Exploring the Mediating Role of Sleep Deficit-Related Functional Status in Subacute Stroke Survivors.

Background: Understanding post-stroke fatigue (PSF) and its associated factors is crucial for effective therapy and rehabilitation. This study aimed to assess the mediating role of the excessive daytime sleepiness-related functional status (SFS) on the relationship between sleep and the severity of fatigue in subacute stroke survivors. Methods: Subacute stroke survivors (n = 50; male = 38; female = 12), completed a cross-sectional study involving the Pittsburgh sleep quality index (PSQI), the Epworth sleepiness scale (ESS), the insomnia severity index (ISI), the functional outcome of the sleep questionnaire (FOSQ), and the fatigue severity scale (FSS). Results: The SFS mediated the association between the severity of fatigue and sleep problems. The PSQI and FOSQ (b = -0.37, p < 0.001), and the FOSQ and FSS were correlated (b = -0.18, p < 0.05), with a significant indirect effect of the PSQI on the FSS. The ISI correlated with the FOSQ (b = -0.20, p < 0.001), with significant direct (b = 0.15, p < 0.001), as well as indirect, effects of the ISI on the FSS. The ESS correlated with the FOSQ (b = -0.23, p < 0.001), with a significant indirect effect of the ESS on the FSS. Conclusions: In subacute stroke survivors, fatigue and sleep are linked. Increased understanding of sleep-PSF may help in exploring new targets for supplement therapy.

Characterizing Canadian funded partnered health research projects between 2011 and 2019: a retrospective analysis.

BACKGROUND AND AIMS: Involving research users in collaborative research approaches may increase the relevance and utility of research findings. Our primary objectives were to (i) identify and describe characteristics of Canadian federally and provincially funded health research projects that included research users and were funded between 2011 and 2019; (ii) explore changes over time; and (iii) compare characteristics between funder required and optional partnerships. METHODS: Retrospective analysis. Inclusion criteria were projects that included research users. We analyzed publicly available project variables, and coded field and type of research using established classification systems. We summarized data with descriptive statistics and compared variables across three funding year blocks and partnership requirement status. RESULTS: We identified 1153 partnered health research projects, representing 137 fields of research and 37 types of research categories. Most projects included a required partnership (80%) and fell into health and social care services research (66%). Project length and funding amount increased from average of 24.8 months and $266 248 CAD in 2011-2013 to 31.6 months and $438 766 CAD in 2017-2019. There were significantly fewer required partnerships in 2017-2019. CONCLUSIONS: Between 2011 and 2019 Canadian federally and provincially funded partnered health research reflected primarily care services research across many fields. The observed breadth suggests that partnered health research approaches are applicable in many fields of research. Additional work to support partnered research across all types of health research (especially biomedical research) is warranted. The administration of larger grants that are funded for longer time periods may address previously identified concerns among research teams engaging in partnered research but may mean that fewer teams receive funding and risk delaying responding to time-sensitive data needs for users. Our process and findings can be used as a starting point for international comparison.

A scoping review of the globally available tools for assessing health research partnership outcomes and impacts.

