The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

Pathological changes in the TMJ and the length of the ramus in patients with confirmed juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is characterized by a progressive destruction of the joints. The temporomandibular joints (TMJ) are especially likely to be affected. The often undetected arthritis in the TMJ in particular can cause significant destruction and craniofacial developmental abnormalities. The aim of this study was to analyze the destructive impact of JIA on TMJ and mandibular development. MATERIAL AND METHODS: We analyzed a total of 92 joints and mandibular rami using digital cone-beam tomography (CBT) and compared 23 consecutively treated JIA patients with 23 healthy controls, matched for age and gender. We evaluated ramus length, vertical depth of the articular fossa, anterior-posterior dimensions of the mandibular head and condylar process. The statistical analysis was performed using non-parametric Wilcoxon and Kruskal-Wallis Rank Sum tests. RESULTS: The JIA patients exhibited significantly more pronounced asymmetries. However, we were unable to detect significant differences in the metric measuring distances. The different JIA subtypes exerted no statistically significant influence. CONCLUSIONS: The possible destruction arising as a result of JIA concerns the TMJ and the length of the mandibular ramus. These craniofacial anomalies demonstrate the central importance of sufficiently early detection and timely treatment in the prevention of such growth disturbances.

Root exudation and root development of lettuce (Lactuca sativa L. cv. Tizian) as affected by different soils.

Development and activity of plant roots exhibit high adaptive variability. Although it is well-documented, that physicochemical soil properties can strongly influence root morphology and root exudation, particularly under field conditions, a comparative assessment is complicated by the impact of additional factors, such as climate and cropping history. To overcome these limitations, in this study, field soils originating from an unique experimental plot system with three different soil types, which were stored at the same field site for 10 years and exposed to the same agricultural management practice, were used for an investigation on effects of soil type on root development and root exudation. Lettuce (Lactuca sativa L. cv. Tizian) was grown as a model plant under controlled environmental conditions in a minirhizotrone system equipped with root observation windows (rhizoboxes). Root exudates were collected by placing sorption filters onto the root surface followed by subsequent extraction and GC-MS profiling of the trapped compounds. Surprisingly, even in absence of external stress factors with known impact on root exudation, such as pH extremes, water and nutrient limitations/toxicities or soil structure effects (use of sieved soils), root growth characteristics (root length, fine root development) as well as profiles of root exudates were strongly influenced by the soil type used for plant cultivation. The results coincided well with differences in rhizosphere bacterial communities, detected in field-grown lettuce plants cultivated on the same soils (Schreiter et al., this issue). The findings suggest that the observed differences may be the result of plant interactions with the soil-specific microbiomes.

Classification of temporomandibular joint erosion, arthritis, and inflammation in patients with juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis is the most common disease in pediatric rheumatology. It is characterized by chronically progressive joint destruction. The temporomandibular joints (TMJs) are involved in up to 87% of patients and may take an asymptomatic course in 69% of cases. Other than contrast-enhanced magnetic resonance imaging (MRI), there are no reliable screening symptoms or non-invasive procedures available to diagnose the inflammation in its acute form. The goal of this study was to establish an imaging-based classification system for TMJ erosion via MRI and cone-beam computed tomography (CBCT) in an effort to improve indication-specific treatment approaches and to facilitate the comparison of findings. MATERIALS AND METHODS: A total of 46 patients were included. Contrast-enhanced MRI and CBCT images obtained during treatment by pediatric rheumatologists and orthodontists were available from 23 patients with juvenile idiopathic arthritis. We devised a classification system combining the findings of both imaging techniques based on this patient sample in comparison with CBCT findings from an age- and gender-matched group of 23 non-arthritis patients, taking into consideration the available literature and administration of contrast medium. RESULTS: Our cohort of 46 patients comprised 60% female and 40% male patients with a mean age of 14 years, providing a total of 92 TMJs for evaluation. We were able to apply the findings efficiently and conveniently to this classification system with no relevant interobserver differences. Mild structural abnormalities were noted in 21% of TMJs in the control group, whereas 83% of TMJs in the arthritis group exhibited severe anomalies, including cases of extreme destruction. Age and gender did not affect the degree of destruction significantly. CONCLUSION: This is the first classification system to link CBCT and MRI with the use of contrast medium. Contrast-enhanced MRI is an internationally recognized technique that permits acute inflammation to be unequivocally diagnosed. Although structural erosion of the TMJs in our arthritis group was generally severe and significant, we were surprised to observe some cases that were clinically asymptomatic.

MAPPED study design: a 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging.

OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.

