Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

The pathologic spectrum of adenovirus nephritis in the kidney allograft.

Adenovirus nephritis (ADVN) is a rare and understudied complication of kidney transplantation. Unlike BK virus nephropathy (BKVN), our knowledge of clinicopathologic manifestations of ADVN remains rudimentary and essentially limited to case reports. To expand on this, we retrospectively studied 11 kidney transplant recipients with ADVN and compared their allograft biopsies to 33 kidney transplant recipients with BKVN using conventional microscopy and the 770 gene Nanostring Banff Human Organ Transplant Profiling Panel. Patients with ADVN had a median age of 44 years, were predominantly male, and developed ADVN at a median of 31 months post-transplantation. Eight patients presented with fever and ten had hematuria. The most common histologic manifestations included granulomas (82%), tubulocentric inflammation (73%), and tubular degenerative changes consistent with acute tubular necrosis (73%). During a median follow-up of 55 months after biopsy, three patients developed allograft failure from subsequent acute rejection. All seven patients with available follow-up PCR showed resolution of viremia at a median of 30 days after diagnosis. Compared to BKVN, ADVN demonstrated more granulomas and less tubulointerstitial scarring. On follow-up, patients with ADVN had more rapid clearance of viral DNA from plasma. Transcriptomic analyses showed that ADVN had increased expression of several pro-inflammatory transcriptomes, mainly related to innate immunity, was associated with increased expression of transcripts with inhibitory effects on inflammatory response and showed higher enrichment with neutrophils, which can cause aggressive but short-lasting damage. Thus, we demonstrate that, despite its association with aggressive neutrophil-rich inflammation, ADVN does not often lead to allograft failure. Hence, preventing subsequent acute rejection following resolution of ADVN may improve allograft survival.

Size Control and Improved Aqueous Colloidal Stability of Surface-Functionalized ZnGa2O4:Cr3+ Bright Persistent Luminescent Nanoparticles.

Near-infrared (NIR)-emitting ZnGa2O4:Cr3+ (ZGO) persistent luminescent nanoparticles (PLNPs) have recently attracted considerable attention for diverse optical applications. The widespread use and promising potential of ZGO material in different applications arise from its prolonged post-excitation emission (several minutes to hours) that eliminates the need for continuous in situ excitation and the possibility of its excitation in different spectral regions (X-rays and UV-vis). However, the lack of precise control over particle size/distribution and its poor water dispersibility and/or limited colloidal stability required for certain biological applications are the major bottlenecks that limit its practical applications. To address these fundamental limitations, herein, we have prepared oleic acid (OA)-stabilized ZGO PLNPs with controlled size (7-12 nm, depending on the type of alcohol used in synthesis) and monodispersity. A further increase in size (8-21 nm), with a concomitant increase in persistent luminescence, could be achieved using a seed-mediated approach, employing the as-prepared ZGO PLNPs from the first synthesis as the seed and growing layers of the same material by adding fresh precursors. To remove their surface oleate groups and make the nanoparticles hydrophilic, two surface modification strategies were evaluated: modification with only poly(acrylic acid) (PAA) as the hydrophilic capping agent and modification with either PAA or cysteamine (Cys) as the hydrophilic capping agent in conjunction with BF4- as the intermediate surface modifier. The latter surface modifications involving BF4- conferred long-term (60 days and longer) colloidal stability to the nanoparticles in aqueous media, which is related to their favorable ζ potential values. The proposed generalized strategy could be used to prepare different kinds of surface-functionalized PLNPs with control of size, hydrophilicity, and colloidal stability and enhanced/prolonged persistent luminescence for diverse potential applications.

Technical notes on prism-dioptre and Prentice's rule.

PURPOSE: To show an alternative interpretation for prism-dioptre and access Prentice's rule accuracy. METHODS: Algebraic calculation. RESULTS: The prism-dioptre can be expressed as a percentage of the distance between the prism and the plane of prismatic dislocation. Prentice's rule is an imprecise mathematical expression prone to expressive errors. CONCLUSIONS: The prism-dioptre seems to be more informative when interpreted as a percentage. Prentice's rule is more effective as a pedagogical approach for introducing the concept of spherical lenses' prismatic image dislocation rather than a method for calculating its actual value.