BACKGROUND: Health research partnership approaches have grown in popularity over the past decade, but the systematic evaluation of their outcomes and impacts has not kept equal pace. Identifying partnership assessment tools and key partnership characteristics is needed to advance partnerships, partnership measurement, and the assessment of their outcomes and impacts through systematic study. OBJECTIVE: To locate and identify globally available tools for assessing the outcomes and impacts of health research partnerships. METHODS: We searched four electronic databases (Ovid MEDLINE, Embase, CINAHL + , PsychINFO) with an a priori strategy from inception to June 2021, without limits. We screened studies independently and in duplicate, keeping only those involving a health research partnership and the development, use and/or assessment of tools to evaluate partnership outcomes and impacts. Reviewer disagreements were resolved by consensus. Study, tool and partnership characteristics, and emerging research questions, gaps and key recommendations were synthesized using descriptive statistics and thematic analysis. RESULTS: We screened 36 027 de-duplicated citations, reviewed 2784 papers in full text, and kept 166 studies and three companion reports. Most studies originated in North America and were published in English after 2015. Most of the 205 tools we identified were questionnaires and surveys targeting researchers, patients and public/community members. While tools were comprehensive and usable, most were designed for single use and lacked validity or reliability evidence. Challenges associated with the interchange and definition of terms (i.e., outcomes, impacts, tool type) were common and may obscure partnership measurement and comparison. Very few of the tools identified in this study overlapped with tools identified by other, similar reviews. Partnership tool development, refinement and evaluation, including tool measurement and optimization, are key areas for future tools-related research. CONCLUSION: This large scoping review identified numerous, single-use tools that require further development and testing to improve their psychometric and scientific qualities. The review also confirmed that the health partnership research domain and its measurement tools are still nascent and actively evolving. Dedicated efforts and resources are required to better understand health research partnerships, partnership optimization and partnership measurement and evaluation using valid, reliable and practical tools that meet partners' needs.

How are health research partnerships assessed? A systematic review of outcomes, impacts, terminology and the use of theories, models and frameworks.

BACKGROUND: Accurate, consistent assessment of outcomes and impacts is challenging in the health research partnerships domain. Increased focus on tool quality, including conceptual, psychometric and pragmatic characteristics, could improve the quantification, measurement and reporting partnership outcomes and impacts. This cascading review was undertaken as part of a coordinated, multicentre effort to identify, synthesize and assess a vast body of health research partnership literature. OBJECTIVE: To systematically assess the outcomes and impacts of health research partnerships, relevant terminology and the type/use of theories, models and frameworks (TMF) arising from studies using partnership assessment tools with known conceptual, psychometric and pragmatic characteristics. METHODS: Four electronic databases were searched (MEDLINE, Embase, CINAHL Plus and PsycINFO) from inception to 2 June 2021. We retained studies containing partnership evaluation tools with (1) conceptual foundations (reference to TMF), (2) empirical, quantitative psychometric evidence (evidence of validity and reliability, at minimum) and (3) one or more pragmatic characteristics. Outcomes, impacts, terminology, definitions and TMF type/use were abstracted verbatim from eligible studies using a hybrid (independent abstraction-validation) approach and synthesized using summary statistics (quantitative), inductive thematic analysis and deductive categories (qualitative). Methodological quality was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). RESULTS: Application of inclusion criteria yielded 37 eligible studies. Study quality scores were high (mean 80%, standard deviation 0.11%) but revealed needed improvements (i.e. methodological, reporting, user involvement in research design). Only 14 (38%) studies reported 48 partnership outcomes and 55 impacts; most were positive effects (43, 90% and 47, 89%, respectively). Most outcomes were positive personal, functional, structural and contextual effects; most impacts were personal, functional and contextual in nature. Most terms described outcomes (39, 89%), and 30 of 44 outcomes/impacts terms were unique, but few were explicitly defined (9, 20%). Terms were complex and mixed on one or more dimensions (e.g. type, temporality, stage, perspective). Most studies made explicit use of study-related TMF (34, 92%). There were 138 unique TMF sources, and these informed tool construct type/choice and hypothesis testing in almost all cases (36, 97%). CONCLUSION: This study synthesized partnership outcomes and impacts, deconstructed term complexities and evolved our understanding of TMF use in tool development, testing and refinement studies. Renewed attention to basic concepts is necessary to advance partnership measurement and research innovation in the field. Systematic review protocol registration: PROSPERO protocol registration: CRD42021137932 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=137932 .

Synthesis and Anti-Cancer Activity of New Pyrazolinyl-Indole Derivatives: Pharmacophoric Interactions and Docking Studies for Identifying New EGFR Inhibitors.

