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Introduction: Recent clinical studies have implicated prostate inflammation and fibrosis in the development of bladder outlet obstruction and lower urinary tract symptoms (LUTS). Studies utilizing rodent models, including work in our laboratory, have shown prostate fibrosis to occur as a consequence of inflammation. However, the relationship between collagen content and inflammation in human tissue samples obtained from surgical treatment of benign prostatic hypererplasia (BPH)/LUTS has not to our knowledge been previously examined., Methods: Prostate tissue specimens from 53 patients (ages 47-88, mean 65.1) treated by open simple prostatectomy or transurethral resection of the prostate for BPH/LUTS were stained to quantitatively assess prostate inflammation and collagen content. Patients with prostate cancer present in greater than 5% of the surgical specimen were excluded. Prostate volume was determined from pelvic CT scan obtained within 2 years of surgery., Results: Analysis of the data showed that inflammation was inversely correlated with collagen content (r = -0.28, p = 0.04). In men with prostates less than 75 cm 3 inflammation increases and collagen content decreases with prostate volume (p = 0.002 and p = 0.03, respectively) while in men with prostate volume over 75 cm 3 inflammation decreases and collagen content increases with prostate volume (p = 0.30 and p = 0.005, respectively)., Conclusions: Our data do not support the assumed positive association of prostate inflammation with collagen content. Coordinated analysis of scatter plots of inflammation and collagen content with prostate volume revealed a subset of prostates with volumes >50 cm 3 prostate characterized by intense inflammation and low collagen content and it is this subgroup that appears most responsible for the inverse correlation of inflammation and collagen., (© 2023 The Authors The Prostate published by Wiley Periodicals LLC.)

Single-cell (SC) analysis provides unique insight into individual cell dynamics and cell-to-cell heterogeneity. Here, we utilize trapped ion mobility separation coupled with dual-polarity ionization mass spectrometry imaging (MSI) to enable high-throughput in situ profiling of the SC lipidome. Multimodal SC imaging, in which dual-polarity-mode MSI is used to perform serial data acquisition runs on individual cells, significantly enhanced SC lipidome coverage. High-spatial resolution SC-MSI identifies both inter- and intracellular lipid heterogeneity; this heterogeneity is further explicated by Uniform Manifold Approximation and Projection and machine learning-driven classifications. We characterize SC lipidome alteration in response to stearoyl-CoA desaturase 1 inhibition and, additionally, identify cell-layer specific lipid distribution patterns in mouse cerebellar cortex. This integrated multimodal SC-MSI technology enables high-resolution spatial mapping of intercellular and cell-to-cell lipidome heterogeneity, SC lipidome remodeling induced by pharmacological intervention, and region-specific lipid diversity within tissue., (© 2023. Springer Nature Limited.)

Artificial intelligence (AI) and machine learning are increasingly utilized across healthcare. More recently, there has been a rise in the use AI within research, particularly through novel conversational AI platforms, such as ChatGPT. In this Controversies paper, we discuss the advantages, limitations, and future directions for ChatGPT and other forms of conversational AI in research and scholarly dissemination., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to declare and this manuscript has not been submitted elsewhere., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this article we explore the relationships amongst anti-doping sciences, 'abjection,' and the protection of 'women's' sport. We introduce three novel concepts: 'abjection bias,' 'abjection potential,' and 'intersectional abjection,' as tools with the potential to provide greater nuance to understanding the context for these contentious issues in contemporary sport. The debate concerning participation in women's sport-especially elite sport-of people who do not fit within traditional definition of 'women' is increasingly fraught with acrimony with anti-doping sciences often recruited as arbitrator. With access to opportunities such as participation at the Olympic Games at stake, emotions run high in arguments that typically centre on inclusion of transgender and gender diverse (TGD) athletes on the one hand and protection of the women's category on the other. While sport theorists have begun the important work of identifying the roots of these problems deep within the structure of modern sport and society itself, they have hitherto paid little attention to the philosophical underpinnings of that structure. Through the lens of feminist critical analysis, we seek, in this paper, to understand the complex role of 'abjection' in framing the current debate in sport and in related anti-doping sciences. From a clear definition of abjection as a perceived existential threat due to violation of the status quo, we introduce the new concepts of 'abjection bias,' 'abjection potential,' and 'intersectional abjection' in order to understand and explain what in common parlance we might call 'gut reaction.' By looking at the few notable previous treatments of sport abjection and highlighting the historical connections between anti-doping sciences and efforts to protect the women's category, we demonstrate that this co-development is, in part, more easily understood in the context of 'abjection.' We conclude that the clarity gained can also help to shed light on current policy decision-making in relation to the question of protecting the women's sport category., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Schneider, Oldham and Butcher.)

