Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides.

Transition metal-catalysed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compounds allowing in situ transformation towards numerous functional groups and organic compounds, including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the organic chemistry toolbox. This review discusses all known transition metal-catalysed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations.

Looking into the crystal ball: quality of life, delinquency, and problems experienced by young male adults after discharge from a secure residential care setting in the Netherlands.

BACKGROUND: Adolescents in residential care are a vulnerable population with many problems in several life areas. For most of these adolescents, these problems persist after discharge and into adulthood. Since an accumulation of risk factors in multiple domains increases the likelihood of future adverse outcomes, it would be valuable to investigate whether there are differences in life after residential care between subgroups based on multiple co-occurring risk factors. AIMS AND HYPOTHESIS: The aim of this exploratory follow-up study is to explore differences between young adults-classified in four risk profiles-in relation to life after discharge from a secure residential care setting. It is hypothesised that young adults with a profile with many risks in multiple domains will experience more problems after discharge, such as (persistent) delinquency, compared to young adults with a profile with lower risks. METHODS: Follow-up data were collected from 46 former patients of a hospital for youth forensic psychiatry and orthopsychiatry in the Netherlands. In order to illustrate these young adults' life after discharge, self-reported outcome measures divided into five domains (i.e., quality of life, daily life, social life, problems, and delinquency) were used. Differences between four classes based on pre-admission risk factors, which were identified in a previous study by latent class analysis, were explored by three (non-)parametric statistical tests. RESULTS: Life after discharge for most young adults was characterised by close friends and a high quality of life, but also by substance abuse, professional support, debts, and delinquency. Only a few significant differences between the classes were found, primarily between young adults with risk factors in the individual, family, school, and peer domains and young adults in the other three classes. CONCLUSIONS: Young adults experience a high quality of life after discharge from secure residential care, despite the presence of persistent problems. Some indications have been found that young adults with risk factors in four domains are at greatest risk for persistent problems in young adulthood. Because of the high amount of persistent problems, residential treatment and aftercare should focus more on patients' long-term needs.

[Prescribing psychotropic medication by the nurse practitioner in mental health care: an explorative study]. / Voorschrijven van psychofarmaca door verpleegkundig specialist ggz: een exploratief onderzoek.

BACKGROUND: Since January 1, 2012, nurse practitioners (NP) working in mental health care are allowed to prescribe psychotropic medication. So far, there has been very little research on the results of this decision that now let NPS share with doctors prescribing psychotropic drugs. AIM: To provide insight into how patients and psychiatrists experience the prescribing behaviours of NPS and how NPS themselves regard their extended role. METHOD: We performed an explorative study in which we used the data given in prescriptions written by NPS, questionnaires exploring patients' experiences and semi-structured interviews with psychiatrists and NPS. RESULTS: Between May 2014 and May 2015, 13 NPS wrote 3542 prescriptions for 565 unique patients. On the whole, patients, psychiatrists and NPS expressed positive views on the prescribing of psychotropic medication by NPS. CONCLUSION: Our research project confirms that the various stakeholders are satisfied with the prescribing practices of NPS. A follow-up study is needed in order to ascertain whether there are qualitative differences between the prescriptions of NPS and those of doctors.

IBX-mediated oxidation of unactivated cyclic amines: application in highly diastereoselective oxidative Ugi-type and aza-Friedel-Crafts reactions.

The first o-iodoxybenzoic acid (IBX) mediated oxidation of unactivated amines to imines is described. A range of meso-pyrrolidines were shown to be suitable substrates. The chemical space was further explored with one-pot oxidative Ugi-type and aza-Friedel-Crafts reactions, which proved to be highly diastereoselective.

Molecular changes associated with prostate cancer development.

The epidemiologic characteristics of prostate cancer (PCa) have been recognized for several decades. It is of great importance to understand the factors responsible for prostate carcinogenesis, why some carcinomas remain "clinically silent" during life, whereas other tumors progress to present clinically and may lead to PCa-related death. A better understanding of these mechanisms in molecular genetic terms should point to more rational approaches to disease prevention, intervention and treatment. The aim of this review is to provide a comprehensive overview of the current state of knowledge regarding the molecular alterations of PCa.

Branching activity in the human prostate: a closer look at the structure of small glandular buds.