Newly designed series of indole-containing pyrazole analogs, pyrazolinylindoles, were synthesized, and their structures were confirmed based on the spectral data of the 1H NMR, 13C NMR, and HR-MS analyses. Preliminary anti-cancer activity testings were carried out by the National Cancer Institute, United States of America (NCI, USA). Compounds HD02, HD05, and HD12 demonstrated remarkable cytotoxic activities against nine categories of cancer types based cell line panels which included leukemia, colon, breast, melanoma, lungs, renal, prostate, CNS, and ovarian cancer cell lines. The highest cytotoxic effects were exhibited by the compounds HD02 [1-(5-(1-H-indol-3-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenylethanone], HD05 [1-(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenoxyethanone], and HD12 [(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone] against some of the 56 types of NCI-based cell lines in different panels. Compound HD05 showed the maximum range of cancer cell growth inhibitions against all categories of the cell lines in all nine panels. On average, in comparison to the referral standard, imatinib, at a dose level of 10 µM, the HD05 showed significant activity against leukemia in the range of 78.76%, as compared to the imatinib at 9% of cancer cells' growth inhibitions. Molecular docking simulation studies were performed in silico on the epidermal growth factor receptor (EGFR) tyrosine kinase, in order to validate the activity.

Catalytic roles, immobilization and management of recalcitrant environmental pollutants by laccases: Significance in sustainable green chemistry.

We are facing a high risk of exposure to emerging contaminants and increasing environmental pollution with the concomitant growth of industries. Persistence of these pollutants is a major concern to the ecosystem. Laccases, also known as "green catalysts" are multi-copper oxidases which offers an eco-friendly solution for the degradation of these hazardous pollutants to less or non-toxic compounds. Although various other biological methods exist for the treatment of pollutants, the fact that laccases catalyze the oxidation of broad range of substrates in the presence of molecular oxygen without any additional cofactor and releases water as the by-product makes them exceptional. They have a good possibility of utilization in various industries, especially for the purpose of bioremediation. Besides this, they have also been used in medical/health care, food industry, bio-bleaching, wine stabilization, organic synthesis and biosensors. This review covers the catalytic behaviour of laccases, their immobilization strategies, potential applications in bioremediation of recalcitrant environmental pollutants and their engineering. It provides a comprehensive summary of most factors to consider while working with laccases in an industrial setting. It compares the benefits and drawbacks of the current techniques. Immobilization and mediators, two of the most significant aspects in working with laccases, have been meticulously discussed.

Glycosphingolipids (GSLs) from Sphingomonas paucimobilis Increase the Efficacy of Liposome-Based Nanovaccine against Acinetobacter baumannii-Associated Pneumonia in Immunocompetent and Immunocompromised Mice.

Due to the high propensity of drug resistance in Acinetobacter baumannii, the number of currently available therapeutic drugs has become very limited. Thus, it becomes incredibly important to prepare an effective vaccine formulation capable of eliciting an effective immune response against A. baumannii. In this study, we prepared a liposomal vaccine formulation bearing glycosphingolipids (GSLs) from Sphingomonas paucimobilis and loaded with the whole cell antigen (WCAgs-GSLs-liposomes) of A. baumannii. The immune-stimulating potential and prophylactic efficacy of WCAgs-GSLs-liposomes were compared with those of WCAgs-liposomes (without GSLs) or free WCAgs in both immunocompetent and immunodeficient mice. The efficacy of vaccine formulations was determined by analyzing antibody titer, cytokine levels, and survival studies in the immunized mice. The findings revealed that vaccination with WCAgs-GSLs-liposomes stimulated a greater secretion of antibodies and cytokines, higher lymphocyte proliferation, and increased expression of the co-stimulatory molecules. Anti-sera from WCAgs-GSLs-liposomes-immunized mice remarkably reduced the biofilm formation by A. baumannii. Most importantly, WCAgs-GSLs-liposomes-vaccinated mice demonstrated a higher defiance against the pathogen, as compared to the immunizations with WCAgs-liposomes (without GSLs) or free WCAgs. Immunocompetent mice immunized with WCAgs-GSLs-liposomes showed a 100% survival rate, while those immunized with WCAgs-liposomes exhibited a 60% survival rate. The protective effect of WCAgs-GSLs-liposomes was also found to be higher in immunocompromised mice, as the immunized mice showed a 50% survival rate, which was greater than the 20% survival rate of those immunized with WCAgs-liposomes. The survival data was also supported by the findings of bacterial load and histological analysis that substantiated the greatest prophylactic potential of the WCAgs-GSLs-liposomes. These findings recommend that WCAgs-GSLs-liposomes may be reckoned as a prospective vaccine to protect the persons against A. baumannii infection.