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins. We delivered a single dose of a widespread environmental contaminant present in the serum of most Americans [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1 µg/kg], and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues, and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Lower urinary tract symptoms (LUTS) in aging men are commonly attributed to bladder outlet obstruction from benign prostatic hyperplasia (BPH) but BPH/LUTS often reflects a confluence of many factors. We performed a hierarchical cluster analysis using four objective patient characteristics (age, HTN, DM, and BMI), and five pre-operative urodynamic variables (volume at first uninhibited detrusor contraction, number of uninhibited contractions, Bladder Outlet Obstruction Index (BOOI), Bladder Contractility Index (BCI) and Bladder Power at Qmax) to identify meaningful subgroups within a cohort of 94 men undergoing surgery for BPH/LUTS. Two meaningful subgroups (clusters) were identified. Significant differences between the two clusters included Prostate Volume (95 vs 53 cc; p-value = 0.001), BOOI (mean 70 vs 49; p-value = 0.001), BCI (mean 129 vs 83; p-value <0.001), Power (689 vs 236; p-value <0.001), Qmax (8.3 vs 4.9 cc/sec; p-value <0.001) and post-void residual (106 vs 250 cc; p-value = 0.001). One cluster is distinguished by larger prostate volume, greater outlet resistance and better bladder contractility. The other is distinguished by smaller prostate volume, lower outlet resistance and worse bladder contractility. Remarkably, the second cluster exhibited greater impairment of urine flow and bladder emptying. Surgery improved flow and emptying for patients in both clusters. These findings reveal important roles for both outlet obstruction and diminished detrusor function in development of diminished urine flow and impaired bladder emptying in patients with BPH/LUTS., Competing Interests: The authors have declared that no competing interests exist.

Previous studies identified Sox9 as a critical mediator of prostate development but the precise stage when Sox9 acts had not been determined. A genetic approach was used to delete Sox9 from mouse urogenital sinus epithelium (UGE) prior to prostate specification. All prostatic bud types (anterior, dorsolateral and ventral) were stunted in Sox9 conditional knockouts (cKOs) even though the number of prostatic buds did not differ from that of controls. We concluded that Sox9 is required for prostatic bud elongation and compared control male, control female, Sox9 cKO male and Sox9 cKO female UGE transcriptomes to identify potential molecular mediators. We identified 702 sex-dependent and 95 Sox9-dependent genes. Thirty-one genes were expressed in both a sex- and Sox9-dependent pattern. A comparison of Sox9 cKO female vs control female UGE transcriptomes revealed 74 Sox9-dependent genes, some of which also function in cell migration. SOX9 regulates, directly or indirectly, a largely different profile of genes in male and female UGE. Eighty-three percent of Sox9-dependent genes in male UGE were not Sox9-dependent in female UGE. Only 16 genes were Sox9-dependent in the UGE of both sexes and seven had cell migration functions. These results support the notion that Sox9 promotes cell migration activities needed for prostate ductal elongation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Potency assays for mesenchymal stromal cells (MSCs) need to be defined in advanced clinical trials. Here, we have developed an assay matrix approach that captures the signal transducer and activator of transcription (STAT) phosphorylation of MSCs upon stimulation with their combined secretome that arose with the interaction of activated peripheral blood mononuclear cells (PBMCs). Secretome of heat-inactivated (HI) MSCs cocultured with and without activated PBMCs was used as an internal reference. We have compared the short-term phosphorylation status of STAT1, STAT3, STAT4, STAT5, and STAT6 on MSCs derived from human bone marrow, adipose tissue, and umbilical cord using phosflow technology. Secretome of live MSCs cocultured with activated PBMCs downregulate STAT1 and STAT3 phosphorylation on MSCs, whereas the secretome of HI-MSCs or PBMCs do not. Thus, investigation of the combined secretome of MSC and PBMC interaction on MSCs determine the potency of MSCs as the generator and sensor of the secretome. Bone marrow, adipose, and umbilical cord MSCs are comparable in modulating STAT1 and STAT3 responses. Measurements of STAT1 and STAT3 phosphorylation on MSCs as responder cells correlate and predict allogeneic T-cell suppression. Our comparative phosphomatrix approach between live and reference HI-MSCs defines the potency of MSCs as both stimulators and responders as part of a robust platform for predictive potency analysis. Stem Cells 2019;37:1119-1125., (© AlphaMed Press 2019.)

