ionone and intracellular Ca2+ activation of PSGR the PSGR β-ionone to LNCaP cells elicited a in the intracellular Ca2+ that the Ca2+ was due to PSGR activation, we reduced the expression using a plasmid for in expression of interfering as an fluorescent which the of the and of Ca2+ responses specifically in the cells. that cells of PSGR Ca2+ in LNCaP cells were with the Ca2+ in cells not and of the Ca2+ that siRNA expression reduced the Ca2+ The responses from the cells in but on significantly in cells. of not the Ca2+ the expression of scrambled siRNA not also a Ca2+ in LNCaP cells, in the range and the of PSGR signaling in prostate cells, we treated the LNCaP and PC-3 cell and the primary prostate cells with β-ionone for and which resulted in a of cell proliferation in prostate cells, with a inhibition at for the LNCaP cell line A and Moreover, the of could be in LNCaP or primary cells by β-ionone A and were the cells with or The not proliferation rates of HEK293 cells or prostate cancer cells not PSGR Moreover, the of β-ionone on LNCaP cells could be by the of the specific inhibitor the intracellular of β-ionone signaling in LNCaP cells, we the phosphorylation of members of the MAP kinase which are known to be in the of cell and in prostate cells. LNCaP cells of the extracellular kinase after not but a in phosphorylation of p38 and SAPK/JNK which to 30 min of of LNCaP cells with inhibitors of p38 and SAPK/JNK kinases to with β-ionone the of β-ionone on cell proliferation The p38 MAPK inhibitor the proliferation at the only of the SAPK/JNK inhibitor 1 for and for were only not The inhibitors not cell proliferation of LNCaP cells at the used We the PSGR and identified steroid hormones and the odorant β-ionone as Moreover, we identified β-ionone as specific inhibitor for the receptor. PSGR is therefore a membrane receptor for of on intracellular signaling steroid have been identified in cells intracellular steroid receptors and in the of and for which GPCRs been identified as the of the receptor that these responses E. M. A. K. M. 2003; PubMed Scopus Google Scholar). In the we the of G-protein-coupled membrane steroid which to the superfamily of odorant receptors. to the E. M. J. Clin. 2000; PubMed Scopus Google Scholar), responses to be at steroid not be by inhibitors of transcription or and be in the of for the receptors. of these for the activation of PSGR in LNCaP cells by the androstenone derivatives that we identified as PSGR of the steroid ligands we identified as a PSGR is which can be by of is by cells of the and is the androgen in can a of and to is known to the on androgen receptors. was to be to by a to the family M. D. D. K. A. PubMed Scopus Google Scholar, K. Google Scholar). The that the of is the which the role in steroid hormone the steroid of rat that might have physiological relevance J.A. 1991; PubMed Scopus Google Scholar). The other steroid that we on to β-ionone and are not known to occur in the human body as is known to as an inhibitor the of to and is used in of cancer of the prostate A.M. C.H. J. Steroid PubMed Scopus Google Scholar). on sequence PSGR to the superfamily of odorant receptors. In ORs allow the recognition of a wide range of in the olfactory sensory neurons of the L.B. PubMed Scopus Google Scholar). Recently, human OR was identified as a steroid the steroid hormones androstenone and androstadienone in a recombinant expression (16Keller A. Zhuang H. Chi Q. Vosshall L.B. Matsunami H. Nature. 2007; 449: 468-472Crossref PubMed Scopus (466) Google Scholar). Although activation of the endogenous receptor by steroid hormones was not is that receptor also rapid steroid because in the receptor the of the respective by the of and may the OR signaling in the sensory neurons (16Keller A. Zhuang H. Chi Q. Vosshall L.B. Matsunami H. Nature. 2007; 449: 468-472Crossref PubMed Scopus (466) Google Scholar). the that ORs were found to be expressed in different tissues (17Feldmesser E. Olender T. Khen M. Yanai I. Ophir R. Lancet D. BMC Genomics. 2006; 7: 121Crossref PubMed Scopus (194) Google Scholar, 18Zhang X. De la Cruz O. Pinto J.M. Nicolae D. Firestein S. Gilad Y. 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Moreover, PSGR could also be detected in human olfactory epithelium, of the role of receptor also in the olfactory Our data give support for the hypothesis that at some expressed ORs may have functions and a role for in to its sequence to odorant PSGR can be activated by the odorant a of is an found in and as a of Science. PubMed Scopus Google Scholar). have been to cancer growth and development inhibition of D.M. P. H. Proc. Biol. 1999; PubMed Scopus Google Scholar, H. J. 1999; PubMed Scopus (156) Google Scholar), but the β-ionone and have been to by a that is not to D. A. M.C. 2004; PubMed Scopus Google Scholar). The and cell of β-ionone and are therefore by the detection of a β-ionone OR in prostate epithelial cells, we a by which and other can growth of tumor cells. In the we that PSGR is a G-protein-coupled membrane steroid receptor in prostate cells. PSGR to the superfamily of ORs and a for the of at some In we found that intracellular signaling in cell are activated by which might be used in the as a in prostate cancer We H. and J. for B. of for on the and J. and T. for with

BACKGROUND: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). METHODS: Patients received oral regorafenib 60-220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. RESULTS: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0-7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7-280 days). The most common treatment-related toxicities included hand-foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66-161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. CONCLUSION: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

OBJECTIVE: To assess the efficacy of glutamine (Gln) dipeptide-enriched total parenteral nutrition (TPN) on selected metabolic, immunologic, and clinical variables in surgical patients. SUMMARY BACKGROUND DATA: Depletion of Gln stores might lead to severe clinical complications. Recent studies indicate that the parenteral provision of Gln or Gln-containing dipeptides improves nitrogen balance, maintains the intracellular Gln pool, preserves intestinal permeability and absorption, and shortens hospital stay. METHODS: Twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24 g nitrogen kg(-1) day(-1)) and isoenergetic (29 kcal/122 kJ kg(-1) day(-1)) TPN over 5 days. Controls received 1.5 g of amino acids kg(-1) day(-1), and the test group received 1.2 g of amino acids and 0.3 g of L-alanyl-L-glutamine (Ala-Gln) kg(-1) day(-1). Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acids. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. RESULTS: No side effects or complaints were noted. Patients receiving Gln dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 +/- 3.6 vs. -23.0 +/- 2.6 g nitrogen), improved lymphocyte recovery on day 6 (2.41 +/- 0.27 vs. 1.52 +/- 0.17 lymphocytes/nL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 +/- 4.89 vs. 5.03 +/- 3.11 ng/mL). Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. CONCLUSION: We confirm the beneficial effects of Gln dipeptide-supplemented TPN on nitrogen economy, maintenance of plasma Gln concentration, lymphocyte recovery, cysteinyl-leukotriene generation, and shortened hospital stay in surgical patients.