Effects of Silk Fibroin Enzyme Hydrolysates on Memory and Learning: A Review.

Silk protein products have been used for a wide range of applications. This review focuses on the studies conducted relative to cognitive functions with silk fibroin enzyme hydrolysates (FEH) in humans and animals. All known studies reported in PubMed and Google Scholar have been included. Studies have been conducted on children, high school and college students, adults and seniors, ranging in ages from 7-92 years. Doses of 200-600 mg silk FEH per day for three weeks to 16 weeks have been used. Based on these studies, it can be concluded that silk FEH exhibit beneficial cognitive effects with respect to memory and learning, attention, mental focus, accuracy, memory recall, and overall memory and concentration. These conclusions are supported by studies in rats and mice. Mechanistic studies that have been conducted in animals and cell culture systems are also reviewed. These studies indicate that silk FEH exerts its positive effects on memory and learning by providing neuroprotection via a complex mechanism involving its potent antioxidant and inflammation-inhibiting activities. Acetylcholine (ACh) is secreted by cholinergic neurons, and plays a role in encoding new information. Silk FEH were shown to decrease the levels of the pro-oxidant and pro-inflammatory mediators interlukin-1 (IL-1ß), IL-6 and tumor necrosis factor-alpha (TNF-α), protecting the cholinergic system from oxidative stress, thus enhancing ACh levels in the brain, which is known to promote cognitive functions. In addition, the expression of brain-derived neurotrophic factor (BNDF), which is involved in the survival of neurons, is enhanced, and an increase in the expression of the phosphorylated cAMP response element-binding protein (p-CREB) occurs, which is known to play a positive role in cognitive functions. No adverse effects have been reported in association with the use of silk FEH.

Adsorption of lysozyme into a charged confining pore.

Several applications arise from the confinement of proteins on surfaces because their stability and biological activity are enhanced. It is also known that the way in which a protein adsorbs on the surface is important for its biological function since its active sites should not be obstructed. In this study, the adsorption properties of hen egg-white lysozyme, HEWL, into a negatively charged silica pore is examined by employing a coarse-grained model and constant-pH Monte Carlo simulations. The role of electrostatic interactions is taken into account via including the Debye-Hückel potentials into the Cα structure-based model. We evaluate the effects of pH, salt concentration, and pore radius on the protein preferential orientation and spatial distribution of its residues regarding the pore surface. By mapping the residues that stay closer to the pore surface, we find that the increase of pH leads to orientational changes of the adsorbed protein when the solution pH gets closer to the HEWL isoelectric point. Under these conditions, the pKa shift of these important residues caused by the adsorption into the charged confining surface results in a HEWL charge distribution that stabilizes the adsorption in the observed protein orientation. We compare our observations to the results of the pKa shift for HEWL available in the literature and to some experimental data.

Decreased colorectal cancer incidence and mortality in a diverse urban population with increased colonoscopy screening.

BACKGROUND: Although colorectal cancer screening has contributed to decreased incidence and mortality, disparities are present by race/ethnicity. The Citywide Colon Cancer Control Coalition (C5) and NYC Department of Health and Mental Hygiene (DOHMH) promoted screening colonoscopy from 2003 on, and hypothesized future reductions in CRC incidence, mortality and racial/ethnic disparities. METHODS: We assessed annual percent change (APC) in NYC CRC incidence, stage and mortality rates through 2016 in a longitudinal cross-sectional study of NY State Cancer Registry, NYC Vital Statistics, and NYC Community Health Survey (CHS) data. Linear regression tested associations between CRC mortality rates and risk factors. RESULTS: Overall CRC incidence rates from 2000 decreased 2.8% yearly from 54.1 to 37.3/100,000 population in 2016, and mortality rates from 2003 decreased 2.9% yearly from 21.0 to 13.9 in 2016 at similar rates for all racial/ethnic groups. Local stage disease decreased overall with a transient increase from 2002 to 2007. In 2016, CRC incidence was higher among Blacks (42.5 per 100,000) than Whites (38.0), Latinos (31.7) and Asians (30.0). In 2016, Blacks had higher mortality rates (17.9), than Whites (15.2), Latinos (10.4) and Asians (8.8). In 2016, colonoscopy rates among Blacks were 72.2%, Latinos 71.1%, Whites 67.2%, and Asians, 60.9%. CRC mortality rates varied by neighborhood and were independently associated with Black race, CRC risk factors and access to care. CONCLUSIONS: In a diverse urban population, a citywide campaign to increase screening colonoscopy was associated with decreased incidence and mortality among all ethnic/racial groups. Higher CRC burden among the Black population demonstrate more interventions are needed to improve equity.