In order to study the impact of regioisomeric diene ligands on the formation and catalytic activity of Rh complexes, a series of C 2 - and C S -symmetric 2,5-disubstituted bicyclo[3.3.0]octa-2,5-dienes C 2 -L and C S -L, respectively, were synthesized from Weiss diketone by simultaneous deprotonation/electrophilic trapping of both oxo functions, and the catalytic behavior was studied in the presence of [RhCl(C 2 H 4 ) 2 ] 2 . Complexes [RhCl(C 2 -L)] 2 bearing C 2 -symmetric ligands catalyzed effectively the asymmetric arylation of N-tosylaldimines to (S)-diarylamines with yields and ee values up to 99%. In Hayashi-Miyaura reactions, however, the complexes showed poor catalytic activity. When complexes [RhCl(C S -L)] 2 with C S -symmetric ligand or mixtures of [RhCl(C 2 -L)] 2 and [RhCl(C S -L)] 2 were employed in 1,2-additions, racemic addition products were observed, suggesting a C═C isomerization of the diene ligands. X-ray crystal structure analysis of both Rh complexes formed from the [RhCl(C 2 H 4 ) 2 ] 2 precursor and ligands C 2 -L and C S -L revealed that only the C 2 -symmetric ligand C 2 -L coordinated to the Rh, whereas C S -L underwent a Rh-catalyzed C═C isomerization to rac-C 2 -L, which then gave the racemic [RhCl(rac-C 2 -L)] 2 complex. DFT calculations of the relative stabilities of the Rh complexes and the proposed intermediates provided a mechanistic rationale via Rh-mediated hydride transfer.

It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3'-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To examine the effect of positive end-expiratory pressure (PEEP) on right ventricular stroke volume variation (SVV), with possible implications for the number and timing of pulmonary artery catheter thermodilution measurements., Design: Prospective, clinical pilot study., Setting: Academic medical center., Participants: Patients who underwent volume-controlled mechanical ventilation and had a pulmonary artery catheter., Intervention: PEEP was increased from 5-to-10 cmH2O and from 10-to-15 cmH2O with 10-minute intervals, with similar decreases in PEEP, from 15-to-10 cmH2O and 10-to-5 cmH2O., Measurements and Main Results: In 15 patients, right ventricular parameters were measured using thermodilution at 10% intervals of the ventilatory cycle at each PEEP level with a rapid-response thermistor. Mean right ventricular stroke volume and end-diastolic volume declined during incremental PEEP and normalized on return to 5 cmH2O PEEP (p = 0.01 and p = 0.001, respectively). Right ventricular SVV remained unaltered by changes in PEEP (p = 0.26), regardless of incremental PEEP (p = 0.15) or decreased PEEP (p = 0.12). The coefficients of variation in the ventilatory cycle of all other thermodilution-derived right ventricular parameters also were unaffected by changes in PEEP., Conclusions: This study showed that increases in PEEP did not affect right ventricular SVV in critically ill patients undergoing mechanical ventilation despite reductions in mean right ventricular stroke volume and end-diastolic volume. This could be explained by cyclic counteracting changes in right ventricular preloading and afterloading during the ventilatory cycle, independent of PEEP. Changes in PEEP did not affect the number and timing of pulmonary artery catheter thermodilution measurements., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1(+/-);Pten(fl/+) mice, which are genetically predisposed to prostate neoplasia, were exposedin uteroand during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 μg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 β-estradiol (2.5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants.In uteroand lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Alcohol consumption during pregnancy may lead to severe foetal damage, such as foetal alcohol spectrum disorders. It is known that pregnant women under-report to questionnaires about alcohol consumption. It is therefore necessary to determine alcohol consumption during pregnancy objectively. We present 2 pregnant women with negative urine tests for ethyl glucuronide (EtG) and alcohol. However, analysis of two other biomarkers, phosphatidylethanol (PEth) in blood and fatty acid ethyl esters (FAEE) in meconium, revealed alcohol consumption during pregnancy by both women. Analysis of PEth can yield additional information alongside EtG testing. This is due to the much longer half-life of PEth. Meconium testing for FAEE provides relevant information about alcohol consumption during the second and third trimesters. Both PEth and meconium analysis can help identify women who have consumed alcohol during pregnancy. Appropriate counselling and follow-up can be given to these mothers and their children.

Purpose: The aim of this study is to evaluate the effect of different levels of realism of context learning on the prescribing competencies of medical students during the clinical clerkship in internal medicine., Methods: Between 2001 and 2007, 164 medical students took part in the prospective explorative study during their clinical clerkship in internal medicine at the VU University Medical Center, Amsterdam, The Netherlands. In a fixed order, each student had to formulate a treatment plan for a real patient in three situations of increasing realism: a minimal level (studying a patient record), medium level (preparing for a therapeutic consultation), and optimal level (preparing for and performing a therapeutic consultation with the patient)., Results: In comparison to studying a patient record (minimal context level), preparing a therapeutic consultation (medium context) improved four of the six steps of the WHO six-step plan. Preparing and performing a therapeutic consultation with a real patient (optimal context) further improved three essential prescribing competencies, namely checking for contraindications and interactions, prescription writing, and instructions to the patient., Conclusion and Recommendations: The results of this first explorative study suggest that enrichment of the learning context (responsibility for patient care) might be an important factor to improve the training of rational prescribing skills of medical students during their clinical clerkship in internal medicine. Clinical (pharmacology) teachers should be aware that seemingly small adaptations in the learning context of prescribing training during clinical clerkships (i.e., with or without involvement with and responsibility for patient care) may have relatively large impact on the development of prescribing competencies of our future doctors.