A collinear self-emission and laser-backlighting imaging diagnostic.

In this work we demonstrate a design for obtaining laser backlighting (e.g., interferometry) and time-resolved extreme ultraviolet self-emission images along the same line-of-sight. This is achieved by modifying a single optical component in the laser collection optics with apertures and pinhole arrangements suitable for single or multiple frame imaging onto a gated detector, such as a microchannel plate. Test results for exploding wire experiments show that machining of the optic does not affect the overall quality of the recovered laser images, and that, even with a multiple frame system, the area sacrificed to achieve collinear imaging is relatively small. The diagnostics can therefore allow direct correlation of laser and self-emission images and their derived quantities, such as electron density in the case of interferometry. Simple methods of image correlation are also demonstrated.

Rayleigh-Taylor instability of an ultrathin foil accelerated by the radiation pressure of an intense laser.

We report experimental evidence for a Rayleigh-Taylor-like instability driven by radiation pressure of an ultraintense (10(21) W/cm(2)) laser pulse. The instability is witnessed by the highly modulated profile of the accelerated proton beam produced when the laser irradiates a 5 nm diamondlike carbon (90% C, 10% H) target. Clear anticorrelation between bubblelike modulations of the proton beam and transmitted laser profile further demonstrate the role of the radiation pressure in modulating the foil. Measurements of the modulation wavelength, and of the acceleration from Doppler-broadening of back-reflected light, agree quantitatively with particle-in-cell simulations performed for our experimental parameters and which confirm the existence of this instability.

Raman spectroscopic study of mixed carbonate materials.

The main parameters for precipitation of mixed carbonate materials have been studied by Raman microscopy. These carbonates are compounds of barium, strontium and calcium. It has been shown that the Raman spectrum of a sample is exclusively controlled by its composition, the precipitation parameters do not affect the crystal structure. Even at relatively low levels, the calcium content of a sample can dominate the vibrational frequencies as measured by Raman spectroscopy. Calcium contents greater than 17% show this effect to a considerable degree, and give the broadest or two Raman peaks and thus the least uniform unit cells. The analysis of the lattice modes demonstrates that each Raman shift observed for a mixed carbonate sample corresponds to a specific crystal structure. Some peaks lie within two or three shifts that are observed for different crystal structures.

The social and gender context of HIV disclosure in sub-saharan Africa: a review of policies and practices

This paper reviews the legal and policy context of HIV disclosure in sub-Saharan Africa; as well as what is known about rates; consequences and social context of disclosure; with special attention to gender issues and the role of health services. Persistent rates of nondisclosure by those diagnosed with HIV raise difficult ethical; public health and human rights questions about how to protect the medical confidentiality; health and well-being of people living with HIV on the one hand; and how to protect partners and children from HIV transmission on the other. Both globally and within the sub-Saharan African region; a spate of recent laws; policies and programmes have tried to encourage or - in some cases - mandate HIV disclosure. These policies have generated ethical and policy debates. While there is consensus that the criminalization of transmission and nondisclosure undermines rights while serving little public health benefit; there is less clarity about the ethics of third party notification; especially in resource-constrained settings. Despite initiatives to encourage voluntary HIV disclosure and to increase partner testing in sub-Saharan Africa; health workers continue to grapple with difficult challenges in the face of nondisclosure; and often express a need for more guidance and support in this area. A large body of research indicates that gender issues are key to HIV disclosure in the region; and must be considered within policies and programmes. Taken as a whole; this evidence suggests a need for more attention to the challenges and dilemmas faced by both clients and providers in relation to HIV disclosure in this region and for continued efforts to consider the perspectives and rights of all those affected

Postsurgery corneal asphericity and spherical aberration due to ablation efficiency reduction and corneal remodelling in refractive surgeries.

PURPOSE: To explain the origin of changes in corneal asphericity and induced spherical aberration after laser refractive surgery. METHODS: A rigorous model, CASIM (corneal ablation simulator), has been developed to model the ablation profile design, the shot-by-shot ablation process and the corneal remodelling that occurs through healing. The dependence of corneal asphericity, induced spherical aberration, and achieved refractive correction on corneal remodelling, and the ablation efficiency reduction caused by the angle of incidence of the excimer beam on the curved cornea are compared to the clinical outcomes reported in the literature. RESULTS: When the exact Munnerlyn formula is used, the CASIM modelling and the clinical data exhibit a high degree of correlation. The modelling predicts that the postoperative cornea will be oblate, with substantial induced spherical aberration. A 6-month postsurgery asphericity is predicted by CASIM with a correlation of R2=0.94. The corneal remodelling included in CASIM accounts, on the average, for 45 and 69% of the increase in asphericity and spherical aberration, respectively, with the remainder due to the ablation efficiency. CONCLUSIONS: The modelling shows that clinically observed increases in corneal asphericity and induction of spherical aberration can be explained by the effects of corneal remodelling due to healing and by the ablation efficiency reduction due to laser angle of incidence. The model is capable of predicting clinical outcomes for procedures performed with flying spot laser systems and could be used to design compensated ablation profiles to improve the clinical outcomes for custom as well as conventional laser refractive procedures.

Modifying wire-array Z-pinch ablation structure using coiled arrays.

A new wire-array configuration has been used to control the modulation of ablated plasma flow for the first time. Cylindrical aluminum coiled arrays, in which each straight wire is replaced with a single helix, were driven by a 1 MA, 240 ns current pulse. Ablated plasma is directed away from the coiled wire cores in a manner that can be understood in terms of Lorentz forces that arise from a complex current path modeled by 3D magnetohydrodynamic simulations. Outside the diameter of the helix, the flow of ablated plasma is axially modulated at the wavelength of the coil.

Supersonic radiatively cooled rotating flows and jets in the laboratory.

The first laboratory astrophysics experiments to produce a radiatively cooled plasma jet with dynamically significant angular momentum are discussed. A new configuration of wire array z pinch, the twisted conical wire array, is used to produce convergent plasma flows each rotating about the central axis. Collision of the flows produces a standing shock and jet that each have supersonic azimuthal velocities. By varying the twist angle of the array, the rotation velocity of the system can be controlled, with jet rotation velocities reaching approximately 18% of the propagation velocity.

Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer.

Oligoarray analysis of a matched pair of prostate cancer and normal cell lines derived from the same radical prostatectomy specimen identified 113 candidate hypomethylated genes that were overexpressed in the cancer cells and contained CpG islands. Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) was confirmed in the cancer cells by bisulfite sequencing. Treatment of the corresponding normal prostate epithelial cells 1542-NPTX with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR) induced higher levels of mRNA expression and partial loss of methylation on these genes. Primary prostate cancers were tested using methylation-specific polymerase chain reaction. WNT5A was hypomethylated in 11/17 (65%) tumors, S100P in 8/16 (50%) and CRIP1 in 13/20 (65%). Bisulfite sequencing of a section of the 5' untranslated region (UTR) of WNT5A revealed that three CpG sites (15, 24 and 35) were consistently methylated (93%) in the normal cell line and normal tissues, but not in the prostate cancer cell line and eight primary prostate cancers. Multiple putative binding sites for the transcription factors SP1 and AP-2 were found adjacent to CpG sites 15 and 24. A putative c-Myb binding site was located within the CpG site 35. Anti-c-Myb antibody co-precipitation with WNT5A was methylation-sensitive in 1542-NPTX cells. It is likely that an epigenetic mechanism regulates WNT5A expression in prostate cancer.

Dynamics of cylindrically converging precursor plasma flow in wire-array Z -pinch experiments.

This paper summarizes the present understanding of the processes leading to precursor column formation in cylindrical wire arrays on the 1 MA MAGPIE generator at Imperial College London. Direct experimental measurements of the diameter variation during the collapse and formation phase of the precursor column are presented, along with soft x-ray emission, and quantitative radiography. In addition, data from twisted cylindrical arrays are presented which give additional information on the behavior of coronal plasma generated in wire array z pinches. Three stages in precursor column formation are identifiable from the data: broad initial density profile, rapid contraction to small diameter, and slow expansion after formation. The correlation of emission to column diameter variation indicates the contraction phase is a nonlinear collapse resulting from the increasing on-axis density and radiative cooling rate. The variation in the minimum diameter is measured for several array materials, and data show good agreement with a pressure balance model. Comparison of column expansion rates to analytical models allows an estimate of column temperature variation, and estimates of the current in the column are also made. Formation data are in good agreement with both fluid and kinetic modeling, but highlight the need to include collisionless flow in the early time behavior.

Insulin detemir under steady-state conditions: no accumulation and constant metabolic effect over time with twice daily administration in subjects with Type 1 diabetes.