Liposome-Mediated Delivery of MERS Antigen Induces Potent Humoral and Cell-Mediated Immune Response in Mice.

The advancements in the field of nanotechnology have provided a great platform for the development of effective antiviral vaccines. Liposome-mediated delivery of antigens has been shown to induce the antigen-specific stimulation of the humoral and cell-mediated immune responses. Here, we prepared dried, reconstituted vesicles (DRVs) from DPPC liposomes and used them as the vaccine carrier system for the Middle East respiratory syndrome coronavirus papain-like protease (DRVs-MERS-CoV PLpro). MERS-CoV PLpro emulsified in the Incomplete Freund's Adjuvant (IFA-MERS-CoV PLpro) was used as a control. Immunization of mice with DRVs-MERS-CoV PLpro did not induce any notable toxicity, as revealed by the levels of the serum alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) in the blood of immunized mice. Immunization with DRVs-MERS-CoV PLpro induced greater antigen-specific antibody titer and switching of IgG1 isotyping to IgG2a as compared to immunization with IFA-MERS-CoV PLpro. Moreover, splenocytes from mice immunized with DRVs-MERS-CoV PLpro exhibited greater proliferation in response to antigen stimulation. Moreover, splenocytes from DRVs-MERS-CoV PLpro-immunized mice secreted significantly higher IFN-γ as compared to splenocytes from IFA-MERS-CoV PLpro mice. In summary, DRVs-MERS-CoV PLpro may prove to be an effective prophylactic formulation to prevent MERS-CoV infection.

Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis.

Garlic's main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of -4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

Natural compounds as antiatherogenic agents.

Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.

JNK2 modulates the CD1d-dependent and -independent activation of iNKT cells.

Invariant natural killer T (iNKT) cells play critical roles in autoimmune, anti-tumor, and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wild-type (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections.

Mortality associated with Fournier's gangrene remains unchanged over 25 years.

OBJECTIVES: To report a case series of Fournier's gangrene (FG) from our institution, and to investigate its mortality over the past 25 years. PATIENTS AND METHODS: Case notes of men presenting to our institution from 2013 to 2016 with FG were reviewed. As well as age, diabetic history, length of stay, length of stay in critical care, and mortality; we calculated (where possible) the Uludag Fournier's Gangrene Severity Index (UFGSI). Published studies and cases series reporting the mortality rates for FG were reviewed from 1993 to 2018. The size of the study, country of origin, average age and gender ratio were collected, alongside mortality. RESULTS: Two of the 11 patients treated for FG at out institution died within 90 days of admission, a mortality rate of 18%. Predicted mortality was significantly higher. A total of 173 publications were identified from the Medical Literature Analysis and Retrieval System Online (MEDLINE) database published between 1993 and 2018, reporting data from 1975 to 2018. Analysis of heterogeneity, by both time and precision, supported exclusion of four retrospective coded database-driven studies from the analysis. From the remaining studies, mortality ranged from 0% to 42%. Of the 6152 reported cases, there were 1220 deaths, giving an overall mortality rate of 19.8%. There was no evidence of a significant change in the mortality rate for FG over time (P = 0.996). CONCLUSIONS: In our case series, the mortality rate for FG was 18%, despite a higher predicated mortality (based on UFGSI scores). The treatment of FG remains appropriate resuscitation, aggressive surgical debridement, and critical care management. Perceived high risk of mortality should not deter aggressive management. Mortality due to FG does not appear to have changed over the past 25 years, and is estimated at 19.8%. In studies identifying cases of FG, careful attention should be paid to case definition, particularly when cases are being abstracted retrospectively from large coded databases.

