Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A2 Type X (sPLA2-X) Inhibitors.

In order to assess the potential of sPLA2-X as a therapeutic target for atherosclerosis, novel sPLA2 inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.

Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridine-2-yl}propanoic Acid.

A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

Children having magnetic resonance imaging: A preparatory storybook and audio/visual media are preferable to anesthesia or deep sedation.

As a magnetic resonance imaging (MRI) examination lasts about 45 minutes and as the technique is sensitive to motion, children are often given sedation or anesthesia. The aim of this study was to examine whether children aged three to nine years could undergo MRI while awake and achieve adequate image quality if age-adjusted routines were used. A two-group controlled experimental design was used. Thirty-six children were assigned to a control group and underwent MRI with the prevalent routines. Thirty-three children were assigned to an intervention group and underwent the MRI while awake. The age-adjusted routine included a booklet and a story book, a model of the MRI scanner with the MRI sound, and a DVD film during the examination. In the control group, 30 children underwent the examination under anesthesia and 6 underwent the examination while they were awake. All had acceptable examinations. In the intervention group, 33 children had their examination while awake and 30 of them had acceptable examinations. The parents' satisfaction with the care was assessed to be equal or higher in the intervention group and the costs were calculated to be lower. Thus, many children receiving age-appropriate preparation and distraction can undergo MRI examinations while awake.

Patient-assessed outcomes in Swedish and Egyptian men undergoing radical cystectomy and orthotopic bladder substitution--a prospective comparative study.

OBJECTIVES: To compare two patient populations with assumed cultural differences undergoing radical cystectomy and orthotopic bladder substitution to determine whether these translate into differences in the answers to self-report instruments. METHODS: The questionnaires Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL), consisting of a general version (FACT-G) and a bladder cancer specific module, and Hospital Anxiety and Depression Scale (HADS) were used preoperatively and 3 and 12 months postoperatively to assess patient well-being, urologic symptoms, depression, and anxiety in 29 and 32 Swedish and Egyptian male patients, respectively. RESULTS: Significant differences were found between the two groups. Higher FACT-G scores (ie, better outcomes) were obtained in the Swedish patients, both preoperatively and 3 months postoperatively, but not after 12 months. Differences were also seen in the urogenital assessment provided by the FACT-BL module. HADS revealed more depression among the Egyptian patients throughout the study period. Also, anxiety was more common preoperatively and 3 months postoperatively in the Egyptian patients, but not after 12 months. CONCLUSIONS: Swedish men scored better than Egyptian men on the FACT-BL and HADS, although the latter improved with time after surgery. These results show that patient-assessed outcomes differ in patients from different sociocultural backgrounds. This should be recognized when analyzing results from comparative studies. Also, the use of culture-fair instruments is important when assessing patients with different sociocultural backgrounds.

It's like being in another world--patients' lived experience of magnetic resonance imaging.

AIM: The aim of this study was to illuminate patients' lived experience during magnetic resonance imaging. BACKGROUND: Magnetic resonance imaging has increased in importance since the early 1980s and is today a common useful diagnostic tool. Although magnetic resonance imaging are non-invasive and considered painless, many patients experience anxiety, sometimes so strong that the scan has to be terminated. DESIGN AND METHODS: The study had an inductive design and a hermeneutic phenomenological methodology was used. RESULTS: The essential theme of going through magnetic resonance imaging was a feeling of being in another world. The strange environment and isolation inside the scanner made the participants' experiences unusual, with varying degrees of difficulty dealing with it. Being in the other world caused a threat to the participants' self-control. There was a relation between threat to self-control, effort and need for support in the sense that the magnitude of threat to self-control had an impact on the effort it took to handle the situation and on the need for support, and conversely that the support received could affect the effort and threat to self-control. CONCLUSIONS: The study shows that the information received and the interaction between patients and staff have a significant influence on patients' lived experiences. The individual experience of threat to self-control requires the need for support to be individualized and care need to be adjusted for each patient.

Quality of life after cystectomy and urinary diversion: an evidence based analysis.

PURPOSE: We critically examined the evidence supporting the widely accepted notion that patients undergoing continent urinary tract reconstruction after cystectomy experience superior quality of life outcomes than patients receiving a conduit. MATERIALS AND METHODS: Based on a comprehensive MEDLINE literature search we retrieved and evaluated all full-length articles published in the English, French, German, Italian and Spanish languages comparing conduit diversion with continent cutaneous diversion and/or orthotopic bladder substitution with respect to quality of life or similar concepts. All studies were rated according to the International Consultation on Urological Diseases modification of Oxford Center for Evidence-Based Medicine levels of evidence. RESULTS: The literature on quality of life after radical cystectomy for bladder cancer was rather extensive but generally of questionable quality. The main problems were flaws in the patient materials and methodologies used. To our knowledge not a single randomized, controlled study exists in the field. Because only few articles achieved a level of evidence better than III, the International Consultation on Urological Diseases rating system does not allow further differentiation among studies. Most studies showed that overall quality of life after cystectomy remained good in most patients irrespective of urinary diversion type. CONCLUSIONS: Existing studies are unable to prove that continent reconstruction after radical cystectomy is superior to conduit diversion. This review emphasizes the importance of performing well designed studies in the future.

Quality of life in patients with bladder cancer.

The objective of this review is to examine the published data regarding quality of life (QOL) in patients with bladder cancer. Not a single, randomized controlled trial exists. Most studies are retrospective, cross-sectional, and have serious methodological flaws. There is no single QOL tool preferably used in bladder cancer. While there is no long-term data after therapy for superficial cancer, most investigations compared the impact of different forms of urinary diversion on QOL. In contrast to the prevailing notion that patients who underwent cystectomy undergoing continent urinary reconstruction have superior QOL than those receiving a conduit, existing reports fail to show significant advantages of one technique over the other.

Diagnostic delay and prognosis in invasive bladder cancer.

OBJECTIVES: To study diagnostic delay in invasive bladder cancer in a population-based material with long-term follow-up, and to evaluate whether delay in diagnosis affects the risk of bladder cancer death. MATERIAL AND METHODS: In a previous study, 177 patients with invasive bladder cancer (T1-T4) diagnosed in 1988 were investigated with regard to diagnostic delay. A review of all available clinical records was performed. In the present study, causes of death for these patients were registered over a 12-year follow-up period, and the impact of diagnostic delay on bladder cancer death was studied by means of survival analysis. RESULTS: The median diagnostic delay in the material was 144 days. When the patients were stratified into groups with diagnostic delays of 0-3, 3-6, 6-12 and >12 months, those with T1 tumours in the two groups with a diagnostic delay of <6 months showed a trend towards a decreased risk of bladder cancer death. In contrast, in patients with muscle-invasive disease, a significantly increased risk of bladder cancer death was noted for those with a diagnostic delay of <6 months. CONCLUSION: A trend towards better prognosis was found for patients with T1 tumours with a shorter diagnostic delay. The poor prognosis of patients with muscle-invasive disease and a short diagnostic delay suggests aggressive behaviour of the tumour and may explain the worse prognosis in these patients.