The reliability of visual ERP components in children across the first year of school.

Event-related potentials (ERPs) are increasingly used as neurophysiological markers of perceptual and cognitive processes conveying risk for psychopathology. However, little is known about the reliability of ERP components during childhood, a time of substantial brain maturation. In the present study, we examine the early visual ERP components (P1, N170, VPP), frequently examined as indicators of attentional bias, for 110 children at kindergarten (T1) and first grade (T2). Children performed a Go/Nogo task at both time points, with exact stimuli changed to reduce habituation. All components showed increases in absolute amplitude and the P1 and VPP also showed decreases in latency. Retest reliability across time was good to very good for amplitude measures (Pearson rs ranging from .54 for N170 to .69 for P1) and low to very good for latencies (rs from .34 for P1 to .60 for N170), despite the change in visual stimuli. Although there was some evidence of moderation by sex, early visual ERP components appear to be a reliable measure of individual differences in attention processing in middle childhood. This has implications for the use of early visual ERP components as trait-like markers for individual differences in perceptual processes in developmental research.

EEG-IP: an international infant EEG data integration platform for the study of risk and resilience in autism and related conditions.

BACKGROUND: Establishing reliable predictive and diganostic biomarkers of autism would enhance early identification and facilitate targeted intervention during periods of greatest plasticity in early brain development. High impact research on biomarkers is currently limited by relatively small sample sizes and the complexity of the autism phenotype. METHODS: EEG-IP is an International Infant EEG Data Integration Platform developed to advance biomarker discovery by enhancing the large scale integration of multi-site data. Currently, this is the largest multi-site standardized dataset of infant EEG data. RESULTS: First, multi-site data from longitudinal cohort studies of infants at risk for autism was pooled in a common repository with 1382 EEG longitudinal recordings, linked behavioral data, from 432 infants between 3- to 36-months of age. Second, to address challenges of limited comparability across independent recordings, EEG-IP applied the Brain Imaging Data Structure (BIDS)-EEG standard, resulting in a harmonized, extendable, and integrated data state. Finally, the pooled and harmonized raw data was preprocessed using a common signal processing pipeline that maximizes signal isolation and minimizes data reduction. With EEG-IP, we produced a fully standardized data set, of the pooled, harmonized, and pre-processed EEG data from multiple sites. CONCLUSIONS: Implementing these integrated solutions for the first time with infant data has demonstrated success and challenges in generating a standardized multi-site data state. The challenges relate to annotation of signal sources, time, and ICA analysis during pre-processing. A number of future opportunities also emerge, including validation of analytic pipelines that can replicate existing findings and/or test novel hypotheses.

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.

How charge regulation and ion-surface affinity affect the differential capacitance of an electrical double layer.

The differential capacitance of an electrical double layer is a topic of great importance to develop more efficient and environment-friendly energy storage devices: electric double layer supercapacitors. In addition to the bare electrostatic interactions, recent experimental and computational studies suggest that electrodes covered by ionizable groups do interact selectively with specific ion types, an effect that can increase the maximal conductivity and voltage of a supercapacitor. Inspired by this, in the present work we investigate how ion-specific non-electrostatic interactions modify the differential capacitance of a flat electrode whose surface is covered by ionizable groups subject to a charge regulation process. The incorporation of hydration interactions by means of ion-specific Yukawa potential into the Poisson-Boltzmann theory allows our model to describe different scenarios of ion-surface affinity and, hence, the selective depletion or accumulation of specific ion types close to a charged surface. We obtained larger capacitance values when considering electrodes that favor the accumulation of cations and the depletion of anions.