Competent patients have the right to refuse treatment and healthcare workers should acknowledge their wishes. In the Netherlands there are conflicting (constitutional) rights of the foetus and of mentally ill patients. This paper describes the legal and ethical problems in the case of a mentally ill patient at 37 weeks of pregnancy who refused an obstetric examination. The patient refused to cooperate and have her physical condition and mental status examined. Her refusal endangered the life of the foetus. The obstetrician decided to perform a caesarean section, even if this would be in conflict with the patient's right to self-determination. In these cases no legal framework exists for providing the best medical care. New legislation should be drawn up to prevent similar cases occurring in the future. If a caesarean section is in conflict with a patient's right to self-determination, it should always be performed as a last resort.

Objective: Disturbed sleep during pregnancy is associated with adverse obstetric outcomes and less mental well-being. In pregnant women with a mental disorder, who frequently suffer from sleep problems, it is unknown whether predominantly objective or subjective sleep quality is more affected. To clarify this, we compared objective and subjective parameters of sleep quality between patients and healthy controls during pregnancy., Methods: This observational study was embedded in an ongoing study among pregnant women with a mental disorder at the department of Psychiatry of Erasmus University Medical Center Rotterdam, the Netherlands. We compared 21 pregnant women with a confirmed mental disorder with 33 healthy controls (gestational age, 23-29 weeks). To measure objective parameters of sleep quality, all participants continuously wore a wrist actigraph for 7 days and nights. Subjective sleep quality was retrospectively assessed using the Pittsburgh Sleep Quality Index (PSQI) and on a daily basis with the Subjective Sleep Quality-scale (SSQ). Differences in parameters of sleep between patients and controls were tested using a multivariate linear regression analysis adjusted for parity, gestational age, educational level, and employment status., Results: Objective parameters of sleep quality and subjective sleep quality as assessed by the PSQI did not differ significantly between patients and controls. Daily sleep reports showed that, relative to controls, patients had a significantly worse average SSQ-score (5.2 vs. 7.6, adjusted β = 0.12, 95%CI = 0.03-0.53, p < 0.01)., Conclusions: Our exploratory study suggests that perceived sleep quality reported on a daily basis by pregnant women with a mental disorder is worse than the sleep quality as measured by wrist actigraphy.

The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development.

In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes ventral prostate agenesis in C57BL/6J mice by preventing ventral prostatic budding in the embryonic urogenital sinus (UGS). TCDD (5 μg/kg, po) administered to pregnant dams on embryonic day 15.5 (E15.5) activates the aryl hydrocarbon receptor in the UGS mesenchyme, disrupting the mesenchymally derived paracrine signaling that instructs epithelial prostatic budding. How TCDD alters the mesenchymal milieu is not well understood. We previously showed that TCDD disrupts some aspects of Wnt signaling in UGSs grown in vitro. Here we provide the first comprehensive, in vivo characterization of Wnt signaling in male E16.5 UGSs during normal development, and after in utero TCDD exposure. Vehicle- and TCDD-exposed UGSs were probed by in situ hybridization to assess relative abundance and localization of RNA from 46 genes that regulate Wnt signaling. TCDD altered the staining pattern of five genes, increasing staining for Wnt10a and Wnt16 and decreasing staining for Ror2, Rspo2, and Wif1. We also used immunohistochemistry to show, for the first time, activation of β-catenin (CTNNB1) signaling in ventral basal epithelium of control UGSs at E16.5. This onset of CTNNB1 signaling occurred immediately prior to the initiation of ventral prostatic budding and is characterized by a pronounced increase in CTNNB1 nuclear localization and subsequent expression of the CTNNB1 signaling target gene, Lef1. In utero TCDD exposure prevented the onset of CTNNB1 signaling and LEF1 expression in the ventral basal epithelium, thereby elucidating a likely mechanism by which TCDD contributes to failed prostatic budding in the ventral UGS., (© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.

