Environmental factors shaping the gut microbiome in a Dutch population.

The gut microbiome is associated with diverse diseases1-3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

Pelvic lymph-node staging with 18F-DCFPyL PET/CT prior to extended pelvic lymph-node dissection in primary prostate cancer - the SALT trial.

PURPOSE: The detection of lymph-node metastases (N1) with conventional imaging such as magnetic resonance imaging (MRI) and computed tomography (CT) is inadequate for primarily diagnosed prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) PET/CT is successfully introduced for the staging of (biochemically) recurrent PCa. Besides the frequently used 68gallium-labelled PSMA tracers, 18fluorine-labelled PSMA tracers are available. This study examined the diagnostic accuracy of 18F-DCFPyL (PSMA) PET/CT for lymph-node staging in primary PCa. METHODS: This was a prospective, multicentre cohort study. Patients with primary PCa underwent 18F-DCFPyL PET/CT prior to robot-assisted radical prostatectomy (RARP) with extended pelvic lymph-node dissection (ePLND). Patients were included between October 2017 and January 2020. A Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram risk probability of ≥ 8% of lymph-node metastases was set to perform ePLND. All images were reviewed by two experienced nuclear physicians, and were compared with post-operative histopathologic results. RESULTS: A total of 117 patients was analysed. Lymph-node metastases (N1) were histologically diagnosed in 17/117 patients (14.5%). The sensitivity, specificity, positive predictive value and negative predictive value for the 18F-DCFPyL PET/CT detection of pelvic lymph-node metastases on a patient level were 41.2% (confidence interval (CI): 19.4-66.5%), 94.0% (CI 86.9-97.5%), 53.8% (CI 26.1-79.6%) and 90.4% (CI 82.6-95.0%), respectively. CONCLUSION: 18F-DCFPyL PET/CT showed a high specificity (94.4%), yet a limited sensitivity (41.2%) for the detection of pelvic lymph-node metastases in primary PCa. This implies that current PSMA PET/CT imaging cannot replace diagnostic ePLND. Further research is necessary to define the exact place of PSMA PET/CT imaging in the primary staging of PCa.

Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial.

PURPOSE: In primary prostate cancer (PCa) patients, accurate staging and histologic grading are crucial to guide treatment decisions. 18F-DCFPyL (PSMA)-PET/CT has been successfully introduced for (re)staging PCa, showing high accuracy to localise PCa in lymph nodes and/or osseous structures. The diagnostic performance of 18F-DCFPyL-PET/CT in localizing primary PCa within the prostate gland was assessed, allowing for PSMA-guided targeted-prostate biopsy. METHODS: Thirty patients with intermediate-/high-risk primary PCa were prospectively enrolled between May 2018 and May 2019 and underwent 18F-DCFPyL-PET/CT prior to robot-assisted radical prostatectomy (RARP). Two experienced and blinded nuclear medicine physicians assessed tumour localisation within the prostate gland on PET/CT, using a 12-segment mapping model of the prostate. The same model was used by a uro-pathologist for the RARP specimens. Based on PET/CT imaging, a potential biopsy recommendation was given per patient, based on the size and PET-intensity of the suspected PCa localisations. The biopsy recommendation was correlated to final histopathology in the RARP specimen. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for clinically significant PCa (csPCa, Gleason score ≥ 3 + 4 = 7) were assessed. RESULTS: The segments recommended for potential targeted biopsy harboured csPCA in 28/30 patients (93%), and covered the highest Gleason score PCa segment in 26/30 patient (87%). Overall, 122 of 420 segments (29.0%) contained csPCa at final histopathological examination. Sensitivity, specificity, PPV and NPV for csPCa per segment using 18F-DCFPyL-PET/CT were 61.4%, 88.3%, 68.1% and 84.8%, respectively. CONCLUSIONS: When comparing the PCa-localisation on 18F-DCFPyL-PET/CT with the RARP specimens, an accurate per-patient detection (93%) and localisation of csPCa was found. Thus, 18F-DCFPyL-PET/CT potentially allows for accurate PSMA-targeted biopsy.