OBJECTIVE: Knowledge regarding cell biologic characteristics of small solid glandular buds in the prostate and their relationship with branching activity in the human prostate is still fragmentary. Our object was to demonstrate, on the basis of immunophenotype, loci that harbor the potential for branching activity within the adult human prostate. MATERIALS AND METHODS: Semiserial sectioning was performed on 13 adult prostates in an effort to identify structures in the prostate that could be considered foci of growth. Selected slides were stained with biomarkers for basal/luminal cells (keratins), proliferation (MIB-1), apoptosis inhibitor (bcl-2), intercellular adhesion (E-cadherin), and stromal-epithelial interactions (tenascin-C). Results were compared with fetal and prepubertal human prostates and microdissected rat prostates. RESULTS: Five histologic epithelial structures were identified in 19 paraffin blocks, which on serial sectioning showed morphologic transitions with a common pattern, consisting of reduction in number and caliber of acini until small solid buds of epithelial cells were reached. Immunophenotypically, the small solid glandular buds had a basal-cell keratin phenotype, expression of bcl-2 in virtually all cells, high proliferative activity, prominent intracellular localization of E-cadherin, and enhanced periglandular tenascin-C immunoreactivity. The budding tips in fetal and prepubertal prostates revealed an immunostaining pattern identical to the small solid glandular buds in the adult, but different to the rat prostate. CONCLUSIONS: Our data suggest that dispersed small solid glandular buds have a capacity for growth, and as such may be considered foci of resumed reawakening branching activity with in the adult human prostate.

Correlation of transrectal ultrasound, computer analysis of transrectal ultrasound and histopathology of radical prostatectomy specimen.

A system for computerised analysis of ultrasonographic prostate images (AUDEX=Automated Urologic Diagnostic EXpert system) for the detection of prostate carcinoma was developed. The ultimate goal is to develop a system that is reliable and non-observer dependent. Results of an earlier study with a small group were encouraging and this study describes the results of the computerised analysis in a larger group. Sixty-two patients who were scheduled to undergo a radical prostatectomy were prospectively analysed. The radical prostatectomy specimens were step-sectioned in the transverse plane, corresponding to the ultrasound pictures. Malignant regions identified by each study were quantified and compared by computer calculation. No correlation was observed between ultrasound analysis and pathology result. For the AUDEX analysis an overall sensitivity of 85% and a specificity of 18% with only a diagnostic accuracy of 57% was noticed when presence or absence of malignancy was evaluated by octant (total 496). When applying a cut-off value of 0.5 ml the numbers were 71%, 33% and 55%, respectively. Correlation was significantly better for the ventral octants. In this study the earlier results of our AUDEX system could not be confirmed. Although sensitivity was good, specificity and especially diagnostic accuracy were lower than expected. We have to conclude that the current settings are inappropriate for routine clinical use. Prostate Cancer and Prostatic Diseases (2001) 4, 56-62

Errors in histological grading by prostatic needle biopsy specimens: frequency and predisposing factors.

Sampling error is an inherent problem of prostate biopsy. Consequently, there are problems in determining whether a given carcinoma is clinically significant on the basis of biopsy results. This study assesses the factors that predispose to errors in biopsy grading, as well as the dimensions of sampling error due to these factors. Among 187 cases, biopsy grading error was retrospectively related to grade heterogeneity in the prostate and to biopsy-related factors. Clinically relevant biopsy grading errors occurred in a quarter of the cases. Of all grading errors, at least 17% resulted from misinterpretation by the pathologist only. Overall, prostates with grade heterogeneity revealed grading errors twice as frequently as specimens without grade heterogeneity. In most cases, however, grading error resulted from multiple factors, such as the number and length of cores obtained (p<0.05). This was an important finding because the mean core length was only 9.4 mm, whereas the biopsy needle is designed to obtain cores of 15 mm. Moreover, clinically relevant biopsy grading error had occurred in almost half of the cases when the Gleason score was based on a tumour deposit measvring less than 0.5 mm (p<0.05). The clinical consequences of these findings are important. Clinicians should try to obtain at least six biopsies, each 15 mm in length, to minimize grading error. Pathologists should be cautious in reporting Gleason scores based on tumour lesions smaller than 400x total magnification field. Interpretation could be refined, when necessary, by warning the urologist of the Limitations of the biopsy report.

The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: a randomized trial.

BACKGROUND: Epidemiologic studies suggest that coffee use might protect against colorectal cancer. Inconsistencies as to the effect of coffee use and colorectal cancer between epidemiologic studies might be related to the type of coffee brew. OBJECTIVE: We studied the effect of unfiltered coffee consumption on putative biomarkers for colonic cancer risk. DESIGN: A total of 64 healthy volunteers (31 men and 33 women), with a mean age of 43 +/- 11 years were randomly assigned to two groups in a crossover design, with two intervention periods of 2 weeks separated by a washout period of 8 weeks. Treatments were 1 L of cafetière (French press) coffee daily or no coffee. At the end of each intervention period, fasting blood samples, colorectal biopsies and 48 h faeces were collected. RESULTS: No effect of coffee on colorectal cell proliferation, assayed by estimating the Proliferating Cell Nuclear Antigen labelling index, was seen. Additionally, no effects were seen on the concentrations of faecal soluble bile acids and colorectal mucosal glutathione S-transferase activity. However, unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Other aminothiols in plasma also increased on coffee. CONCLUSION: Unfiltered coffee does not influence the colorectal mucosal proliferation rate, but might increase the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration. Whether this effect indeed contributes to a lower colon cancer risk remains to be established.