Socioeconomic and demographic factors determining the underweight prevalence among children under-five in Punjab.

BACKGROUND: Underweight prevalence continues to be major public health challenge worldwide, particularly in developing countries like Pakistan. This study is focused on socio-economic and demographic aspects of underweight prevalence among children under-five in Punjab. METHODS: In this study, several socioeconomic and demographic factors are considered using MICS-4 data-set. Only those variables which are usually described in the nutritional studies of children were picked. Covariates include: the age of children, sex of the children, age of mother, total number of children born to women, family wealth index quintile, source of drinking water, type of sanitation, place of residence, parents' education and occupation. All Categorical variables are effect coded. The child's age and the mother's age are assumed to be nonlinear, geographical region is spatial effect, while other variables are parametric in nature. Since, the response is binary, covariate comprises linear terms, nonlinear effects of continues covariates and geographic effects, so we have use Geo-additive models (based on Fully Bayesian approach) with binomial family under logit link. Statistical analysis is performed on Statistical package R using Bayes X and R2 Bayes X Libraries. RESULTS: Underweight status of children was found to be positively associated with number of under-five children in household, total number of children ever born to women and age of mother when the child was born. Whereas, it negatively associated with place of residence, parent's education and family wealth index quintile. On the regional effect, the Southern Punjab has higher prevalence of underweight compared to Central and Northern Punjab. CONCLUSION: Similarity of our results with several other studies demonstrate that the Geo-additive models are an ideal substitute of other statistical models to analyze the underweight prevalence among children. Moreover, our findings suggest the Punjab Government, to introduce target-oriented programs such as poverty reduction and enhancement of education and health facilities for poor population and disadvantaged regions, especially Southern Punjab.

Disseminating the Foundations of Knowledge Translation and Patient Engagement Science Through the KnowledgeNudge Blog and Twitter Profile: Quantitative Descriptive Evaluation.

BACKGROUND: There is a documented need to build capacity for theory- and evidence-informed knowledge translation (KT) and patient engagement (PE) practice in health research. Dissemination of foundational content online coupled with social media promotion may build capacity by increasing awareness, knowledge, and positive attitudes. OBJECTIVE: This retrospective study sought to (1) describe exposure and engagement of the KnowledgeNudge KT and PE dissemination strategy (online blog and Twitter profile) over 2 years and (2) identify and compare characteristics of individual posts with the most and least exposure and reach. METHODS: Exposure was assessed by blog site views per month and Twitter profile impressions per month. Engagement was assessed by Twitter profile interactions per month. Descriptive statistics were calculated for 6-month blocks and compared using one-way analysis of variance or Student t test. Individual post exposure was assessed by average post views per week. Individual post reach was assessed by average post reads per week. High- and low-profile blog posts with the highest and lowest 10th percentile for exposure and reach were identified. RESULTS: A total of 99 posts and 755 tweets were published during the study period. There was a significant increase in exposure (P=.004) and reach (P<.001) during the final 6 months. Seven high-profile and 6 low-profile posts were identified. High-profile posts had a significantly greater average word count than low-profile posts (P=.003). There were no other significant differences between posts. CONCLUSIONS: The increases in KnowledgeNudge exposure and engagement offer preliminary evidence in support of this dissemination strategy for the practice of KT and PE. Variation in individual post exposure and reach warrants further exploration to tailor content to user needs. Future work will include a prospective evaluation strategy to explore the effect of KnowledgeNudge on awareness, knowledge, attitudes, and behavior.

Characteristics of melting heat transfer during flow of Carreau fluid induced by a stretching cylinder.