This study aims to determine the feasibility of incorporating structured therapeutic consultations (TCs) into the clinical clerkship internal medicine. TCs were considered feasible if students were able to draw up a therapeutic plan and carry out a TC, and if students and their supervisors considered TCs workable and useful. From March 2008 to October 2009, medical students carried out a "diagnostic" and subsequent "therapeutic" consultation with the same patient during their clinical clerkship internal medicine at the VU University Medical Center. After the diagnosis was established, the student had to formulate a therapeutic plan and then carry out a TC with the patient, supervised by a clinician. The supervisor assessed the therapeutic plan and how the student conducted the TC. Both the student and the supervisor received a questionnaire about the workability and usefulness of the TC. On average, students' performance in drawing up a therapeutic plan was awarded a score of 4.4 on a five-point scale, and the TC performance of 96 % of the students was considered amply sufficient or better. Eighty-three percent of the supervisors agreed or strongly agreed with the statement that the TC is a worthwhile addition to the clerkship, and 67 % of the students indicated that they would like to perform more TCs. This study shows that incorporating a structured TC with a real patient into the clinical clerkship internal medicine is both feasible and worthwhile. This may be an important step to improving the prescribing skills and attitudes of junior doctors and residents and to reducing their prescribing errors after graduation.

Sport celebrates differences in competitors that lead to the often razor-thin margins between victory and defeat. The source of this variation is the interaction between the environment in which the athletes develop and compete and their genetic make-up. However, a darker side of sports may also be genetically influenced: some anti-doping tests are affected by the athlete's genotype. Genetic variation is an issue that anti-doping authorities must address as more is learned about the interaction between genotype and the responses to prohibited practices. To differentiate between naturally occurring deviations in indirect blood and urine markers from those potentially caused by doping, the "biological-passport" program uses intra-individual variability rather than population values to establish an athlete's expected physiological range. The next step in "personalized" doping control may be the inclusion of genetic data, both for the purposes of documenting an athlete's responses to doping agents and doping-control assays as well facilitating athlete and sample identification. Such applications could benefit "clean" athletes but will come at the expense of risks to privacy. This article reviews the instances where genetics has intersected with doping control, and briefly discusses the potential role, and ethical implications, of genotyping in the struggle to eliminate illicit ergogenic practices.

The irrational prescribing of drugs seems to be a general problem in medical practice, occasionally leading to serious consequences. In order to improve the drug prescribing performance of medical students, a compulsory context-learning pharmacotherapy module was implemented in 1998 in the medical curriculum of 2nd-4th-year medical students at theVU University Medical Center (VUmc), Amsterdam, The Netherlands. As part of this program, preclinical medical students are taught how to select, prescribe, and evaluate a drug regimen rationally. The aim of this study was to investigate the effect of this preclinical pharmacotherapy program on the quality of rational prescribing during the ensuing clinical clerkship of these students in internal medicine. The results of this study indicate that preclinical context-learning in pharmacotherapy leads to the use of more rational prescribing modalities by medical students during their ensuing clinical clerkship in internal medicine. This effect was obtained not only with respect to the clinical topics in which training had been given as part of the pharmacotherapy curriculum, but also for other disease situations that the students dealt with. This implies that students not only remember the specific information they have learned during the training, but are also able to apply the acquired skills in new situations (transfer effect).

Background: The use of natural openings for abdominal surgery started at the beginning of the 21st century. A trans-Douglas endoscopic device has been designed to perform most of the intra-abdominal operations in women through the pouch of Douglas. The posterior vaginal vault is limited in size and could be damaged by an oversized instrument. This study investigates the optimal dimensions of the instrument by measuring the limiting factor in the passage., Methods: In ten female embalmed bodies the transversal and sagittal diameter of the fornix posterior vaginalis was measured by two observers. The pouch of Douglas was filled to its maximal capacity with mouldable latex through an open abdomen. By internal vaginal examination the connective tissue borders of the fornix posterior were palpated and the impression in the cast was measured. The mean value of these two diameters was evaluated in this study. The level of agreement between the observers was calculated., Results: The mean fornix posterior diameter was 2.6 cm (standard deviation, SD 0.5 cm) with a range of 2.0-3.4 cm. The mean difference between the two observers of all measurements was 0.08 cm (not significant). Both observers had an acceptable intraobserver variation. The interobserver agreement was excellent., Conclusion: Instruments with dimensions within the measured limits can be used safely for intra-abdominal operations via the natural orifice of the vagina.