Alterations in expression of cadherin-6 and E-cadherin during kidney development and in renal cell carcinoma.

OBJECTIVES: Cell-cell adhesion mediated by cadherins is tight and stable and preserves tissue integrity. However, during tissue remodeling, e.g., development, adhesion may be modified for morphogenic movement. Similarly, during carcinogenesis, cell-cell adhesion might alter leading to a more aggressive phenotype. Here we describe cadherin expression patterns in developing, adult, and neoplastic kidney. METHODS: Fetal kidneys were obtained from voluntary terminations of pregnancy and 43 renal cell carcinomas (RCC) and normal kidneys were obtained at nephrectomy. Frozen sections of these specimens were stained immunohistochemically using antibodies against E-cadherin (ECD), cadherin-6 (CAD6) and alpha-catenin (alpha-cat). RESULTS: CAD6 was expressed in lower and middle limbs of the S-shaped bodies, structures that will develop into renal proximal tubules, which also express CAD6. Similarly, ECD was expressed in the upper limb of S-shaped bodies, structures which will develop into distal and collecting tubules which also express ECD. Twenty-four out of 43 RCC (55.8%) displayed a CAD6 (+)/ECD (-)/alpha-cat (+) phenotype. The other RCC had a CAD6 (+)/ECD (+)/alpha-cat (+) phenotype (10/43, 23.2%), CAD6 (-)/ECD (+)/alpha-cat (+) phenotype (3/43, 7.0%) or CAD6 (-)/ECD (-)/alpha-cat (+) phenotype (6/43, 14.0%), respectively. On the other hand, normal, heterogeneous, or absent expression of CAD6 was seen in 19, 15, and 9 tumors, whereas in 11, 2, and 30 tumors, respectively, ECD expression was seen. Survival curves showed that abnormal CAD6 expression correlated with a poor prognosis rather than abnormal ECD expression. CONCLUSIONS: The combination of cadherin expression appeared to be fixed relatively early during kidney organogenesis. Since almost all RCC originate from proximal tubular epithelial cells (CAD6 (+)/ECD (-)/alpha-cat (+)), only 55. 8% of RCC retained the original cadherin phenotype. Alterations in expression of these molecules may be a reflection of the degree of dedifferentiation from the primary organ. In addition, scoring of expression patterns including heterogeneous expression could be a useful tool to estimate the malignancy potential of the tumor.

Cadherin switching in human prostate cancer progression.

The progression of carcinomas is associated with the loss of epithelial morphology and a concomitant acquisition of a more mesenchymal phenotype, which in turn is thought to contribute to the invasive and/or metastatic behavior of the malignant process. Changes in the expression of cadherins, "cadherin switching," plays a critical role during embryogenesis, particularly in morphogenetic processes. Loss of E-cadherin is reported to be associated with a poor prognosis; however, thus far, evidence (R. Umbas, et al., Cancer Res. 54: 3929-3933, 1994) for up-regulation of other cadherins has only been reported in vitro, ie., we have found evidence (M. J. G. Bussemakers et al., Int. J. Cancer, 85: 446-450, 2000) for cadherin switching in prostate cancer cell lines (up-regulation of N-cadherin and cadherin-11, two mesenchymal cadherins, in cell lines that lack a functional E-cadherin-catenin adhesion complex). Here, we report on the immunohistochemical analysis of the expression of N-cadherin and cadherin-11 in human prostate cancer specimens. N-cadherin was not expressed in normal prostate tissue; however, in prostatic cancer, N-cadherin was found to be expressed in the poorly differentiated areas, which showed mainly aberrant or negative E-cadherin staining. Cadherin-11 is expressed in the stroma of all prostatic tumors, in the area where stromal and epithelial cells are found. In addition, cadherin-11 is also expressed in a dotted pattern or at the membrane of the epithelial cells of high-grade cancers. In a number of metastatic lesions, N-cadherin and cadherin-11 are expressed homogeneously. These data raise the possibility that cadherin switching plays an important role in prostate cancer metastasis.

Histopathological changes associated with high intensity focused ultrasound (HIFU) treatment for localised adenocarcinoma of the prostate.

AIMS: Investigation of the histopathological changes in prostatectomy specimens of patients with prostate cancer after high intensity focused ultrasound (HIFU) and identification of immunohistochemical markers for tissue damage after HIFU treatment. METHODS: Nine patients diagnosed with adenocarcinoma of the prostate underwent unilateral HIFU treatment seven to 12 days before radical prostatectomy. The prostatectomy specimens were analysed histologically. Immunohistochemical staining and electron microscopy were performed to characterise more subtle phenotypic changes. RESULTS: All prostatectomy specimens revealed well circumscribed HIFU lesions at the dorsal side of the prostate lobe treated. Most epithelial glands in the centre of the HIFU lesions revealed signs of necrosis. Glands without apparently necrotic features were also situated in the HIFU lesions, raising the question of whether lethal destruction had occurred. This epithelium reacted with antibodies to pancytokeratin, prostate specific antigen (PSA), and Ki67, but did not express cytokeratin 8, which is indicative of severe cellular damage. Ultrastructural examination revealed disintegration of cellular membranes and cytoplasmic organelles consistent with cell necrosis. HIFU treatment was incomplete at the ventral, lateral, and dorsal sides of the prostate lobe treated. CONCLUSIONS: HIFU treatment induces a spectrum of morphological changes ranging from apparent light microscopic necrosis to more subtle ultrastructural cell damage. All HIFU lesions are marked by loss of cytokeratin 8. HIFU does not affect the whole area treated, leaving vital tissue at the ventral, lateral, and dorsal sides of the prostate.

Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial.

BACKGROUND: An elevated plasma homocysteine concentration is a putative risk factor for cardiovascular disease. Observational studies have reported an association between coffee consumption and plasma homocysteine concentrations. OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in a crossover trial. We used unfiltered coffee so as to include the possible effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered cafetière (French press) coffee daily for 2 wk. Such coffee is rich in the cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34) received water, milk, broth, tea, and chocolate drinks instead of coffee. After a washout period of 8 wk, both groups received the alternate intervention for another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8 to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine concentrations in volunteers with normal initial concentrations. It is unclear whether the effect is caused by the cholesterol-raising diterpenes present exclusively in unfiltered coffee or by factors that are also present in filtered coffee.

Molecular analysis of multifocal prostate cancer lesions.

To analyse the origin of multifocal prostate cancer lesions, radical prostatectomy specimens from 17 patients were examined. As a marker of genetic lineage, the allelotype based on 33 microsatellite loci was compared between the different tumours present in a given case. Some results provide evidence suggestive of a clonal origin of multiple tumours in a subset of the prostates. In five cases, for example, comparison of multifocal tumour lesions within a given case revealed at least two concordant changes in allelic imbalance (AI) sequence dosages at different loci. In addition, considerable heterogeneity of allelotype was found within and among tumour foci of a given case. In five of the six tumours analysed for intratumour heterogeneity, for example, more than five discordant AI changes were found in one tumour region but not in the other. Conclusions regarding the clonality of such heterogeneous lesions are difficult to draw. A high frequency of AI changes in four lesions exhibiting prostatic intraepithelial neoplasia (mean 6.5 changes per lesion, range 3-6) was found, compared with eight primary tumours present in the same cases (mean 5.8 changes per lesion, range 3-6). The interpretation of AI associated with clinically detected prostate cancer remains a highly complex issue. The fact that no clear evidence was obtained for either a clonal or a non-clonal origin of multiple lesions in a given prostate indicates that several different mechanisms are likely to operate in establishing the allelotype and that additional evidence from unique mutations or selective gene inactivation may be necessary to obtain definitive results.

High-intensity focused ultrasound (HIFU) followed after one to two weeks by radical retropubic prostatectomy: results of a prospective study.

BACKGROUND: High-intensity focused ultrasound (HIFU) consists of focused ultrasound waves emitted from a transducer that are capable of inducing tissue damage. Experimental studies have shown clear damage of malignant tissue exposed to HIFU, but knowledge of in vivo effects is limited. We studied the safety and efficacy of HIFU in patients with a T1-2 N0) M0 prostate carcinoma. METHODS: HIFU treatment was performed under general anesthesia with the Ablatherm device (Technomed Medical Systems, Lyon, France), 7-12 days prior to radical prostatectomy. Only the lobe in which carcinoma was confirmed was treated. The radical prostatectomy specimen was examined histopathologically, and the changes were compared with treatment goals. RESULTS: So far, 9 patients have been treated. On histology, a sharp delineation was noted between areas treated with HIFU and untreated areas. On the dorsal border, however, incomplete destruction of tissue was noted, and in 2 cases a small residual tumor was seen in this region. In all cases complete necrosis was seen in the treated region. CONCLUSIONS: Histology reports of radical prostatectomy specimens of patients operated 7-12 days after HIFU treatment showed marked and complete necrosis in the treated area. Due to incomplete tissue destruction at the dorsal side, however, a small focus of residual vital tumor was found in 2 of 9 patients.

Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma.

In many carcinomas, E-cadherin is considered to be a prognostic marker for patient survivals, and its decreased expression is associated with metastatic disease. Among renal cell carcinomas (RCCs), however, only 20% of tumors express E-cadherin, whereas a much higher percentage express other cadherins, e.g., N-cadherin and cadherin-6 (T. Shimazui et al, Cancer Res., 56: 3234-3237, 1996). Among these cadherins expressed in RCCs, cadherin-6 has been identified as a major cadherin in the renal proximal tubules and in the tumors themselves. Hence, we have investigated the relationship between prognosis and cadherin-6 expression in tumor cells in 43 patients with RCC. Expression of cadherin-6, E-cadherin, and alpha-catenin was detected immunohistochemically and evaluated microscopically as normal, heterogeneous, or absent. Normal, heterogeneous, and absent expression of cadherin-6 were observed in 19, 16, and 8 of 43 cases, respectively. Coexpression of E-cadherin and cadherin-6 was detected in only 10 cases. Among 30 tumors in which E-cadherin expression was absent, 24 expressed cadherin-6. In addition, the expression pattern of alpha-catenin correlated more highly with that of cadherin-6 than it did with E-cadherin (P = 0.0003 versus 0.025). In survival analyses, aberrant expression of cadherin-6 correlated with poor survivals both among all patients (P = 0.0009) and in those with E-cadherin-absent RCC (P = 0.0008). These results suggest that cadherin-6 is a major cadherin playing an essential role in cell-cell adhesion in E-cadherin-absent RCC.

Detection of abnormal E-cadherin expression by simulated prostate biopsy.

PURPOSE: Sampling error is an inherent problem of prostate biopsy. Consequently the determination of whether a given carcinoma is clinically significant based on biopsy results is problematic. We assess the dimensions of sampling error and, thereby, provide insight into the potential value of prognostic markers applied to needle biopsies. MATERIALS AND METHODS: We constructed 3-dimensional computer models of 21 prostatectomy specimens, including outlines of carcinomas, regions of abnormal E-cadherin expression and individual Gleason patterns. The 6 random systematic core biopsy technique and modifications were simulated using a computer algorithm. RESULTS: In 6 of 21 cases the area of abnormal E-cadherin expression and/or high grade carcinoma was not sampled on 6 random systematic core biopsy. The areas missed were either small or inconsistently under sampled regions of the prostate. Modifying the placement of biopsy needles improved the detection of these features. In addition, percent tumor in the needle appeared to be well correlated to percent tumor in the prostate (r = 0.891, r2 = 0.642). CONCLUSIONS: To avoid underestimating the aggressiveness of prostatic carcinoma at least 6 biopsies should be taken from each patient. A more extensive sampling is probably not warranted in all patients but it may prove useful in those in whom extent of disease is unclear or whose general health makes treatment decisions difficult. A reliable estimate of tumor volume in the prostatectomy specimen can be made based on relative amount of tumor in the biopsy specimen on an individual basis.

Tenascin-C expression in prostatic intraepithelial neoplasia (PIN): a marker of progression?

BACKGROUND: Tenascin (tenascin-C) has been suggested to be associated with active epithelial-stromal interactions. We evaluated tenascin expression in tissue remodelling processes presumably associated with PIN and prostate carcinoma (PCa). MATERIALS AND METHODS: Tenascin immunoreactivity was evaluated in 38 PIN lesions (low-grade = 5, high-grade = 33) from 27 paraffin-embedded PCa specimens, and compared with expression in pre-existent (normal) prostate, benign prostatic hyperplasia (BPH), and PCa. RESULTS: Periepithelial stromal tenascin expression was low in low-grade PIN, and similar to normal glands and BPH, whereas expression in high-grade PIN was high and partly overlapped that of well-/moderately differentiated PCa. High-grade PCa usually expressed little, if any tenascin. CONCLUSIONS: The variable periglandular tenascin expression in high-grade PIN may reflect the biologic behaviour of this lesion, and may be indicative of variable levels of tissue remodelling. In well/moderately differentiated PCa tenascin expression levels may be an indicator of tumour progression.