AIMS: This study investigated the pharmacodynamic and pharmacokinetic characteristics of the novel long-acting insulin analogue insulin detemir (IDet) under single-dose and steady-state conditions in comparison with those of NPH insulin at steady state. METHODS: Twenty-five subjects with Type 1 diabetes [seven females, 18 males, mean age (+/- sd) 39 +/- 12 years, body mass index 24 +/- 3 kg/m(2)] participated in three 24-h glucose clamps. IDet or NPH were given at 12-h intervals in fixed, individualized doses. The first clamp assessed the metabolic effect of NPH at steady state, the second investigated the effect of two single injections of IDet. Subjects continued IDet treatment for 7-14 days, after which the third clamp was performed to investigate IDet at steady state. RESULTS: At steady state, the metabolic effect of IDet was constant over 24 h while a clear peak in the metabolic effect [expressed as glucose infusion rates (GIR)] was observed with NPH after each injection. The fluctuation in the metabolic effect (maximum GIR divided by the average of the GIR values at the interval ends) was significantly lower in the second 12 h of the experiments with IDet under steady-state conditions compared with NPH (fluctuation(12-24 h) 1.27 +/- 0.17 vs. 1.56 +/- 0.72, P < 0.05). The overall metabolic effect of IDet at steady state was comparable with that of NPH [GIR-area under curve (AUC)(0-24 h): 5697 +/- 1861 vs. 5929 +/- 1965 mg/kg] whereas a significantly lower effect (5187 +/- 1784 mg/kg, P = 0.01 vs. steady state) was observed following the first two IDet injections. GIR values at the end of clamp day 2 (first doses) and clamp day 3 (steady state) were comparable [GIR(trough 24 h) 3.7 +/- 1.7 vs. 3.8 +/- 1.6 mg/(kg x min) NS], indicating that IDet had reached steady state after the first two injections. CONCLUSIONS: IDet administered twice daily reached steady state after the second injection and showed a constant metabolic effect over time under steady-state conditions. This should facilitate basal insulin substitution and decrease the risk of hypoglycaemia in insulin-treated subjects.

Allelic imbalance and biochemical outcome after radical prostatectomy.

OBJECTIVE: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. PATIENTS AND METHODS: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. RESULTS: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P=0.03). CONCLUSIONS: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.

Study of three-dimensional structure in wire-array z pinches by controlled seeding of axial modulations in wire radius.

Three-dimensional perturbations have been seeded in wire-array z pinches by etching 15 microm diameter aluminum wires to introduce 20% modulations in radius with a controlled axial wavelength. These perturbations seed additional three-dimensional imploding structures that are studied experimentally and with magnetohydrodynamics calculations, highlighting the role of current path nonuniformity in perturbation-induced magnetic bubble formation.

p21WAF1/CIP1 gene is inactivated in metastatic prostatic cancer cell lines by promoter methylation.

INTRODUCTION: p21WAF1/CIP1 may act as a tumour suppressor gene (TSG) and loss of the p21WAF1/CIP1 gene has been reported in several solid tumours. The aim of this study was to see whether p21WAF1/CIP1 was expressed in metastatic prostate cancer cell lines and to determine if there was methylation of the p21WAF1/CIP1 promoter. METHOD: PC3, LNCaP and DU145 metastatic prostate cancer cell lines, 1542NP normal prostate, and RD rhabdomyosarcoma cell lines were cultured in the demethylating agent 5-Aza-2 deoxycytidine (5-Aza-CdR). p21WAF1/CIP1 mRNA expression was analysed by RT-PCR. DNA from untreated cell lines was modified with sodium bisulphite and promoter sequencing was performed. RESULTS: p21WAF1/CIP1 was expressed at low or undetectable levels in metastatic prostate cancer cell lines but expression was reactivated by treatment with 5-Aza-CdR. Sequence analysis of the promoter region revealed several sites of methylation at the 5' end of a CpG island in the PC3, LNCaP and DU145 cell line DNA but not in the normal prostate control DNA. Most notably the Sis-inducible element (SEI)-1-a STAT1-binding site, was methylated. CONCLUSIONS: In this study, we show that p21WAF1/CIP1 expression in metastatic prostate cancer cell lines is enhanced as a result of demethylation of the DNA. Furthermore, several cytosine residues in the promoter region are methylated, including critical binding sites. The inhibition of the STAT1-signalling pathway by methylation of the promoter may inactivate the p21WAF1/CIP1 TSG in prostate cancer.

Effect of radial-electric-field polarity on wire-array Z-pinch dynamics.

The formation of plasma in wire-array Z-pinch experiments was found to depend upon the polarity of the radial-electric field near the wires. Reversing the radial-electric field midway along the length of an array resulted in the ablation rate of one-half of the array being reduced by 50%, significantly delaying the start of its implosion and altering its acceleration towards the axis. The observed phenomena cannot be explained by the standard magnetohydrodynamic models of array behavior, suggesting that effects such as electron emission may be important, especially during wire initiation.