High-Intensity Versus Low-Intensity Surveillance for Patients With Colorectal Adenomas: A Cost-Effectiveness Analysis.

Background: Surveillance of patients with colorectal adenomas has limited long-term evidence to support current practice. Objective: To compare the lifetime benefits and costs of high- versus low-intensity surveillance. Design: Microsimulation model. Data Sources: U.S. cancer registry, cost data, and published literature. Target Population: U.S. patients aged 50, 60, or 70 years with low-risk adenomas (LRAs) (1 to 2 small adenomas) or high-risk adenomas (HRAs) (3 to 10 small adenomas or ≥1 large adenoma) removed after screening with colonoscopy or fecal immunochemical testing (FIT). Time Horizon: Lifetime. Perspective: Societal. Intervention: No further screening or surveillance, routine screening after 10 years, low-intensity surveillance (10 years after LRA removal and 5 years after HRA removal), and high-intensity surveillance (5 years after LRA removal and 3 years after HRA removal). Outcome Measures: Colorectal cancer (CRC) incidence and incremental cost-effectiveness. Results of Base-Case Analysis: Without surveillance or screening, lifetime CRC incidence for patients aged 50 years was 10.9% after LRA removal and 17.2% after HRA removal at screening colonoscopy. Subsequent colonoscopic screening, low-intensity surveillance, or high-intensity surveillance decreased incidence by 39%, 46% to 48%, and 55% to 56%, respectively. Incidence of CRC and surveillance benefits were higher for adenomas detected at FIT screening and lower for older patients. High-intensity surveillance cost less than $30 000 per quality-adjusted life-year (QALY) gained compared with low-intensity surveillance. Results of Sensitivity Analysis: High-intensity surveillance cost less than $100 000 per QALY gained in most alternative scenarios for adenoma recurrence, CRC incidence, longevity, quality of life, screening ages, surveillance ages, test performance, disutilities, and cost. Limitation: Few surveillance outcome data exist. Conclusion: The model suggests that high-intensity surveillance as recommended in the United States provides modest but clinically relevant benefits over low-intensity surveillance at acceptable cost. Primary Funding Source: National Cancer Institute.

p-Synephrine, ephedrine, p-octopamine and m-synephrine: Comparative mechanistic, physiological and pharmacological properties.

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and m-synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, ß-1 and ß-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m-synephrine. As a consequence, the effects of ephedrine and m-synephrine cannot be directly extrapolated to p-synephrine and p-octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.

Highly Bioavailable Forms of Curcumin and Promising Avenues for Curcumin-Based Research and Application: A Review.

Curcumin exerts a wide range of beneficial physiological and pharmacological activities, including antioxidant, anti-amyloid, anti-inflammatory, anti-microbial, anti-neoplastic, immune-modulating, metabolism regulating, anti-depressant, neuroprotective and tissue protective effects. However, its poor solubility and poor absorption in the free form in the gastrointestinal tract and its rapid biotransformation to inactive metabolites greatly limit its utility as a health-promoting agent and dietary supplement. Recent advances in micro- and nano-formulations of curcumin with greatly enhanced absorption resulting in desirable blood levels of the active forms of curcumin now make it possible to address a wide range of potential applications, including pain management, and as tissue protective. Using these forms of highly bioavailable curcumin now enable a broad spectrum of appropriate studies to be conducted. This review discusses the formulations designed to enhance bioavailability, metabolism of curcumin, relationships between solubility and particle size relative to bioavailability, human pharmacokinetic studies involving formulated curcumin products, the widely used but inappropriate practice of hydrolyzing plasma samples for quantification of blood curcumin, current applications of curcumin and its metabolites and promising directions for health maintenance and applications.

Role of Vitamin D and Its Receptors in the Pathophysiology of Chronic Rhinosinusitis.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group. METHODS: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted. RESULTS: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data. CONCLUSIONS: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS.