Enantiomeric separation of racemic 4-aryl-1,4-dihydropyridines and 4-aryl-1,2,3,4-tetrahydropyrimidines on a chiral tetraproline stationary phase.
The chromatographic chiral resolution of 4-aryl-1,4-dihydropyridines (1-32), 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38), and 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) was studied on a tetraproline-immobilized chiral column synthesized in our lab. This tetraproline chiral stationary phase can resolve most of these compounds. The 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38) and 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) were more efficiently resolved than the racemic 4-aryl-1,4-dihydropyridines on the tetraproline chiralstationary phase. Analytes with 5,5-dimethyl groups (39-41) were less efficiently resolved than analytes without 5,5-dimethyl substituents (1-16). The 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) without a sulfur atom were much more efficiently resolved than 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38). No obvious electronic effects on the resolution of any of these analytes (1-41) were observed on the tetraproline chiral stationary phase. The tetraproline chiral stationary phase separated enantiomers mainly via hydrogen bonding interactions.


Prevalence and Ascertainment of Dementia Cases in the Malmö Diet and Cancer Study.
Register diagnoses, both hospital-based and from open clinic care, are often used in research studies in Sweden. The validity of such diagnoses has been debated and a validation assessment can improve the diagnostic accuracy for use in research studies. The aim of this study was to investigate the quality of register-derived dementia diagnoses in the Malmö Diet and Cancer population study (MDCS) and to validate these diagnoses using systematic criteria. MDCS is a population-based prospective study comprising 30,446 participants. Register diagnoses of dementia for the MDCS population were derived from the Swedish National Patient Register (NPR) and validated through re-evaluation of available medical records by physicians. In the MDCS cohort, 2,206 participants were diagnosed with dementia according to the NPR during a mean follow-up of 18.1 years. The general dementia diagnosis was valid in 96% of the cases, but 40% of the specific dementia diagnoses were changed during the process of reevaluation. The diagnostic validity varied between 25.2% and 82.9% for the different diagnoses. The results from the validity assessment per diagnostic category revealed that the validity of the NPR diagnoses was higher for the more specific diagnoses and lower for unspecified dementia. The major diagnostic shift during the re-evaluation was from unspecified dementia to more specific diagnoses. Validation of dementia diagnoses using medical records results in more precise diagnoses. Dementia diagnoses derived from registers should be validated in order to study associations between influential factors and different dementia diagnoses.


Evidence-based interventions for cancer- and treatment-related cognitive impairment.
Cancer- and cancer treatment-related cognitive impairment is a common, bothersome, and potentially debilitating symptom incurred by cancer survivors. Cognitive impairment has a significant impact on patients' day-to-day functioning and quality of life, but it remains under-recognized and undertreated. This article, which is an update from the initial Oncology Nursing Society Putting Evidence Into Practice for cancer- and cancer treatment-related cognitive impairment, provides a comprehensive critical review and summary of the evidence regarding interventions addressing cognitive impairment for cancer survivors. This article examines the effectiveness of interventions focused on cancer- and cancer treatment-related cognitive impairment, makes recommendations for practice, and identifies gaps in knowledge and areas for further research.


The adolescent family environment and cohabitation across the transition to adulthood.
This study draws upon a sample of men and women from Waves I and IV of Add Health to examine the linkages between the adolescent family environment and cohabitation behavior across the transition to adulthood. Using event history modeling the current paper considers the association between a variety of family factors and both the timing of first cohabiting unions and their outcomes (marriage, break up, still cohabiting). This paper also considers whether the impact of predictors for cohabitation timing and outcomes varies depending on the age of individuals. Results indicate that exposure during adolescence to family instability, parental cohabitation, lower parental SES, and low family belonging were associated with an elevated likelihood of entering into cohabiting unions, but primarily during adolescence and early adulthood. Family factors, including family belonging and parental relationship history, were also associated with the outcomes of first cohabitations.


Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase.
An epidermal-growth-factor(EGF)-receptor preparation isolated by calmodulin-affinity chromatography from rat liver plasma membranes is able to phosphorylate calmodulin. Calmodulin phosphorylation was enhanced 3-8-fold by EGF, was dependent on the presence of a polycation or basic protein and was inhibited by micromolar concentrations of Ca2+. Phosphate incorporation into calmodulin occurs predominantly on tyrosine residues. Partial proteolysis of phosphocalmodulin by thrombin identifies Tyr99, located in the third calcium-binding domain of calmodulin, as the phosphorylated residue. Stoichiometric measurements show a 32P/calmodulin molar ratio of approximately 1 when optimal phosphorylation conditions are used.


The relationship between sleep disturbance and glycaemic control in adults with type 2 diabetes: An integrative review.
To explore and synthesise current research to assess the state of science about the relationship between sleep disturbance and glycaemic control in adults with type 2 diabetes. Sleep disturbance is suggested a risk factor for type 2 diabetes. Diabetes alone is a leading cause of death, but when coupled with sleep disturbance poses additional health risks. However, little is known about the relationship between sleep disturbance and glycaemic control in people with overt diabetes. An integrative review. Whittemore and Knafl's methodology guided this integrative review. Original studies published before October 2016 were identified through systematic searches of seven databases using terms: diabet*; sleep or insomnia; glycem* or glucose or A1C or HbA1c or sugar; and their combinations. The matrix and narrative synthesis were employed to organise and synthesise the findings, respectively. The Crowe Critical Appraisal Tool was used to evaluate the study quality. A total of 26 studies were identified; 17 of which reported significant relationships between sleep measures and glycaemic control. In 13 studies, sleep duration was associated with glycaemic control in both linear (n = 2) and nonlinear (n = 3) relationships; however, eight studies reported no significant relationships. Sleep quality was significantly related to glycaemic control in 14 of 22 studies. Nine studies found no relationship between any measure of sleep and glycaemic control. There is strong evidence supporting the relationship between sleep quality and glycaemic control but further examination of the relationship between sleep duration and glycaemic control is warranted. Sleep disturbance, particularly impaired sleep quality, could potentially influence glycaemic control in adults with type 2 diabetes. Nurses who treat patients with diabetes should include assessment of sleep, education for healthy sleep, and referral for treatment of sleep disturbance in order to maximise the potential for achieving good glycaemic control.


Breeding for QX disease resistance negatively selects one form of the defensive enzyme, phenoloxidase, in Sydney rock oysters.
QX disease in Sydney rock oysters (Saccostrea glomerata) is caused by the paramyxean protozoan, Marteilia sydneyi. Disease outbreaks occur during summer (January to May) and can result in up to 95% mortality. The New South Wales Department of Primary Industries has been selectively breeding S. glomerata for resistance to QX disease since 1996. Previous work suggests that this breeding program has specifically affected the defensive phenoloxidase enzyme system of oysters. The current study more thoroughly characterises the effect of selection on the different forms of phenoloxidase found in oyster populations. Native polyacrylamide gel electrophoresis (native-PAGE) identified five discrete types of phenoloxidase in non-selected (wild type) and fourth generation QX disease resistant (QXR4) oysters. One electrophoretically distinct form of phenoloxidase, POb, is significantly less frequent in resistant oysters when compared to the wild type population. The frequency of POb also decreased in both the wild type and QXR4 populations over the course of a QX disease outbreak. This suggests that possession of POb makes oysters susceptible to QX disease and that breeding for resistance has resulted in negative selection against this form of phenoloxidase.


[Current status of ultrasound examination of the superficial organs (breast and thyroid)].
The ultrasound examination of superficial organs began with the application of the breast and thyroid. After the development of the high resolution real-time echography, this method has also been used for the examination of the salivary gland, parathyroid and lymph nodes, and it has become an indispensable diagnostic equipment, owing to low price, high diagnostic accuracy rate, short examination time and no invasiveness. Recently, colour Doppler equipment has developed and it has altered the reliability of ultrasound. [Breast]. The real-time method brought about the evaluation of compressibility and mobility by the dynamic test, and the interruption of the borderline of the mammary gland was added to the diagnostic criteria for breast cancer. Colour Doppler imaging will become a useful method to diagnose tumours, by evaluating the vascularity, blood flow volume or flow velocity. For nonpalpable tumours, ultrasonically guided aspiration cytology and biopsy were devised and they showed good results. [Thyroid]. Thyroid echography, together with aspiration cytology, became an integral part of the diagnostic method for thyroid cancer, and the necessity of the X-ray of the thyroid has decreased. The accuracy rate for papillary carcinoma recorded more than 80%. In the screening, the detection rate of carcinoma is now 1%. The differential diagnosis between carcinoma and adenoma, which both have a follicular pattern, is a problem yet to be solved. [Parathyroid]. Hyperplasia and adenoma of the parathyroid show hypoechoic and hypervascular area. In addition, the salivary gland and lymph nodes can also be evaluated with echography.


Machine Learning-Boosted Docking Enables the Efficient Structure-Based Virtual Screening of Giga-Scale Enumerated Chemical Libraries.
The emergence of ultra-large screening libraries, filled to the brim with billions of readily available compounds, poses a growing challenge for docking-based virtual screening. Machine learning (ML)-boosted strategies like the tool HASTEN combine rapid ML prediction with the brute-force docking of small fractions of such libraries to increase screening throughput and take on giga-scale libraries. In our case study of an anti-bacterial chaperone and an anti-viral kinase, we first generated a brute-force docking baseline for 1.56 billion compounds in the Enamine REAL lead-like library with the fast Glide high-throughput virtual screening protocol. With HASTEN, we observed robust recall of 90% of the true 1000 top-scoring virtual hits in both targets when docking only 1% of the entire library. This reduction of the required docking experiments by 99% significantly shortens the screening time. In the kinase target, the employment of a hydrogen bonding constraint resulted in a major proportion of unsuccessful docking attempts and hampered ML predictions. We demonstrate the optimization potential in the treatment of failed compounds when performing ML-boosted screening and benchmark and showcase HASTEN as a fast and robust tool in a growing arsenal of approaches to unlock the chemical space covered by giga-scale screening libraries for everyday drug discovery campaigns.


Four-component domino reaction providing an easy access to multifunctionalized tricyclo[220.127.116.11(1,6)]dodecane derivatives.
A novel four-component domino reaction has been discovered. The reaction is easy to perform simply by mixing four common reactants and Cs(2)CO(3) in ethylene glycol under microwave heating. The reaction proceeds at fast rates and can be finished within 15-24 min, which makes workup convenient. Four stereogenic centers with one quaternary carbon-amino function have been controlled completely. The stereochemistry has been unequivocally determined by X-ray structural analysis. The resulting tricyclo[184.108.40.206(1,6)]dodecane derivatives are of importance for organic and medicinal research.


Electrical Impedance Tomography-Based Abdominal Subcutaneous Fat Estimation Method Using Deep Learning.
This paper proposes a deep learning method based on electrical impedance tomography (EIT) to estimate the thickness of abdominal subcutaneous fat. EIT for evaluating the thickness of abdominal subcutaneous fat is an absolute imaging problem that aims at reconstructing conductivity distributions from current-to-voltage data. Existing reconstruction methods based on EIT have difficulty handling the inherent drawbacks of strong nonlinearity and severe ill-posedness of EIT; hence, absolute imaging may not be possible using linearized methods. To handle nonlinearity and ill-posedness, we propose a deep learning method that finds useful solutions within a restricted admissible set by accounting for prior information regarding abdominal anatomy. We determined that a specially designed training dataset used during the deep learning process significantly reduces ill-posedness in the absolute EIT problem. In the preprocessing stage, we normalize current-voltage data to alleviate the effects of electrodeposition and body geometry by exploiting knowledge regarding electrode positions and body geometry. The performance of the proposed method is demonstrated through numerical simulations and phantom experiments using a 10 channel EIT system and a human-like domain.


Analysis of ethylene biosynthesis and perception during postharvest cold storage of Marsh and Star Ruby grapefruits.
Grapefruits are among the citrus species more sensitive to cold and develop chilling injury symptoms during prolonged postharvest storage at temperatures lower than 8 ℃-10 ℃. The plant hormone ethylene has been described either to protect or potentiate chilling injury development in citrus whereas little is known about transcriptional regulation of ethylene biosynthesis, perception and response during cold storage and how the hormone is regulating its own perception and signaling cascade. Then, the objective of the present study was to explore the transcriptional changes in the expression of ethylene biosynthesis, receptors and response genes during cold storage of the white Marsh and the red Star Ruby grapefruits. The effect of the ethylene action inhibitor, 1-MCP, was evaluated to investigate the involvement of ethylene in the regulation of the genes of its own biosynthesis and perception pathway. Ethylene production was very low at the harvest time in fruits of both varieties and experienced only minor changes during storage. By contrast, inhibition of ethylene perception by 1-MCP markedly induced ethylene production, and this increase was highly stimulated during shelf-life at 20 ℃, as well as transcription of ACS and ACO. These results support the auto-inhibitory regulation of ethylene in grapefruits, which acts mainly at the transcriptional level of ACS and ACO genes. Moreover, ethylene receptor1 and ethylene receptor3 were induced by cold while no clear role of ethylene was observed in the induction of ethylene receptors. However, ethylene appears to be implicated in the transcriptional regulation of ERFs both under cold storage and shelf-life.


Histopathology of the small intestinal mucosa in Nematodirus spathiger infection in rabbits.
Rabbits were experimentally infected with two levels (5000 and 17,000) infective larvae of Nematodirus spathiger. Histological (villus length, mucosa to serosa ratio, crypt surface) and biochemical (protein content, alkaline phosphatase and leucine aminopeptidase activities) measurements relating to the small intestinal mucosa were examined along the entire length of the organ. In the proximal intestine, the presence of worms was associated with villus abrasion, increased crypt surface and decreased alkaline phosphatase and leucine aminopeptidase activities. Conversely, beyond the main site of infection in the distal small intestine, some signs of hypertrophied villi and crypts were noted without any changes in enzyme activities. These distal variations were similar to those previously described in experimental Trichostrongylus colubriformis infections of rabbits. These results tend to confirm the use of the rabbit as an experimental model to study Nematodirus infection. They also suggest that the distal adaptive process in the nematode-parasitized small intestine could occur independently of the worm species.


[Phosphate containing enemas: one undervalued risky practice? The management of an adverse event].
The phosphate-containing enemas are widely used, both to manage constipation and as a preparation for endoscopic procedures and surgery in adults and children. Many studies report that the use of these laxatives can be dangerous. To identify possible prevention strategies starting from a severe adverse reaction due to repeated administrations of phosphate enemas. A working group was started, the literature was reviewed and recommendations for an appropriate use of enemas were discussed and implemented, to improve patients' safety. Phosphate-containing enemas were replaced with 125 ml water enemas; recommendations were spread to strongly limit the use of phosphate containing enemas and the use of laxative in the first and second semester of 2012, were confronted showing a change in habits and a reduction in the use of phosphate containing enemas. The implementation of several strategies, originated from an adverse event, succeeded in modifying the use of laxatives and phosphate-containing enemas.


Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus.
The marine environment is important yet generally underexplored. It contains new sources of functional constituents that can affect various pathways in food processing, storage, and fortification. Bioactive secondary metabolites produced by marine microorganisms may have significant potential applications for humans. Various components isolated from disparate marine microorganisms, including fungi, microalgae, bacteria, and myxomycetes, showed considerable biological effects, such as anticancer, antioxidant, antiviral, antibacterial, and neuroprotective activities. Growing studies are revealing that potential anticancer effects of marine agents could be achieved through the modulation of several organelles. Mitochondria are known organelles that influence growth, differentiation, and death of cells via influencing the biosynthetic, bioenergetic, and various signaling pathways related to oxidative stress and cellular metabolism. Consequently, mitochondria play an essential role in tumorigenesis and cancer treatments by adapting to alterations in environmental and cellular conditions. The growing interest in marine-derived anticancer agents, combined with the development and progression of novel technology in the extraction and cultures of marine life, led to revelations of new compounds with meaningful pharmacological applications. This is the first critical review on marine-derived anticancer agents that have the potential for targeting mitochondrial function during tumorigenesis. This study aims to provide promising strategies in cancer prevention and treatment.


Influence of bromocriptine on the pressor responses to afferent nervous stimulation.
The effects of intravenous bromocriptine were studied on the systolic pressor responses elicited by stimulation of afferent nerves (vagus, saphenous and superior laryngeal nerves) in urethane anaesthetized dogs. Bromocriptine alone decreased these pressor responses. Pretreatment with sulpiride failed to modify the depressor action of bromocriptine on the pressor responses to vagal stimulation. In contrast, sulpiride prevented bromocriptine-induced decrease in the pressor responses elicited by saphenous or laryngeal activation. These data confirm the potential antihypertensive properties of bromocriptine and show that this effect is only partly due to an activation of prejunctional dopaminergic receptors. They suggest that the mechanism of the antihypertensive action of bromocriptine may vary according to the level of blood pressure, the kind of arterial hypertension and the species.


Presence and co-localization of vasoactive intestinal polypeptide with neuronal nitric oxide synthase in cells and nerve fibers within guinea pig intrinsic cardiac ganglia and cardiac tissue.
The presence of vasoactive intestinal polypeptide (VIP) has been analyzed in fibers and neurons within the guinea pig intrinsic cardiac ganglia and in fibers innervating cardiac tissues. In whole-mount preparations, VIP-immunoreactive (IR) fibers were present in about 70% of the cardiac ganglia. VIP was co-localized with neuronal nitric oxide synthase (nNOS) in fibers innervating the intrinsic ganglia but was not present in fibers immunoreactive for pituitary adenylate cyclase-activating polypeptide, choline acetyltransferase (ChAT), tyrosine hydroxylase, or substance P. A small number of the intrinsic ChAT-IR cardiac ganglia neurons (approximately 3%) exhibited VIP immunoreactivity. These few VIP-IR cardiac neurons also exhibited nNOS immunoreactivity. After explant culture for 72 h, the intraganglionic VIP-IR fibers degenerated, indicating that they were axons of neurons located outside the heart. In cardiac tissue sections, VIP-IR fibers were present primarily in the atria and in perivascular connective tissue, with the overall abundance being low. VIP-IR fibers were notably sparse in the sinus node and conducting system and generally absent in the ventricular myocardium. Virtually all VIP-IR fibers in tissue sections exhibited immunoreactivity to nNOS. A few VIP-IR fibers, primarily those located within the atrial myocardium, were immunoreactive for both nNOS and ChAT indicating they were derived from intrinsic cardiac neurons. We suggest that, in the guinea pig, the majority of intraganglionic and cardiac tissue VIP-IR fibers originate outside of the heart. These extrinsic VIP-IR fibers are also immunoreactive for nNOS and therefore most likely are a component of the afferent fibers derived from the vagal sensory ganglia.


[Roles of active forms of vitamin D in supporting innate immune systems and in reducing excess inflammation in COVID-19].
A reduced supply of micronutrient vitamin D leads to a more severe course of coronavirus infection (COVID-19). Vitamin D deficiency is combined with a decrease in innate antiviral immunity and excess of inflammation. Vitamin D supplementation stimulates the synthesis of antibacterial peptides and is important for weakening the cytokine storm, reducing excessive acute and chronic inflammation, and also for compensating for chronic comorbid pathologies. Active forms of vitamin D (alfacalcidol, etc.) are of particular importance for compensating for vitamin D deficiency in elderly patients, endocrine-immune dysfunction, sarcopenia, chronic renal failure (in which the metabolism of vitamin D in the kidneys is disturbed).


First mesomorphic and DFT characterizations for 3- (or 4-) n-alkanoyloxy benzoic acids and their optical applications.
New liquid crystalline hydrogen bonded 3- (or 4)-n-alkanoyloxy benzoic acids were synthesized and probed theoretically and experimentally. The molecular structures of these compounds were elucidated by proton NMR, carbon-13 NMR and elemental analyses. Differential scanning calorimetry (DSC) was used to investigate the thermal and mesomorphic properties of all the symmetrical dimers that bearing identical alkanoyloxy chains. Moreover, polarized optical microscopy (POM) was used to determine their mesophases. The findings show that all the designed symmetrical dimers exhibit the smectic mesophase with relative thermal stability that depends on the length of their terminal side chain. Additionally, the experimental findings of the mesomorphic behavior are further supported by DFT calculations. The alkanoyloxy benzoic acid para-derivatives (In) were shown to be more stable than their meta-substituted (IIn) analogues due to stronger hydrogen bonding interactions. The computed reactivity parameters showed that the position of ester moiety has a significant impact on the acids reactivity. The absorbance spectra of both the 3- (or 4)-n-alkanoyloxy benzoic acids revealed a blue shift with the increment of the of alkyl chain size; however, the energy band gaps of 3-n-alkanoyloxy benzoic derivatives were found to be slightly higher than those of the 4-n-alkanoyloxy benzoic acids. Moreover, the photoluminescence spectrum of the prepared materials is rather broad, and exhibited a red shift as the alkyl chain length increases. The fluorescence lifetime shown to rise as alkyl chain length grows longer, and 3-n-alkanoyloxy benzoic acids have slightly longer lifetime compared to their 4-n-alkanoyloxy benzoic analogues.


[Risk perception, use of PPE and injuries among firefighters].
The present study, situated in the safety at work issue, is aimed to evaluate the risk perception and preventive behaviour (the use of individual protection devices) in the fire brigade work, with reference to the most typical risk for these workers: cylinder blast; fire and exhalation of toxic steam; road accidents; falls, cuts, contusions; stress and physical strain. To this end a psychosocial perspective is adopted and different dimensions of risk perception are considered. Data were collected through a questionnaire filled in by 115 fire brigade workers and were statistically analysed to describe the risk perception about the different risks, to evaluate the relationship between the different dimensions of risk perception and to verify the variables that are more predictive of injuries. Cylinder blast is perceived as the most severe risk and participants report to be more exposed and trained to this specific risk in comparison with others. Falls, cuts, contusions as well as stress and fatigue are considered to be contributing factors of injuries. Participants with previous injuries are more likely to report to be exposed (r = .23; p < .05) and to be in danger (r = .22; p < .05) to occupational risks and to report less compliance with individual protective devices (r = .23; p < .05). Results show the relevance of promotion of safe-related behaviours among fire fighters and to take into account specific risk related to the job.


Effective Recruitment Strategies Utilized to Examine Dietary Practices of Blacks in New York City in the Midst of the COVID-19 Pandemic.
Black Americans have long been considered a hard-to-reach population for research studies, whether quantitative surveys or for clinical research. Studies have explored multiple rationales for why Blacks are hard to reach, and the explanations have included historical mistrust, the need to assess the benefits from participating in research, and the expense of spending time participating in research, among others. What has not been explored is the continuous merging of all individuals who identify as Black, particularly when exploring reasonings for a lower interest in participating in research. This paper addresses this issue by investigating the participation rate of individuals identifying as Black in New York City in a study exploring dietary practices as a predictor of colorectal cancer screening behavior. Participants were asked to self-report screening behavior, intent to screen, and dietary and other lifestyle practices. In this analysis, we discuss the unique experience encountered in recruiting Black American participants to participate in this study, particularly amid a worldwide pandemic of COVID-19. The methodology for this study included a systematic review of the literature, a two-part recruitment process, and data analysis. The first part of the recruitment process involved registering individuals who were interested in participating in the study and consented to be contacted and reminded to come to the location where they were recruited on a scheduled date to complete the actual survey. With this part of the recruitment process, we engaged with n = 488 Black men and women between November 2019 and February 2020. The second part of the recruitment process utilized availability sampling outside of NYC subway stations and other high traffic areas as well as large community events. We engaged with n = 319 individuals. Total engagement with n = 807 individuals yielded a sample size for the survey of 504 completed surveys. Of the total engaged (n = 807), 14% declined to participate due to a lack of time, 11% chose not to participate in the study because the incentive was not enough to compensate for their time 0.02% declined due to not trusting institutions conducting research, and 0.03% did not feel comfortable understanding the questions due to a language barrier. We had a sample size of (n = 504) of the total 807 individuals engaged. Recruiting Black Americans into our colorectal cancer study did not prove to be challenging with the two-tiered model of recruitment that involved consistent engagement and having the primary researcher lead this recruitment process. Extracting within race differences is critical in demystifying the conclusion of numerous studies that African Americans specifically are hesitant to participate due to historical mistrust related to tragedies such as the Tuskegee Experiment and numerous other occurrences of African Americans being treated as guinea pigs for the advancement of research. This data contributes knowledge to this field regarding understanding recruitment challenges in the Black population, but further work needs to be conducted. Mistrust in this study primarily came from the individuals engaged in Caribbean neighborhoods, where many expressed more comfort with home remedies and bush doctors when asked about colorectal cancer screening and declined to participate. Innovative communication, qualitative research, and recruitment strategies tailored to the Caribbean population are needed in future studies to address this recruitment challenge that we experienced.


The Distribution of Climate Change Public Opinion in Canada.
While climate scientists have developed high resolution data sets on the distribution of climate risks, we still lack comparable data on the local distribution of public climate change opinions. This paper provides the first effort to estimate local climate and energy opinion variability outside the United States. Using a multi-level regression and post-stratification (MRP) approach, we estimate opinion in federal electoral districts and provinces. We demonstrate that a majority of the Canadian public consistently believes that climate change is happening. Belief in climate change's causes varies geographically, with more people attributing it to human activity in urban as opposed to rural areas. Most prominently, we find majority support for carbon cap and trade policy in every province and district. By contrast, support for carbon taxation is more heterogeneous. Compared to the distribution of US climate opinions, Canadians believe climate change is happening at higher levels. This new opinion data set will support climate policy analysis and climate policy decision making at national, provincial and local levels.


Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer.
The development of resistance is the major cause of mortality in cancer. Combination chemotherapy is used clinically to reduce the probability of evolution of resistance. A similar trend toward the use of combinations of drugs is also emerging in the application of cancer nanomedicine. However, should a combination of two drugs be delivered from a single nanoparticle or should they be delivered in two different nanoparticles for maximal efficacy? We explored these questions in the context of adaptive resistance, which emerges as a phenotypic response of cancer cells to chemotherapy. We studied the phenotypic dynamics of breast cancer cells under cytotoxic chemotherapeutic stress and analyzed the data using a phenomenological mathematical model. We demonstrate that cancer cells can develop adaptive resistance by entering into a predetermined transitional trajectory that leads to phenocopies of inherently chemoresistant cancer cells. Disrupting this deterministic program requires a unique combination of inhibitors and cytotoxic agents. Using two such combinations, we demonstrate that a 2-in-1 nanomedicine can induce greater antitumor efficacy by ensuring that the origins of adaptive resistance are terminated by deterministic spatially constrained delivery of both drugs to the target cells. In contrast, a combination of free-form drugs or two nanoparticles, each carrying a single payload, is less effective, arising from a stochastic distribution to cells. These findings suggest that 2-in-1 nanomedicines could emerge as an important strategy for targeting adaptive resistance, resulting in increased antitumor efficacy.


A comparative study of the influence of two types of PHEMA stents on the differentiation of ASCs to myocardial cells.
In the present study, subcutaneous fat was obtained from adult women that had undergone conventional liposuction surgery. A comparative study was performed to investigate the effect of transparent and white poly‑β‑hydroxyethyl methacrylate (PHEMA) stents, which have different surface and cross‑sectional morphological characteristics, on the differentiation of adipose‑derived stem cells (ASCs) into myocardial cells. The cell counting kit‑8 assay revealed that cell growth increased at varying rates among the different treatment groups. The absorbance of the experimental transparent PHEMA treated group increased in a time‑dependent manner with the duration of incubation. The highest levels of proliferation were observed in the transparent PHEMA group. In addition, the transparent PHEMA treated group exhibited the strongest cell adhesion ability, which was significantly different to that of the white PHEMA group (P<0.01 and P<0.05 for Matrigel and fibronectin assay, respectively). Comparisons between the two stent materials with the inducer control group revealed statistically significant differences in the rate of ASC differentiation (P<0.05). The level of differentiation was the greatest in the transparent PHEMA group, and was significantly different to the white PHEMA group (P<0.05) and the blank control group (P<0.01). The results suggest that the inducers 5-aza-2-deoxycytidin and laminin, and material microstructure stents effectively promote the proliferation, growth and adhesion of ASCs. However, the transparent material microstructure may be a more suitable candidate for ASC‑associated injections. The present study provides further evidence that a PHEMA stent structure, comprised of a high number of matrixes and a low water content, induces a high level of ASC differentiation to myocardial cells.


Selective capillary electrophoresis separation of mono and divalent cations within a high-surface area-to-volume ratio multi-lumen capillary.
In this study, the separation of inorganic mono and divalent cations using multi-lumen silica capillaries (MLCs) of 126 channels, each with either 4 or 8 μm inner diameter, was investigated using capillary electrophoresis and on-capillary capacitively coupled contactless conductivity detection (CE-C4D). MLCs provided sufficiently high surface area-to-volume ratios to generate significant wall ion-exchange interactions for the divalent cations, which significantly affected resultant selectivity, whereas monovalent cations were predominantly separated by simple electrophoresis. The resultant hybrid selectivity was seen for both 4 and 8 μm channel multi-lumen capillaries, without any preconditioning or capillary wall modification. Remarkably, the electrophoretic mobilities for the divalent cations Mg2+ and Ca2+ were reduced 7.5 times compared to those determined using a single channel open tubular capillary of 50 μm i.d., providing much improved selectivity. Apparent electrophoretic mobilities of divalent cations increased as the concentration of BGE increased, while those of monovalent cations decreased parallel to electroosmotic mobility. These results show the electrostatic interaction between the divalent cations and the silica wall. At least, this specific separation of mono- and divalent cations were clearly observed with a mixture standards solution of less than 200 μmol L-1. Using a MLC with 126 × 8 μm i.d. channels and 49.1 cm in length, together with a 20 mmol L-1 MES/His BGE, containing 2 mmol L-1 18-crown-6, monovalent cations (NH4+, K+ Na+ and Li+) and divalent cations (Ca2+ and Mg2+) could be completely separated within 4 min. For monovalent cations, on-capillary detection using C4D provided calibration curve (0-200 μmol L-1) correlation coefficients in the range R2 = 0.995-0.999, and limits of detection of 2.2-6.6 μmol L-1. Relative standard deviations for migration times were less than 0.6%, and recoveries ranged from the 93.8%-105.4%. The new method was applied to the separation and quantitative determination of monovalent and divalent cations in drinking waters and soil extracts.


[Peritoneal dissemination of scirrhous type 4 gastric cancers].
We examined 198 cases of primary scirrhous type 4 gastric cancer at our department from 1984 to 2003. Of these, 139 cases underwent gastrectomy. The essential cause of inoperability was peritoneal dissemination with malignant abdominal abscises. The incidence of peritoneal dissemination was 48.2% of all resected cases. The 5-year survival rate of all resected cases was 12% and that of non-resectable cases was 0%. One of the 59 nonresectable cases who responded remarkably to treatment by TS-1/paclitaxel combination chemotherapy obtained survival of 12 months. Six cases with peritoneal dissemination were treated by chemotherapy with cisplatin and etoposide infused intra-peritoneally and 2 of them were diagnosed as P 0 after 4 weeks. One case with type 4 gastric cancer who had right hydronephrosis and malignant abdominal ascites underwent curative resection after successful treatment with TS-1. We have selected the way of conventional chemotherapy for inoperable type 4 gastric cancers, but the prognosis is still poor. It is thought necessary to improve survival by newly developed anticancer agents such as TS-1, etoposide and taxanes. Immuno-cellular therapy with autologous tumor cell stimulated lymphocyte may be examined as a neo-adjuvant therapy as well as chemotherapy.


Prediction of severe CRS and determination of biomarkers in B cell-acute lymphoblastic leukemia treated with CAR-T cells.
CAR-T cell therapy is a novel approach in the treatment of hematological tumors. However, it is associated with life-threatening side effects, such as the severe cytokine release syndrome (sCRS). Therefore, predicting the occurrence and development of sCRS is of great significance for clinical CAR-T therapy. The study of existing clinical data by artificial intelligence may bring useful information. By analyzing the heat map of clinical factors and comparing them between severe and non-severe CRS, we can identify significant differences among these factors and understand their interrelationships. Ultimately, a decision tree approach was employed to predict the timing of severe CRS in both children and adults, considering variables such as the same day, the day before, and initial values. We measured cytokines and clinical biomarkers in 202 patients who received CAR-T therapy. Peak levels of 25 clinical factors, including IFN-γ, IL6, IL10, ferritin, and D-dimer, were highly associated with severe CRS after CAR T cell infusion. Using the decision tree model, we were able to accurately predict which patients would develop severe CRS consisting of three clinical factors, classified as same-day, day-ahead, and initial value prediction. Changes in serum biomarkers, including C-reactive protein and ferritin, were associated with CRS, but did not alone predict the development of severe CRS. Our research will provide significant information for the timely prevention and treatment of sCRS, during CAR-T immunotherapy for tumors, which is essential to reduce the mortality rate of patients.


Caring for obese pregnant women.
Women who are overweight or obese during their childbearing years are at an increased risk for pregnancy-induced hypertension, gestational diabetes, labor induction, cesarean births, and failed vaginal birth after cesarean. During the postpartum, they experience increased rates of puerperal infection and decreased rates of breastfeeding initiation or continuation. Their infants are at higher risk for having congenital anomalies or being stillborn. Nurses can use this knowledge to adapt the care they provide and to encourage health-promoting behaviors.


Antiproliferative and apoptotic activities of ketonucleosides and keto-C-glycosides against non-small-cell lung cancer cells with intrinsic drug resistance.
We compared the biological activity of a new group of keto-C-glycosides to that of a narrow spectrum of unsaturated ketonucleosides in a panel of non-small-cell lung cancer (NSCLC) cells with various levels of intrinsic resistance to standard chemotherapy drugs. Unlike cisplatin, etoposide, adriamycin, or taxol, for which a significant difference in the cytotoxic effect was observed between sensitive cell lines (H460, H125, and MGH4) and drug-resistant cell lines (H661, MGH7, and FADU), nucleoside analogs were equally cytotoxic in NSCLC cell lines, with compound 92 being 10-fold more active than compound 43, 44, 81, or 161, while compound 3 was the least active. Apoptotic measurements with flow cytometric analysis of terminal uridine deoxynucleotide nick end-labeled cells revealed that the cytotoxic activity of these nucleosides correlated with their potency to induce apoptosis. Compound 92 triggered death in cells with wild-type p53, mutated p53, or p53 gene deletion. Our findings suggest that keto-C-glycosides may be promising alternative anticancer agents which merit further studies in in vivo cancer models refractory to standard chemotherapy drugs.


A predictive pattern of computed barriers for C-h hydroxylation by compound I of cytochrome p450.
The communication presents DFT calculations of 10 different C-H hydroxylation barriers by the active species of the enzyme cytochrome P450. The work demonstrates the existence of an excellent barrier-bond energy correlation. The so-obtained equation of the straight line is demonstrated to be useful for predicting barriers of related C-H activation processes, as well as for assessing barrier heights within the protein environment. This facility is demonstrated be estimating the barrier of camphor hydroxylation by P450cam.


Angiotensin Receptor-Neprilysin Inhibition.
The novel combination sacubitril/valsartan represents a new therapeutic approach in the management of heart failure. With the simultaneous blockage of the enzyme neprilysin (by sacubitril) and angiotensin II receptors (by valsartan), this combination reduces the degradation of natriuretic peptides and other counterregulatory peptide systems while avoiding the deleterious effect of angiotensin II receptors activation and thereby encompasses a beneficial impact of 2 important neurohormonal pathways activated in heart failure. As opposed to previously tested neprilysin inhibitors, sacubitril/valsartan represents a more effective method in reducing morbidity and mortality in heart failure, while preserving a safety profile comparable to well-established, standard, angiotensin-converting enzyme inhibitor's therapy.


[Islet perifusion: a new method to evaluate first-phase insulin secretory function of beta-cell in vitro].
To set up islet perifusion system, a new method to evaluate first-phase insulin secretory function of beta-cell in vitro. Islet perifusion system was set up, including perifusion framework, waterbath system, infusion pump system, afferent system, islet capsule, and efferent system. Kinetics of insulin release in vitro was studied using the perifusion system. Pancreatic islets were isolated as mentioned above and used freshly after isolation. Size-matched 50 islets were placed in each column. Then the columns were gently closed with the top adaptors, immersed in vertical position and controlled temperature in the water bath at 37 degrees C. The perifusion medium was maintained at 37 degrees C in a water bath. And all columns were perifused in parallel at a flow rate of 0.5 ml/min with KRBB (2.8 mmol/L glucose) at 37 degrees C. After 60 min static incubation with KRBB (2.8 mmol/L glucose), the islets were stimulated in the continuous presence of a high concentration of 16.7 mmol/L glucose. Samples were collected every 20-second until 2 min, every 1 min until 5 min, thereafter every 5 min until 30 min. Samples were immediately stocked at -80 degrees C until further analysis. Insulin concentration was measured with an insulin RIA kit. An Islet perifusion system was established successfully, and kinetic curves of insulin secretion of db/m and db/db mice were traced out. An established islet perifusion system, could be widely used to evaluate insulin secretory function of beta-cell in in vitro research of diabetes.


TMEM187-IRAK1 Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin.
Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n = 408) compared with age-matched controls (n = 471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.


Implementation of Informatics to Support the NIH All of Us Research Program in a Healthcare Provider Organization.
The NIH All of Us Research Program, a national effort to collect biospecimens and health data for over one million participants from across the United States, requires participating healthcare provider organizations (HPOs) to use informatics tools maintained by the NIH to manage participant consent, biospecimen processing, physical measurements, and other workflows. HPOs also maintain distinct workflows for handling overlapping tasks within their individual aegis, which do not necessarily achieve seamless interoperability with NIH-maintained cloud-based systems. At our HPO, we implemented informatics to address gaps in enrollment workflows and hardware, clinical workflow integration, patient engagement, laboratory support, and study team reporting. In this case report we detail our approach to inform efforts at other institutions for the NIH All of Us Research Program and other studies.