Early lesion detection with 18F-DCFPyL PET/CT in 248 patients with biochemically recurrent prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) PET/CT is increasingly used in patients with biochemically recurrent prostate cancer (BCR), mostly using gallium-68 (168Ga)-labelled radiotracers. Alternatively, fluorine-18 (18F)-labelled PSMA tracers are available, such as 18F-DCFPyL, which offer enhanced image quality and therefore potentially increased detection of small metastases. In this study we evaluate the lesion detection efficacy of 18F-DCFPyL PET/CT in patients with BCR and determine the detection efficacy as a function of their PSA value. METHODS: A total of 248 consecutive patients were evaluated and underwent scanning with 18F-DCFPyL PET/CT for BCR between November 2016 and 2018 in two hospitals in the Netherlands. Patients were examined after radical prostatectomy (52%), external-beam radiation therapy (42%) or brachytherapy (6%). Imaging was performed 120 min after injection of a median dose of 311 MBq 18F-DCFPyL. RESULTS: In 214 out of 248 PET/CT scans (86.3%), at least one lesion suggestive of cancer recurrence was detected ('positive scan'). Scan positivity increased with higher PSA values: 17/29 scans (59%) with PSA values <0.5 ng/ml; 20/29 (69%) with PSA 0.5 to <1.0 ng/ml; 35/41 (85%) with PSA 1.0 to <2.0 ng/ml; 69/73 (95%) with PSA 2.0 to <5.0 ng/ml; and 73/76 (96%) with PSA ≥5.0 ng/ml. Interestingly, suspicious lesions outside the prostatic fossa were detected in 39-50% of patients with PSA <1.0 ng/ml after radical prostatectomy (i.e. candidates for salvage radiotherapy). CONCLUSION: 18F-DCFPyL PET/CT offers early detection of lesions in patients with BCR, even at PSA levels <0.5 ng/ml. These results appear to be comparable to those reported for 68Ga-PSMA and 18F-PSMA-1007, with potentially increased detection efficacy compared to 68Ga-PSMA for patients with PSA <2.0.

Intake, digestibility, and growth performance of Girolando bulls supplemented on pasture in Bahia, Brazil.

The objective of this trial was to evaluate intake, digestibility, and growth performance of Girolando bulls submitted to two nutritional planes while grazing on Brachiaria brizantha cv. Marandu pasture. Twenty-two animals, with average initial body weight = 209.1 ± 8.2 kg, were used in this trial. The experimental design was repeated measurements, in a 2 × 3 factorial arrangement, with two nutritional planes (NP1 and NP2) and three seasons of the year, with 11 replicates per treatment. The animals of the NP1 received mineral mixture ad libitum during rainy season 1 (15 February through 5 July 2014), energy protein supplement in the amount of 1 g d kg BW-1 during the dry season (from 6 July through 22 November 2014), and again mineral mixture ad libitum during rainy season 2 (from 23 November 2014 through 9 March 2015). The NP2 animals received 2 g d kg BW-1, 2 g d kg BW-1, and 1 g d kg BW-1 of energy-protein supplement in the respective seasons of the year. Forage intakes were similar between nutritional planes, 6.8 and 7.6 kg DM day-1 and 2.1 and 2.22% BW for NP1 and NP2, respectively. There was no statistical difference (level) between the intakes of neutral detergent fiber corrected for ash and protein (4.1 and 4.3 kg day-1 and 1.2 and 1.3% BW, respectively for nutritional planes 1 and 2). For the other nutrients, NP2 showed greater values. The highest intakes and digestibilities of dry matter, organic matter, and non-fiber carbohydrate were in rainy season 2. Performance and feed conversion were similar among NPs. This study showed that lower levels of supplementation could be done in order to reduce feeding costs with no impact on performance.

Local staging with multiparametric MRI in daily clinical practice: diagnostic accuracy and evaluation of a radiologic learning curve.