The response of arterial PO(2) (P(a)O(2)) to airway pressure has been used as a measure of recruitment in mechanically ventilated patients. We hypothesised that mixed venous PO(2) (P(mv)O(2)) directly affects P(a)O(2). Sixteen patients with acute lung injury (ALI, lung injury score > or = 1) on volume-controlled mechanical ventilation (F(I)O(2) 0.40) were studied. Positive end-expiratory pressure (PEEP) was increased and decreased. Incremental PEEP increased median values of P(a)O(2), diminished venous admixture (Q(va)/Q(t)) and cardiac index, but maintained arterial PCO(2) and tissue O(2) uptake. These changes were reversed during decremental PEEP. However P(a)O(2) did not increase in 37% of PEEP steps and changes in P(a)O(2) correlated to those in P(mv)O(2) (r(s) = 0.45, p < 0.001). Changes in P(mv)O(2) contributed to changes in Q(va)/Q(t) in determining changes in P(a)O(2) (p < 0.05). P(mv)O(2) may be an independent determinant of P(a)O(2) during mechanical ventilation for ALI, so that dosing PEEP to recruit the lung should not be guided by arterial blood oxygenation alone. Arterial hypoxaemia with increasing PEEP may improve by reducing PEEP (or increasing tissue O(2) delivery), when the fall in P(mv)O(2) is greater than about 0.133 kPa.

The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.

Background: As many sufferers from phobic and panic (phobia/panic) disorders cannot get to suitable therapists, routine aspects of therapy were delegated to internet-accessed computer-aided self-help with or without exposure instructions., Methods: Phobia/panic referrals were randomised to computer-aided self-help via the internet at home in a 2:1 ratio either by self-exposure cognitive behaviour therapy (CBT) [FearFighter (FF), n = 45] or by minimal CBT without exposure [Managing Anxiety (MA), n = 23]. All had brief backup phone advice from a clinician concerning their computer guidance., Results: On self-ratings and blinded assessor ratings, patients improved equally with each form of self-help over 10 treatment weeks but significantly more on 5 out of 10 measures by week 14 (1-month follow-up) when the self-help included self-exposure instructions than when it did not. In accord with this, standardised effect sizes (Cohen's d) indicated superiority of FF over MA on 5 measures by week 14. Satisfaction with treatment in all patients pooled correlated positively with improvement after treatment and at 1-month follow-up., Conclusions: At the end of treatment, computer-aided CBT self-help at home via the internet plus brief live helpline support was effective with or without exposure instructions, and at 1-month follow-up it was more effective on some measures if exposure instructions had been included. Analysis is needed of how non-exposure CBT produced its shorter-term effect.

Three drug-addicted prostitutes, who were 37, 27 and 25 weeks pregnant respectively, were admitted to a psychiatric department under court order. After the birth, the children were placed in foster families. The mothers withdrew from further treatment. In Rotterdam, The Netherlands, there is a city network made up of doctors and social workers; in the case of addicted pregnant prostitutes they advise the Child Protection Agency of the Ministry of Justice about the care of the child after its birth. The combination of heavy addiction and prostitution in a pregnancy without any prenatal care can be considered a psychiatric disorder. Consequently, an addicted woman can be compulsorily admitted because of the threat she forms to her unborn child. In these cases the mother's right to self-determination must be limited in the interest of the child.

The purpose of this study was to evaluate right ventricular (RV) loading and cardiac output changes, by using the thermodilution technique, during the mechanical ventilatory cycle. Fifteen critically ill patients on mechanical ventilation, with 5 cmH(2)O of positive end-expiratory pressure, mean respiratory frequency of 18 breaths/min, and mean tidal volume of 708 ml, were studied with help of a rapid-response thermistor RV ejection fraction pulmonary artery catheter, allowing 5-ml room-temperature 5% isotonic dextrose thermodilution measurements of cardiac index (CI), stroke volume (SV) index, RV ejection fraction (RVEF), RV end-diastolic volume (RVEDV), and RV end-systolic volume (RVESV) indexes at 10% intervals of the mechanical ventilatory cycle. The ventilatory modulation of CI and RV volumes varied from patient to patient, and the interindividual variability was greater for the latter variables. Within patients also, RV volumes were modulated more by the ventilatory cycle than CI and SV index. Around a mean value of 3.95 +/- 1.18 l. min(-1). m(-2) (= 100%), CI varied from 87.3 +/- 5.2 (minimum) to 114.3 +/- 5.1% (maximum), and RVESV index varied between 61.5 +/- 17.8 and 149.3 +/- 34.1% of mean 55.1 +/- 17.9 ml/m(2) during the ventilatory cycle. The variations in the cycle exceeded the measurement error even though the latter was greater for RVEF and volumes than for CI and SV index. For mean values, there was an inspiratory decrease in RVEF and increase in RVESV, whereas a rise in RVEDV largely prevented a fall in SV index. We conclude that cyclic RV afterloading necessitates multiple thermodilution measurements equally spaced in the ventilatory cycle for reliable assessment of RV performance during mechanical ventilation of patients.

Three women, aged 21, 20 and 30 years, were cocaine users and pregnant. There had been no prenatal monitoring until they reported with uterine contractions. Blood of the first two women was then tested; serology revealed active syphilis infections: their children had died in utero. The blood of the third woman had been tested as part of a street project; it revealed an active syphilitic infection but she could not be found for treatment. After delivery, the child showed withdrawal symptoms. The first and third women and the child of the third woman were treated with benzylpenicillin. The system for screening and treating drug-addicted pregnant women should be intensified.

