Pharmacological studies of 8-OH-DPAT-induced pupillary dilation in anesthetized rats

Serotonin (5-HT) receptor agonists have been reported to produce mydriasis in mice, and miosis in rabbits and humans. However, the underlying mechanisms for this action are unclear. This study was undertaken in an attempt to explore the mechanism by which 5-HT receptors are involved in the modulation of pupillary size in pentobarbital-anesthetized rats. Intravenous administration of the 5-HT receptor agonist, (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.003-3 mg/kg), elicited dose-dependent pupillary dilation, which was not affected by section of the preganglionic cervical sympathetic nerve. 8-OH-DPAT-elicited mydriatic responses were attenuated by the selective 5-HT receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide maleate (WAY 100635; 0.3-1 mg/kg, i.v.), as well as by the selective a -adrenoceptor antagonist, (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-dechydro-3-methoxy-12- (ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydrochloride (RS 79948; 0.3 mg/kg, i.v.), but not by the selective a -adrenoceptor antagonist, prazosin (0.3 mg/kg, i.v.). Mydriatic responses elicited by the a -adrenoceptor agonist, guanabenz (0.003-0.3 mg/kg, i.v.), were not antagonized by WAY 100635 (0.3-1 mg/kg, i.v.). To determine whether central nervous system (CNS) 5-HT receptors, like a -adrenoceptors, are involved in reflex mydriasis, voltage response curves of pupillary dilation were constructed by stimulation of the sciatic nerve in anesthetized rats. WAY 100635 (1 mg/kg, i.v.) did not antagonize the evoked reflex mydriasis, which, however, was blocked by RS 79948 (0.3 mg/kg, i.v.). Taken together, these results suggest that 8-OH-DPAT produces pupillary dilation in anesthetized rats by stimulating CNS 5-HT receptors, which in turn trigger the release of norepinephrine, presumably from the locus coeruleus. The latter reduces parasympathetic neuronal tone to the iris sphincter muscle by stimulation of postsynaptic a - adrenoceptors within the Edinger-Westphal nucleus. Unlike a - adrenoceptors, 5-HT receptors in the CNS do not mediate reflex mydriasis evoked by sciatic nerve stimulation. © 2004 Elsevier B.V. All rights reserved.

Microstructural analysis of non-woven fabrics using scanning electron microscopy and image processing. Part 1:Development and verification of the methods

This paper reports image analysis methods that have been developed to study the microstructural changes of non-wovens made by the hydroentanglement process. The validity of the image processing techniques has been ascertained by applying them to test images with known properties. The parameters in preprocessing of the scanning electron microscope (SEM) images used in image processing have been tested and optimized. The fibre orientation distribution is estimated using fast Fourier transform (FFT) and Hough transform (HT) methods. The results obtained using these two methods are in good agreement. The HT method is more demanding in computational time compared with the Fourier transform (FT) method. However, the advantage of the HT method is that the actual orientation of the lines can be concluded directly from the result of the transform without the need for any further computation. The distribution of the length of the straight fibre segments of the fabrics is evaluated by the HT method. The effect of curl of the fibres on the result of this evaluation is shown.

Unraveling the synergy between gold nanoparticles and chromium- hydrotalcites in aerobic oxidation of alcohols

The combination of gold nanoparticles (AuNPs) with chromium-substituted hydrotalcite (Cr-HT) supports makes very efficient heterogeneous catalysts (Au/Cr-HT) for aerobic alcohol oxidation under soluble-base-free conditions. The Au-support synergy increases with increasing Cr content of the support and decreasing AuNP size. In situ UV-Raman, X-ray absorption and photoelectron spectroscopic studies firmly establish that the strong Au-Cr synergy is related to a Cr ↔ Cr redox cycle at the Au/Cr-HT interface, where O activation takes place accompanied by electron transfer from Cr-HT to Au. The interfacial Cr species can be reduced by surface Au-H hydride and negative-charged Au species to close the catalytic cycle. A study of kinetic isotope effect indicates that alcohol O-H cleavage is facilitated by the presence of Cr, making a-C-H bond cleavage step more rate-controlling. Accordingly, a dual synergistic effect of Au/Cr-HT catalysts on the activation of O2 and alcohol reactants is proposed.