PURPOSE: To estimate the diagnostic accuracy of multiparametric MRI (mpMRI) for the detection of locally advanced prostate cancer (T-stage 3-4) prior to radical prostatectomy, in a multicenter cohort representing daily clinical practice. In addition, the radiologic learning curve for the detection of locally advanced disease is evaluated. METHODS: Preoperative mpMRI findings of 430 patients (2012-2016) were compared to pathology results following radical prostatectomy. The diagnostic accuracy (sensitivity, specificity, PPV, and NPV) for the detection of locally advanced disease was calculated and compared for all years separately, to evaluate the presence of a radiological learning curve. RESULTS: Of all 137 patients with locally advanced disease, 62 patients were preoperatively detected with mpMRI [sensitivity 45.3% (95% CI 36.9-53.6%), specificity 75.8% (CI 70.9-80.7%), PPV 46.6% (CI 38.1-55.1%), and NPV 74.7% (CI 69.8-79.7%)]. The diagnostic accuracy did not improve significantly over time (sensitivity p = 0.12; specificity p = 0.57). CONCLUSIONS: In daily clinical practice, the diagnostic accuracy of mpMRI for the detection of locally advanced prostate cancer remains limited. It, therefore, seems questionable whether mpMRI is adequate to guide preoperative decision-making. No significant radiologic learning curve for the detection of locally advance disease was observed.

Essential diseases in prescribing: A national Delphi study towards a core curriculum in pharmacotherapy education.

AIMS: Prescribing is a core skill for junior doctors, yet 8-10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors. METHODS: A two-round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five-point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases. RESULTS: Sixty-two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases. CONCLUSION: This is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence.

Reliability of clinician rated physical effort determination during functional capacity evaluation in patients with chronic musculoskeletal pain.

INTRODUCTION: Functional capacity evaluation (FCE) can be used to make clinical decisions regarding fitness-for-work. During FCE the evaluator attempts to assess the amount of physical effort of the patient. The aim of this study is to analyze the reliability of physical effort determination using observational criteria during FCE. METHODS: Twenty-one raters assessed physical effort in 18 video-recorded FCE tests independently on two occasions, 10 months apart. Physical effort was rated on a categorical four-point physical effort determination scale (PED) based on the Isernhagen criteria, and a dichotomous submaximal effort determination scale (SED). Cohen's Kappa, squared weighted Kappa and % agreement were calculated. RESULTS: Kappa values for intra-rater reliability of PED and SED for all FCE tests were 0.49 and 0.68 respectively. Kappa values for inter-rater reliability of PED for all FCE tests in the first and the second session were 0.51, and 0.72, and for SED Kappa values were 0.68 and 0.77 respectively. The inter-rater reliability of PED ranged from κ = 0.02 to κ = 0.99 between FCE tests. Acceptable reliability scores (κ > 0.60, agreement ≥80 %) for each FCE test were observed in 38 % of scores for PED and 67 % for SED. On average material handling tests had a higher reliability than postural tolerance and ambulatory tests. CONCLUSION: Dichotomous ratings of submaximal effort are more reliable than categorical criteria to determine physical effort in FCE tests. Regular education and training may improve the reliability of observational criteria for effort determination.

Determination of the precision and accuracy of morphological measurements using the Kinect™ sensor: comparison with standard stereophotogrammetry.

The recent availability of the Kinect™ sensor, a low-cost Markerless Motion Capture (MMC) system, could give new and interesting insights into ergonomics (e.g. the creation of a morphological database). Extensive validation of this system is still missing. The aim of the study was to determine if the Kinect™ sensor can be used as an easy, cheap and fast tool to conduct morphology estimation. A total of 48 subjects were analysed using MMC. Results were compared with measurements obtained from a high-resolution stereophotogrammetric system, a marker-based system (MBS). Differences between MMC and MBS were found; however, these differences were systematically correlated and enabled regression equations to be obtained to correct MMC results. After correction, final results were in agreement with MBS data (p = 0.99). Results show that measurements were reproducible and precise after applying regression equations. Kinect™ sensors-based systems therefore seem to be suitable for use as fast and reliable tools to estimate morphology. Practitioner Summary: The Kinect™ sensor could eventually be used for fast morphology estimation as a body scanner. This paper presents an extensive validation of this device for anthropometric measurements in comparison to manual measurements and stereophotogrammetric devices. The accuracy is dependent on the segment studied but the reproducibility is excellent.

Reliability and safety of functional capacity evaluation in patients with whiplash associated disorders.

INTRODUCTION: Whiplash-associated disorders (WAD) are a burden for both individuals and society. It is recommended to evaluate patients with WAD at risk of chronification to enhance rehabilitation and promote an early return to work. In patients with low back pain (LBP), functional capacity evaluation (FCE) contributes to clinical decisions regarding fitness-for-work. FCE should have demonstrated sufficient clinimetric properties. Reliability and safety of FCE for patients with WAD is unknown. METHODS: Thirty-two participants (11 females and 21 males; mean age 39.6 years) with WAD (Grade I or II) were included. The FCE consisted of 12 tests, including material handling, hand grip strength, repetitive arm movements, static arm activities, walking speed, and a 3 min step test. Overall the FCE duration was 60 min. The test-retest interval was 7 days. Interclass correlations (model 1) (ICCs) and limits of agreement (LoA) were calculated. Safety was assessed by a Pain Response Questionnaire, observation criteria and heart rate monitoring. RESULTS: ICCs ranged between 0.57 (3 min step test) and 0.96 (short two-handed carry). LoA relative to mean performance ranged between 15 % (50 m walking test) and 57 % (lifting waist to overhead). Pain reactions after WAD FCE decreased within days. Observations and heart rate measurements fell within the safety criteria. CONCLUSIONS: The reliability of the WAD FCE was moderate in two tests, good in five tests and excellent in five tests. Safety-criteria were fulfilled. Interpretation at the patient level should be performed with care because LoA were substantial.

Preoperative multiparametric MRI does not lower positive surgical margin rate in a large series of patients undergoing robot-assisted radical prostatectomy.

To optimize functional outcomes after robot-assisted radical prostatectomy (RARP), surgical preservation of the neurovascular bundle is desired. However, nerve-sparing surgery (NSS) is only feasible in the absence of extraprostatic tumour extension (T-stage 3) to avoid the risk of positive surgical margins (PSM). Multiparametric magnetic-resonance imaging (MRI) is increasingly performed for primary prostate cancer and provides information on local tumour stage. In this study, we evaluated whether the availability of information from MRI influenced the incidence of PSM. A total of 523 patients undergoing RARP for localized prostate cancer in a single Dutch reference centre for prostate-cancer surgery were retrospectively evaluated (2013-2017). Patient characteristics and postoperative outcomes were retrieved. Patients were stratified according to the presence of a preoperative MRI. The incidence of PSM and proportion of patients receiving NSS was analysed using Chi-square tests and logistic regression analysis. N = 139 of 523 (26.6%) patients had a preoperative MRI scan available. Patients with MRI had identical preoperative characteristics compared to the patients without MRI, except for a higher percentage of patients having a prostate-specific antigen value ≥ 20 ng/mL (20.1% versus 9.4%, p = 0.004). PSM were present in 107/384 (27.9%) patients without MRI compared to 36/139 (25.9%) patients with an MRI scan before surgery (p = 0.66). Unilateral NSS was performed more often in the MRI group (26.6% vs. 11.7%), but NSS on both sides was more frequently performed in patients without MRI (57.6% versus 69.8%) (p < 0.001). MRI was not associated with PSM in multivariate analysis (p = 0.265). Preoperative mpMRI imaging was not associated with lower rates of positive surgical margins in patients undergoing RARP for localized prostate cancer.

bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice.

Malignant melanoma is a prime example of cancers that respond poorly to various treatment modalities including chemotherapy. A number of chemotherapeutic agents have been shown recently to act by inducing apoptosis, a type of cell death antagonized by the bcl-2 gene. Human melanoma expresses Bcl-2 in up to 90% of all cases. In the present study we demonstrate that bcl-2 antisense oligonucleotide treatment improves the chemosensitivity of human melanoma grown in severe combined immunodeficient (SCID) mice. Our findings suggest that reduction of Bcl-2 in melanoma, and possibly also in a variety of other tumors, may be a novel and rational approach to improve chemosensitivity and treatment outcome.

[Considerations about the endovascular treatment of infrarenal aortic aneurysms]. / Consideratii privind tratamentului endovascular al anevrismelor aortice infrarenale.

The introduction of the endovascular repair of aortic aneurysm (EVAR) in the clinical practice by Parodi was a milestone in the development of aortic surgery. This minimal invasive procedure promised a significant lower postoperative mortality and complications rate. Despite numerous controversies, the endovascular technique was wide accepted and fast implemented in the clinical practice. But the first prospective randomized trials showed that the benefit of the patients was limited and this innovative approach leads to particular postoperative problems. Due to a continuous improvement of the endovascular devices and increasing experience in endovascular treatment a lot of early problems have been resolved. The new generation of endografts makes possible the endovascular approach of aneurysm with shorter or angulated proximal neck. However, the anatomical suitability is still the most important limited factor of the endovascular treatment. An accurate analysis of suitability, the proper choice of the device and correct implantation allows good postoperative results. The significance of specific complications must be recognized in order to make the right surgical decision.

Fatigue and the prediction of negative health outcomes: A systematic review with meta-analysis.

INTRODUCTION: Fatigue is a common complaint among older adults. Evidence grows that fatigue is linked to several negative health outcomes. A general overview of fatigue and its relationship with negative health outcomes still lacks in the existing literature. This brings complications for healthcare professionals and researchers to identify fatigue-related health risks. Therefore, this study gives an overview of the prospective predictive value of the main negative health outcomes for fatigue in community-dwelling older adults. METHODS: PubMed, Web of Knowledge and PsycINFO were systematically screened for prospective studies regarding the relationship between fatigue and negative health outcomes resulting in 4595 articles (last search 5th March 2020). Meta-analyses were conducted in RevMan using Odds ratios (ORs), Hazard ratios (HRs) and relative risk ratios (RR) that were extracted from the included studies. Subgroup-analyses were performed based on (1) gender (male/female), (2) length of follow-up and (3) fatigue level (low, medium and high). RESULTS: In total, thirty articles were included for this systematic review and meta-analysis encompassing 152 711 participants (age range 40-98 years), providing information on the relationship between fatigue and health outcomes. The results showed that fatigue is related to an increased risk for the occurrence of all studied health outcomes (range OR 1.299-3.094; HR/RR 1.038-1.471); for example, mortality OR 2.14 [1.74-2.63]; HR/RR 1.44 [1.28-1.62]), the development of disabilities in basic activities of daily living (OR 3.22 [2.05-5.38]), or the occurrence of physical decline (OR 1.42 [1.29-1.57]). CONCLUSION: Overall fatigue increases the risk for developing negative health outcomes. The analyses presented in this study show that fatigue related physical decline occurs earlier than hospitalization, diseases and mortality, suggesting the importance of early interventions.

The ideal location of the male nipple-areolar complex: A pinpointing algorithm.

Background: In the treatment of gender dysphoria, appropriate nipple-areola complex (NAC) positioning is essential for achieving a natural appearing male chest after subcutaneous mastectomy. An accurate predictive model for the ideal personalized position of the NAC is still lacking. The aim of this study is to determine the anthropometry of the male chest to create individualized guidelines for appropriate NAC positioning in the preoperative setting. Materials and methods: Cisgender male participants were recruited. Multiple chest measurements were manually recorded. Best subset regression using linear models was used to select predictors for the horizontal coordinate (nipple-nipple distance; NN) and vertical coordinate (sternal notch-nipple distance; SNN) of the NAC. Internal validation was assessed using bootstrapping. Furthermore, a cohort of transgender men who had received a mastectomy with replantation of nipples according to current practice was identified. Comparison testing between the algorithm and standard practice was performed to test the limitations of standard practice. Results: One hundred and fifty cis male participants were included (median age: 26, IQR: 22-34 years). Four predictors were found to predict NN (age, weight, chest circumference (CC), anterior-axillar fold to anterior-axillar fold (AUX-AUX)) and reads as follows: NN = 4.11 + 0.035*age + 0.041*weight + 0.093*CC + 0.140*AUX-AUX Two predictors were found to predict SNN (NN and weight), and reads as follows: SNN = 7.248 + 0.303*NN + 0.072*weight. Both models performed well (Bootstrapped R2: 0.63 (NN), 0.50 (SNN)) and outperformed previous models predicting NAC position. Ninety-six transgender men were eligible for evaluation of current practice and showed an average placement error of -0.9 cm for NN and +2.2 cm for SNN. Conclusion: The non-standardized approach of NAC repositioning results in a significant error of nipple placement. We suggest that the two predictive models for NN and SNN can be used to optimize NAC positioning on the masculinized chest wall.Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1884926.

Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes. METHODS: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B. RESULTS: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04]. CONCLUSIONS: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.

Correction to: Letter to the Editor re: Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake.

The article was updated to correct the following errors due to an error in production.

Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound.

BACKGROUND: Development of betulinic acid derivatives for clinical use has been hampered by adverse pharmacological and physico-chemical characteristics of this class of compounds. We here present a novel semi-synthetic betulinic acid-derived drug candidate well suited for further clinical development. MATERIALS AND METHODS: In vitro activity and mode of action of NVX-207 were determined using normal as well as cancer cell lines. Gene expression profiling was performed with Affymetrix U133 microarrays. NVX-207 binding partners were identified using a heterobifunctional chemical crosslinker system. Potential binding proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Clinical studies were conducted in canine cancer patients suffering from spontaneously arising pre-treated tumours. RESULTS: NVX-207 showed anti-tumour activity (mean IC(50) = 3.5 microM) against various human and canine cell lines. NVX-207-induced apoptosis was associated with activation of the intrinsic apoptotic pathway via cleavage of caspases -9, -3, -7 and of poly (ADP-ribose) polymerase (PARP). Global gene expression profiling demonstrated regulation of genes associated with lipid metabolism, most notably an upregulation of genes coding for insulin-induced gene 1 (Insig-1), low-density lipoprotein receptor (LDL-R) and of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). NVX-207 bound to apolipoprotein A-I, a major regulator of lipid metabolism and cholesterol transport. A phase I/II study in dogs suffering from naturally occurring cancer receiving local treatment of NVX-207 (10 mg mL(-1)) showed excellent clinical responses including a complete remission in so far 5/5 treated animals. CONCLUSIONS: NVX-207 is well tolerated and has significant anti-cancer activity in vitro and in vivo in dogs with treatment-resistant malignancies.

Removal of Common Bile Ducts Stones via Percutaneous Access with a Flexible Ureteroscope and Laser Assistance.

Two patients are described with large stones in the common bile duct. Standard ERCP was not possible. Both patients were successfully treated with percutaneous access and use of the ureteroscope with the holmium laser.

Validation of the Wii Balance Board to assess balance modifications induced by increased respiratory loads in healthy subjects.

BACKGROUND: There is a link between breathing and balance and posture. When the inspiratory loads are increased by pathologies, there is a decrease of postural control. The increase of the inspiratory load on respiratory muscles is a common feature in various chronic pulmonary pathologies. Consequently, the balance of those patients is likely affected. RESEARCH QUESTION: The aim of this study is to validate the use of the Nintendo Wii Balance Board (WBB) to assess balance modifications induced by increased respiratory loads in healthy subjects. METHODS: Thirty-seven healthy young participants (25 ± 4 years old, 17 women) participated in this study. Five different conditions were tested: without anything (control), throughout a mouthpiece, and throughout three inspiratory threshold loads (ITL) at 10% (low), 40% (mid) and 60% (high) of the maximal inspiratory pressure. Each trial lasted for 60 s. Nine parameters were extracted based on center of pressure displacement based on a previously-validated method. ANOVA tests were used to compare the different conditions followed by Bonferroni's corrections. RESULTS: Highly statistically significant differences (all p < 0.01) and large effect sizes (all ω2 > 0.24) were obtained for all parameters between the different loads and the mouthpiece condition. There is a linear relationship between the load and balance perturbation. SIGNIFICANCE: In this study, we demonstrated the validity of the WBB to detect the effect of the inspiratory load on balance in young healthy subjects. Further studies are needed to determine if such a kind of evaluation can be used in clinics with patients suffering from chronic respiratory disease.