This article provides a comprehensive analysis of the energy transportation by virtue of the melting process of high-temperature phase change materials. We have developed a two-dimensional model for the boundary layer flow of non-Newtonian Carreau fluid. It is assumed that flow is caused by stretching of a cylinder in the axial direction by means of a linear velocity. Adequate local similarity transformations are employed to determine a set of non-linear ordinary differential equations which govern the flow problem. Numerical solutions to the resultant non-dimensional boundary value problem are computed via the fifth-order Runge-Kutta Fehlberg integration scheme. The solutions are captured for both zero and non-zero curvature parameters, i.e., for flow over a flat plate or flow over a cylinder. The flow and heat transfer attributes are witnessed to be prompted in an intricate manner by the melting parameter, the curvature parameter, the Weissenberg number, the power law index and the Prandtl number. We determined that one of the possible ways to boost the fluid velocity is to increase the melting parameter. Additionally, both the velocity of the fluid and the momentum boundary layer thickness are higher in the case of flow over a stretching cylinder. As expected, the magnitude of the skin friction and the rate of heat transfer decrease by raising the values of the melting parameter and the Weissenberg number.

Estimation of coronary wave intensity analysis using noninvasive techniques and its application to exercise physiology.

Wave intensity analysis (WIA) has found particular applicability in the coronary circulation where it can quantify traveling waves that accelerate and decelerate blood flow. The most important wave for the regulation of flow is the backward-traveling decompression wave (BDW). Coronary WIA has hitherto always been calculated from invasive measures of pressure and flow. However, recently it has become feasible to obtain estimates of these waveforms noninvasively. In this study we set out to assess the agreement between invasive and noninvasive coronary WIA at rest and measure the effect of exercise. Twenty-two patients (mean age 60) with unobstructed coronaries underwent invasive WIA in the left anterior descending artery (LAD). Immediately afterwards, noninvasive LAD flow and pressure were recorded and WIA calculated from pulsed-wave Doppler coronary flow velocity and central blood pressure waveforms measured using a cuff-based technique. Nine of these patients underwent noninvasive coronary WIA assessment during exercise. A pattern of six waves were observed in both modalities. The BDW was similar between invasive and noninvasive measures [peak: 14.9 ± 7.8 vs. -13.8 ± 7.1 × 10(4) W·m(-2)·s(-2), concordance correlation coefficient (CCC): 0.73, P < 0.01; cumulative: -64.4 ± 32.8 vs. -59.4 ± 34.2 × 10(2) W·m(-2)·s(-1), CCC: 0.66, P < 0.01], but smaller waves were underestimated noninvasively. Increased left ventricular mass correlated with a decreased noninvasive BDW fraction (r = -0.48, P = 0.02). Exercise increased the BDW: at maximum exercise peak BDW was -47.0 ± 29.5 × 10(4) W·m(-2)·s(-2) (P < 0.01 vs. rest) and cumulative BDW -19.2 ± 12.6 × 10(3) W·m(-2)·s(-1) (P < 0.01 vs. rest). The BDW can be measured noninvasively with acceptable reliably potentially simplifying assessments and increasing the applicability of coronary WIA.

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In this study we first show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids and intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Second, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.

Comparative evaluation of genotoxicity by micronucleus assay in the buccal mucosa over comet assay in peripheral blood in oral precancer and cancer patients.

Early detection and quantification of DNA damage in oral premalignancy or malignancy may help in management of the disease and improve survival rates. The comet assay has been successfully utilised to detect DNA damage in oral premalignant or malignancy. However, due to the invasive nature of collecting blood, it may be painful for many unwilling patients. This study compares the micronucleus (MN) assay in oral buccal mucosa cells with the comet assay in peripheral blood cells in a subset of oral habit-induced precancer and cancer patients. For this, MN assay of exfoliated epithelial cells was compared with comet assay of peripheral blood leucocytes among 260 participants, including those with oral lichen planus (OLP; n = 52), leukoplakia (LPK; n = 51), oral submucous fibrosis (OSF; n = 51), oral squamous cell carcinoma (OSCC; n = 54) and normal volunteers (n = 52). Among the precancer groups, LPK patients showed significantly higher levels of DNA damage as reflected by both comet tail length (P < 0.0001) and micronuclei (MNi) frequency (P = 0.0009). The DNA damage pattern in precancer and cancer patients was OLP < OSF < LPK < OSCC, and with respective oral habits, it was multiple habits > cigarette + khaini > cigarette smokers > areca + khaini > areca. There was no significant difference in the comet length and MNi frequency between males and females who had oral chewing habits. An overall significant correlation was observed between MNi frequency and comet tail length with r = 0.844 and P < 0.0001. Thus, the extent of DNA damage evaluation by the comet assay in peripheral blood cells is perfectly reflected by the MN assay on oral exfoliated epithelial cells, and MNi frequency can be used with the same effectiveness and greater efficiency in early detection of oral premalignant conditions.

Transperineal template prostate biopsies in men with raised PSA despite two previous sets of negative TRUS-guided prostate biopsies.

BACKGROUND: The possibility of prostate cancer as a cause for steadily rising PSA despite previously negative transrectal ultrasound (TRUS)-guided prostate biopsies is a major concern. An initial negative TRUS-guided prostate biopsy does not necessarily exclude the presence of clinically significant prostate cancer. We determined the role of transperineal template prostate biopsy (TPTPB) in prostate cancer detection in men with raised PSA despite two previous sets of negative TRUS biopsies. METHODS: Between January 2008 and August 2012, a total of 122 men's records were reviewed after having 36-core TPTPB following two previous sets of negative TRUS biopsies despite raised PSA. A retrospective record of PSA levels, clinicopathological parameters and histological outcomes was made. RESULTS: Mean age was 63 years (range 49-77), and mean PSA was 18.0 (range 2.0-119.0). A total of 71/122 (58 %) men were diagnosed with prostate cancer on TPTPB. Of these, 28 (39 %), 34 (48 %), 5 (7 %), and 4 (6 %) had Gleason score 6, 7 (3 + 4), 7 (4 + 3), and 9 (4 + 5), respectively. The mean number of positive cores was 7 (range 1-22). Of these, only 15 (21 %) had ≤2 cores positive and Gleason score of 6. Of the 51 (42 %) men with a negative histology on TPTPB, 11 (22 %), 10 (19 %), and 30 (59 %) had atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, or benign pathology. CONCLUSION: TPTPB is associated with a high rate of clinically significant prostate cancer diagnosis (58 %) in men with raised PSA despite two previous sets of negative TRUS biopsies.

Regulation of the actin cytoskeleton by Rho kinase controls antigen presentation by CD1d.

CD1d molecules are MHC class I-like molecules that present lipid Ags to NKT cells. Although we have previously shown that several different cell signaling molecules can play a role in the control of Ag presentation by CD1d, a defined mechanism by which a cell signaling pathway regulates CD1d function has been unclear. In the current study, we have found that the Rho kinases, Rho-associated, coiled-coil containing protein kinase (ROCK)1 and ROCK2, negatively regulate both human and mouse CD1d-mediated Ag presentation. Inhibition of ROCK pharmacologically, through specific ROCK1 and ROCK2 short hairpin RNA, or by using dendritic cells generated from ROCK1-deficient mice all resulted in enhanced CD1d-mediated Ag presentation compared with controls. ROCK regulates the actin cytoskeleton by phosphorylating LIM kinase, which, in turn, phosphorylates cofilin, prohibiting actin fiber depolymerization. Treatment of APCs with the actin filament depolymerizing agent, cytochalasin D, as well as knockdown of LIM kinase by short hairpin RNA, resulted in enhanced Ag presentation to NKT cells by CD1d, consistent with our ROCK inhibition data. Therefore, our overall results reveal a model whereby CD1d-mediated Ag presentation is negatively regulated by ROCK via its effects on the actin cytoskeleton.