Prediction of surface roughness during hard turning of AISI 4340 steel (69 HRC)

In this study, 39 sets of hard turning (HT) experimental trials were performed on a Mori-Seiki SL-25Y (4-axis) computer numerical controlled (CNC) lathe to study the effect of cutting parameters in influencing the machined surface roughness. In all the trials, AISI 4340 steel workpiece (hardened up to 69 HRC) was machined with a commercially available CBN insert (Warren Tooling Limited, UK) under dry conditions. The surface topography of the machined samples was examined by using a white light interferometer and a reconfirmation of measurement was done using a Form Talysurf. The machining outcome was used as an input to develop various regression models to predict the average machined surface roughness on this material. Three regression models - Multiple regression, Random Forest, and Quantile regression were applied to the experimental outcomes. To the best of the authors’ knowledge, this paper is the first to apply Random Forest or Quantile regression techniques to the machining domain. The performance of these models was compared to each other to ascertain how feed, depth of cut, and spindle speed affect surface roughness and finally to obtain a mathematical equation correlating these variables. It was concluded that the random forest regression model is a superior choice over multiple regression models for prediction of surface roughness during machining of AISI 4340 steel (69 HRC).

Parametric design optimization of hard turning of AISI 4340 steel (69 HRC)

Continuous research endeavors on hard turning (HT), both on machine tools and cutting tools, have made the previously reported daunting limits easily attainable in the modern scenario. This presents an opportunity for a systematic investigation on finding the current attainable limits of hard turning using a CNC turret lathe. Accordingly, this study aims to contribute to the existing literature by providing the latest experimental results of hard turning of AISI 4340 steel (69 HRC) using a CBN cutting tool. An orthogonal array was developed using a set of judiciously chosen cutting parameters. Subsequently, the longitudinal turning trials were carried out in accordance with a well-designed full factorial-based Taguchi matrix. The speculation indeed proved correct as a mirror finished optical quality machined surface (an average surface roughness value of 45 nm) was achieved by the conventional cutting method. Furthermore, Signal-to-noise (S/N) ratio analysis, Analysis of variance (ANOVA), and Multiple regression analysis were carried out on the experimental datasets to assert the dominance of each machining variable in dictating the machined surface roughness and to optimize the machining parameters. One of the key findings was that when feed rate during hard turning approaches very low (about 0.02mm/rev), it could alone be most significant (99.16%) parameter in influencing the machined surface roughness (Ra). This has, however also been shown that low feed rate results in high tool wear, so the selection of machining parameters for carrying out hard turning must be governed by a trade-off between the cost and quality considerations.

Patient-reported 'ever had' and 'current' long term physical symptoms following prostate cancer treatments

OBJECTIVE: To document prostate cancer patient reported 'ever experienced' and 'current' prevalence of disease specific physical symptoms stratified by primary treatment received.
PATIENTS: 3,348 prostate cancer survivors 2-15 years post diagnosis.
METHODS: Cross-sectional, postal survey of 6,559 survivors diagnosed 2-15 years ago with primary, invasive PCa (ICD10-C61) identified via national, population based cancer registries in Northern Ireland and Republic of Ireland. Questions included symptoms at diagnosis, primary treatments and physical symptoms (impotence/urinary incontinence/bowel problems/breast changes/loss of libido/hot flashes/fatigue) experienced 'ever' and at questionnaire completion ("current"). Symptom proportions were weighted by age, country and time since diagnosis. Bonferroni corrections were applied for multiple comparisons.
RESULTS: Adjusted response rate 54%; 75% reported at least one 'current' physical symptom ('ever':90%), with 29% reporting at least three. Prevalence varied by treatment; overall 57% reported current impotence; this was highest following radical prostatectomy (RP)76% followed by external beam radiotherapy with concurrent hormone therapy (HT); 64%. Urinary incontinence (overall 'current' 16%) was highest following RP ('current'28%, 'ever'70%). While 42% of brachytherapy patients reported no 'current' symptoms; 43% reported 'current' impotence and 8% 'current' incontinence. 'Current' hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more often by patients on HT.
CONCLUSION: Symptoms following prostate cancer are common, often multiple, persist long-term and vary by treatment. They represent a significant health burden. An estimated 1.6% of men over 45 is a prostate cancer survivor currently experiencing an adverse physical symptom. Recognition and treatment of physical symptoms should be prioritised in patient follow-up. This information should facilitate men and clinicians when deciding about treatment as differences in survival between radical treatments is minimal.