Mal II, a 19-residue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thrombospondin-1 (TSP-1), was inactive in angiogenesis assays. Yet the substitution of any one of three L-amino acids by their D-enantiomers conferred on this peptide a potent antiangiogenic activity approaching that of the intact 450-kDa TSP-1. Substituted peptides inhibited the migration of capillary endothelial cells with an ED50 of 8.5 nM for the D-Ile-15 substitution, 10 nM for the D-Ser-4 substitution, and 0.75 nM for the D-Ser-5 substitution. A peptide with D-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal II D-Ile derivative inhibited a broad range of angiogenic inducers, was selective for endothelial cells, and required CD36 receptor binding for activity. A variety of end modifications further improved peptide potency. An ethylamide-capped heptapeptide was also active systemically in that when injected i.p. it rendered mice unable to mount a corneal angiogenic response, suggesting the potential usefulness of such peptides as antiangiogenic therapeutics.

Objective: The medical practitioner is faced with an increasing list of protocols and algorithms related to patient care. These recommendations are often difficult to recall, particularly in stressful emergency situations. Using advanced cardiac life support (ACLS) protocols, we built a computer-based system to exhibit precompiled response plans for medical emergencies. To validate the usefulness of this prompting device, we tested application of two of the nine ACLS algorithms, pulseless ventricular fibrillation/ventricular tachycardia (Vfib/Vtach) and bradycardia, in a simulated operating room (OR) environment., Methods: The system utilized the software authoring system IconAuthor (Aimtec Inc., Nashua, NH) and a touch-screen monitor (DiamondScan, Microtouch, Methuen, MA). Prior to testing our system, all 39 subjects were given time to familiarize themselves with its operation. Subsequently, all subjects were videotaped while managing a standard simulated anesthetic. During the anesthetic, the subjects were presented with two emergency scenarios, not viewed during the familiarization period. The electrocardiographic (EKG) signals for normal sinus rhythm, ventricular fibrillation, and second-degree heart block were presented. By random selection, the prompter was available to half of the subjects for help with arrhythmia management (experimental group), while to half it was not (control group)., Results: A total of 39 subjects completed the exercise. Use of the prompter enabled significantly more subjects to administer correct drugs and dosages during ventricular fibrillation. The correct lidocaine dose was chosen more often by the experimental group than by the control (p = 0.015); similarly MgSO4 was appropriately ordered more often in the experimental group (p = 0.003). During second-degree heart block, atropine was correctly followed with a dopamine infusion (p = 0.004), and epinephrine infusion was ordered for refractory bradycardia (p = 0.002) more often in the experimental than the control group., Conclusions: These data demonstrate the value of a prompting device at the anesthesia workstation. We foresee the use of such prompters in many areas of medicine.

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

In order to compare ibopamine (IBO), a dopamine congener, with isosorbide mononitrate (ISMN) and to study their interaction in effects on the capacitance vasculature in congestive heart failure (CHF), a prospective, randomized, placebo-controlled, double-blind clinical trial was performed in 32 patients with New York Heart Association class II-IV CHF, randomly assigned to receive single oral doses of placebo, 200 mg IBO, 20 mg ISMN, or both IBO and ISMN. After labelling of red cells with 99mTc, changes in regional radioactivity, indicative of changes in blood volume, were recorded using a gamma-camera before and at 30, 60 and 120 min after drug administration. At 30 and 60 min, arterial systolic and pulse pressures were higher with IBO than with ISMN and placebo (for pulse pressure by mean 13.7 mmHg, 95% confidence interval 4.5-23.0 mmHg, at 30 min), probably reflecting an IBO-induced rise in stroke volume at unchanged heart rate and mean arterial pressure. IBO did not change regional radioactivity except for a transient increase of 4.4% (0.5-7.6%) in the thorax at 30 min. This was attenuated by concomitant ISMN treatment since, starting at 30 min, the drug increased radioactivity in the legs, compared with patients not receiving the drug, by 8.0% (95% confidence interval 0.2-15.8%), leading to a fall in thoracic and left ventricular radioactivity at 30 min of 3.4% (0.3-7.0%) and 6.4% (0.8-11.9%), respectively, and a fall of 5.5% (0.5-10.5%) in hepatic radioactivity at 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Study Objective: To examine the effect of cardiac surgery with cardiopulmonary bypass (CPB) on pulmonary vascular permeability., Design: A prospective, serial study., Setting: Department of nuclear medicine and intensive care units of a university hospital., Patients: Twelve consecutive patients were studied, before and immediately after elective cardiac surgery using CPB (group 1), and 4 consecutive, artificially ventilated patients with acute cardiogenic pulmonary edema (group 2)., Measurements and Results: The kinetics in blood and over both lungs were measured, using two mobile probes at the bedside, of intravenously injected 67Ga, assumed to bind to circulating transferrin, and in vitro 99mTc-labeled red blood cells to account for pulmonary blood volume. From data recorded in time (1 h), a pulmonary leak index (PLI), the time constant of transport of 67Ga from the intravascular to the extravascular space of the lung, was calculated and values for both lungs were averaged. In group 1, the PLI (.10(-3).min-1, mean +/- SD) was 8.2 +/- 3.7 before and 17.0 +/- 13.5 after CPB surgery (p < 0.01) and changes directly related to the duration of CPB. In four patients with a CPB duration > or = 120 min, the PLI, 31.1 +/- 16.3.10(-3).min-1, exceeded 2 SD plus mean preoperative PLI. Changes in PLI tended to relate inversely to changes in arterial WBC, which, in turn, inversely related to CPB duration. The PaO2/FIO2 ratio decreased and tended to relate inversely to PLI after surgery. No patient developed alveolar pulmonary edema on chest radiograph. In group 2, the PLI was 11.1 +/- 3.1.10(-3).min-1 (NS from group 1 preoperative PLI)., Conclusions: Cardiopulmonary bypass induces a pulmonary vascular leak, as assessed by 67Ga kinetics using a bedside detection technique, in some cardiac surgery patients with prolonged CPB. This leak may reflect pulmonary vascular injury and increased permeability, following activation of leukocytes by CPB and subsequent pulmonary sequestration, rather than increased filtration through pressure factors. It may contribute to impaired gas exchange, even in the absence of manifest alveolar edema of the lungs, after surgery.