Disseminated tumor cells and their prognostic significance in nonmetastatic prostate cancer patients

Detection of pretreatment disseminated cells (pre-DTC) reflecting its homing to bone marrow (BM) in prostate cancer (PCa) might improve the current model to predict recurrence or survival in men with nonmetastatic disease despite of primary treatment. Thereby, pre-DTC may serve as an early prognostic biomarker. Post-treatment DTCs (post-DTC) finding may supply the clinician with additional predictive information about the possible course of PCa. To assess the prognostic impact of DTCs in BM aspirates sampled before initiation of primary therapy (pre-DTC) and at least 2 years after (post-DTC) to established prognostic factors and survival in patients with PCa. Available BM of 129 long-term follow-up patients with T1-3N0M0 PCa was assessed in addition to 100 BM of those in whom a pretreatment BM was sampled. Patients received either combined therapy [n = 81 (63%)], radiotherapy (RT) with different duration of hormone treatment (HT) or monotherapy with RT or HT alone [n = 48 (37%)] adapted to the criteria of the SPCG-7 trial. Mononuclear cells were deposited on slides according to the cytospin methodology and DTCs were identified by immunocytochemistry using the pancytokeratin antibodies AE1/AE3. The median age of men at diagnosis was 64.5 years (range 49.5-73.4 years). The median long-term follow-up from first BM sampling to last observation was 11 years. Categorized clinically relevant factors in PCa showed only pre-DTC status as the statistically independent parameter for survival in the multivariate analysis. Pre-DTCs homing to BM are significantly associated with clinically relevant outcome independent to the patient's treatment at diagnosis with nonmetastatic PCa.

Comparative functional responses predict the invasiveness and ecological impacts of alien herbivorous snails.

Understanding determinants of the invasiveness and ecological impacts of alien species is amongst the most sought-after and urgent research questions in ecology. Several studies have shown the value of comparing the functional responses (FRs) of alien and native predators towards native prey, however, the technique is under-explored with herbivorous alien species and as a predictor of invasiveness as distinct from ecological impact. Here, in China, we conducted a mesocosm experiment to compare the FRs among three herbivorous snail species: the golden apple snail, Pomacea canaliculata, a highly invasive and high impact alien listed in “100 of the World's Worst Invasive Alien Species”; Planorbarius corneus, a non-invasive, low impact alien; and the Chinese native snail, Bellamya aeruginosa, when feeding on four locally occurring plant species. Further, by using a numerical response equation, we modelled the population dynamics of the snail consumers. For standard FR parameters, we found that the invasive and damaging alien snail had the highest “attack rates” a, shortest “handling times” h and also the highest estimated maximum feeding rates, 1/hT, whereas the native species had the lowest attack rates, longest handling times and lowest maximum feeding rates. The non-invasive, low impact alien species had consistently intermediate FR parameters. The invasive alien species had higher population growth potential than the native snail species, whilst that of the non-invasive alien species was intermediate. Thus, while the comparative FR approach has been proposed as a reliable method for predicting the ecological impacts of invasive predators, our results further suggest that comparative FRs could extend to predict the invasiveness and ecological impacts of alien herbivores and should be explored in other taxa and trophic groups to determine the general utility of the approach.

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial

Importance: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT.

Objective: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients.

Design, Setting, and Participants: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011.

Exposures: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry.

Main Outcomes and Measures: Failure-free survival (FFS) and overall survival.

Results: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]).

Conclusions and Relevance: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease.

Trial Registration: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF-mutant colorectal cancer cell lines.

Background: Oncogenic mutations in BRAF occur in 8% of patients with advanced colorectal cancer (CRC) and have been shown to correlate with poor prognosis. In contrast to BRAF mutant (MT) melanoma, where the BRAF inhibitor Vemurafenib (PLX4032) has shown significant increases in response rates and overall survival, only minor responses to Vemurafenib treatment have been reported in BRAFMT CRC. Clear understanding of the vulnerabilities of BRAFMT CRC is important, and identification of druggable targets uniquely required by BRAFMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel resistance mechanisms to MEK inhibition in BRAFMT CRC. Methods: Paired BRAFMT/WT RKO and VACO432 CRC cells and non-isogenic BRAFMT LIM2405, WiDR, HT-29 and COLO205 CRC cells were used. Changes in protein expression/activity were assessed by Western Blotting. Interactions between MEK1/2 and JAK1/2 or c-MET inhibition were assessed using the MTT cell viability assays and Flow Cytometry. Apoptosis was measured using Western Blotting for PARP, cleaved caspase 3, 8 and 9, and caspase 3/7 and 8 activity assays. Results: Treatment with MEK1/2 inhibitors AZD6244, trametinib, UO126 and PD98059 resulted in acute increases in STAT3 activity in the BRAFMT RKO and VACO432 cells but not in their BRAFWT clones and this was associated with increases in JAK2 activity. Inhibition of JAK/STAT3 activation using gene specific siRNA or small molecule inhibitors TG101348 or AZD1480, abrogated this survival response and resulted in synergy and significant increases in cell death when combined with MEK1/2 inhibitors AZD6244 or trametinib in BRAFMT CRC cells. The RTK c-MET is activated upstream of STAT3 following MEK1/2 inhibition. Inhibition of c-MET and MEK1/2, using pharmacological inhibitors (crizotinib and AZD6244), results in synergy and increased cell death in BRAFMT CRC cells. Conclusions: We have identified JAK/STAT3 activation as an important escape mechanism for BRAFMT CRC following MEK1/2 inhibition in vitro. Combinations of JAK/MEKi or MET/MEKi can be a potential novel treatment strategy for poor prognostic BRAFMT advanced CRC patients.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.
Background: It is important to assess the clinical competence of nursing students to gauge their professional development and educational needs. This can be measured by self-assessment tools. Anema and McCoy (2010) contended that the currently available measures need further psychometric testing.
Aim: To test the psychometric properties of Nursing Competencies Questionnaire (NCQ) and Self-Efficacy in Clinical Performance (SECP) clinical competence scales.

Method: A non-randomly selected sample of n=248 2nd year nursing students completed NCQ, SECP and demographic questionnaires (June and September 2013). Mokken Scaling Analysis (MSA) was used to test the structural validity and scale properties, convergent and discriminant validity and reliability were subsequently tested.

Results: The NCQ provided evidence of a unidimensional scale which had strong scale scalability coefficients Hs =0.581; but limited evidence of item rankability HT =0.367. MSA undertaken with the SECP scale identified two potential unidimensional scales the SECP28 and SECP7, each with adequate evidence of good/reasonable scalablity psychometric properties as a summed scale but no/very limited evidence of scale rankability (SECP28: Hs = 0.55, HT=0.211; SECP7: Hs = 0.61, HT=0.049). Analysis of between cohort differences and NCQ/ SECP scale scores produced evidence of convergent and discriminant validity and good internal reliability: NCQ α = 0.93, SECP28 α = 0.96, and SECP7 α=0.89.

Discussion: The NCQ was verified to have evidence of reliability and validity; however, as the SECP findings are new, and the sample small, with reference to Straat and colleagues (2014), the SECP results should be interpreted with caution and verified on a second sample.

Conclusions: Measurement of perceived self-competence could inform the development of nursing competence and could start early in a nursing programme. Further testing of the NCQ and SECP scales with larger samples and from different years is indicated.


References:
Anema, M., G and McCoy, JK. (2010) Competency-Based Nursing Education: Guide to Achieving Outstanding Learner Outcomes. New York: Springer.
Straat, JH., van der Ark, LA and Sijtsma, K. (2014) Minimum Sample Size Requirements for Mokken Scale Analysis Educational and Psychological Measurement 74 (5), 809-822.

Branding strategies for high technology products: The effects of consumer and product innovativeness

Choice of an appropriate branding strategy is a critical determinant of new product success. Prior work on fast-moving-consumer-goods (FMCG) prescribes that new products carry new (vs. existing) brand names to appeal to earlier adopters - a critical target for new products. However, such a prescription may not be prudent for high-technology (HT) products, as they often involve considerably more consumer perceived risk than FMCG. By drawing on Dowling and Staelin's (1994) framework of perceived-risk handling, we propose that both earlier and later adopters will favor existing brands to cope with the elevated risk associated with an innovative HT product. Two studies - one conducted in an experimental setting and the other in a field setting - support the proposition that both earlier and later adopters respond more favorably to existing (vs. new) brands on innovative HT products.