We studied the prevalence of multiple organ system failure (MOSF), the relations between age, pre-existing chronic conditions, local complications, systemic infection, organ system failure, and mortality in patients with acute pancreatitis. During the study period, 267 consecutive patients were admitted to a tertiary hospital with acute pancreatitis. Multivariate analyses were used to identify factors predictive of MOSF occurrence and mortality. Using a previously developed MOSF scoring system at our center, MOSF (> or = 2 organ systems) was found to occur in 63 (24%) of the patients. Cardiovascular, pulmonary, renal, and hepatic failure predominated. Advanced age (> 55 yr) and chronic disease were related to local complications and systemic infection (both, P < .001). Local complications and systemic infection occurred in 68% and 75% of patients, respectively. In multiple logistic regression, advanced age, chronic disease, local complications, and systemic infection independently contributed to the development of MOSF. Overall mortality was 19%. MOSF accounted for 96% of deaths; mortality increased from 1% to 79% in patients without and with MOSF, respectively. In multiple logistic regression, advanced age, chronic disease, local complications, failure of the cardiovascular, renal, hepatic, gastrointestinal, and neurological systems independently contributed to mortality prediction. Advanced age and prior chronic disease may reflect diminished physiological reserve and predispose to local complications, systemic infection, and MOSF. Although local complications and systemic infection are important predisposing factors for MOSF, a host-dependent response to unknown specific or nonspecific factors may have a role in the pathogenesis of the syndrome in 25% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The author maintains that financial officers should take a leadership role to improve the processes that provide value to a company's internal and external customers. He suggests several ways that the financial function can participate in and contribute to total quality management.

The purpose of the present study was to determine the effect of volume loading alone (CONTR) vs. volume loading in combination with dobutamine (DOBU) or norepinephrine (NOR) on total body blood volume distribution in septic shock. After instrumentation, injection of in vitro labelled 99mTc red blood cells, and baseline measurements, anesthetized, ventilated pigs (n = 21) received 3-4.10(8).kg-1 live E. coli bacteria intravenously. Images of thorax, abdomen, and hindlimb were obtained by using a gamma camera simultaneously with hemodynamic measurements. E. coli infusion resulted in a decrease in arterial pressure, ventricular filling pressures, and cardiac output with a concomitant increase in pulmonary arterial pressure. Blood volume was redistributed from the heart, lungs, spleen, abdomen, and leg to the liver. After randomization, the CONTR group (I, n = 5) was subjected to volume loading, and treatment groups (each n = 8) received volume loading in combination with DOBU (group II, 5-10 micrograms/kg/min) or NOR (group III, 0.25-0.50 micrograms/kg/min). As compared to volume loading alone, DOBU and NOR increased cardiac output but only NOR restored arterial pressure. Volume loading increased blood volume in all regions studied; however, it was unequally distributed amongst organs with a preference for the liver. Neither DOBU nor NOR influenced the partitioning of the infused volume between organs. However, NOR prevented pooling of blood in the leg.