Percutaneous Tracheostomy by Physician Intensivists.
To assess the safety of percutaneous tracheostomy when performed by physician intensivists. Descriptive study. Adult Medical ICU in the Department of Critical Care Medicine, Military Hospital, Rawalpindi, Pakistan, from September 2013 to August 2016. Departmental record for percutaneous tracheostomies, performed by physician intensivifts, was evaluated. Variables studied were underlying primary diagnosis, details of the operating doctors, presence of immediate complications, departmental protocol for the procedure, pre-procedure safety checklist, written instructions on procedure steps, use of ultrasound and bronchoscopy. Portex Percutaneous Dilation Tracheostomy Kit with Single-Stage Dilator was used in all the patients. Fifty-six percutaneous tracheostomy procedures were performed with a male to female ratio 3:1; more than 2/3rd (80%) had an underlying neurological illness. All doctors performing the procedures were physicians having minimum qualification of Fellowship with at least one year experience in intensive care and had observed at least five procedures. Departmental protocol for the procedure was followed in all the cases. Minor complications were observed in three patients (5.35%). These included para-tracheal misplacement, accidental de-cannulation, and endotracheal tube cuff puncture. None of the patient died due to direct complications of the procedure. Percutaneous tracheostomy is safe in Medical ICUs of developing countries, when performed by experienced physician intensivists under defined protocols.


Creutzfeldt-Jakob disease in the obstetric patient.
Recent reports have indicated the presence of transmissible spongiform encephalopathy or Creutzfeldt-Jakob disease in the United States. This disease can occur as a rare, sporadic disease with no recognizable pattern of transmission or as a familial disease associated with prion protein gene mutations. This article discusses the presence of sporadic Creutzfeldt-Jakob disease in a woman who became pregnant early in the course of the disease and subsequent care pre- and postdelivery.


Asymmetric dual-reagent catalysis: Mannich-type reactions catalyzed by ion pair.
The combination of a new bifunctional phosphine and an acrylate generate a zwitterion in situ and it serves as an efficient catalyst for asymmetric reactions through a homogeneous ion-pairing mode. This new catalytic system has been successfully applied to Mannich-type reactions to give excellent results and it demonstrates a broad substrate scope. Such reactivity is not accessible with general organophosphine catalytic modes. Preliminary investigations into the mechanism are also presented.


MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia.
MSI2 is highly expressed in human myeloid leukemia (AML) cell lines, and high expression of MSI2 mRNA is associated with decreased survival in AML, suggesting its use as a new prognostic marker. To test this, we measured MSI2 protein level by immunohistochemistry in 120 AML patients. Most cases (70%) showed some nuclear or cytoplasmic positivity, but the percentage of positive cells was low in most cases. Despite this, MSI2 protein expression was negatively associated with outcome, particularly for patients with good cytogenetic subgroup. For practical diagnostic purposes, the strongest significance of association was seen in cases with > 1% of cells showing strong MSI2 staining, these having a very poor outcome (P < .0001). Multivariate analysis with cytogenetic category, age, white cell count, and French-American-British subtype demonstrated that nuclear MSI2 levels were independently predictive of outcome (P = .0497). These results confirm the association of MSI2 expression with outcome in AML at the protein level and demonstrate the utility of MSI2 protein as a clinical prognostic biomarker. In addition, although positive at some level in most cases, its prognostic power derived from few positive cells, supporting its role in control of normal hematopoietic stem cell function and highlighting its role in disease progression.


Total and orbital density-based analyses of molecules revealing long-range interaction regions.
Total and orbital electron densities of molecules are explored for the effect of the long-range correction (LC) for density functional theory (DFT) exchange functionals by comparing to the effect of the ab initio coupled cluster singles and doubles (CCSD) method. Calculating the LC effect on the total electron densities shows that the LC stabilizes the electrons around the long-range interaction regions of kinetic energy density, which are assumed to be electrons other than free electrons and self-interacting electrons, while the CCSD method stabilizes the electrons in the long-range interaction regions in the vertical molecular planes. As a more precise test, the LC effect on orbital densities are compared to the CCSD effect on Dyson orbital densities. Surprisingly, these effects are similar for the unoccupied orbitals, indicating that the LC covers the effects required to reproduce the CCSD Dyson unoccupied orbitals. For exploring the discrepancies between these effects on the occupied orbitals, the photoionization cross sections are calculated as a direct test for the shapes of the HOMOs to investigate the differences between these effects on the occupied orbitals. Consequently, the LC clearly produces the canonical HOMOs close to the CCSD Dyson and experimental ones, except for the HOMO of benzene molecule that mixes with the HOMO - 1 for the CCSD Dyson orbitals. This indicates that the orbital analyses using the photoionization cross sections are available as a direct test for the quality of DFT functionals.


The Two Nursing Disciplinary Scientific Revolutions: Florence Nightingale and Martha E. Rogers.
The purpose of this essay is to share Kan Koffi's ideas about scientific revolutions in the discipline of nursing. Koffi has proposed that the works of Florence Nightingale and Martha E. Rogers represent two scientific revolutions in nursing as a learned discipline. The outcome of these two scientific revolutions is a catalyst for critical disciplinary and paradigmatic debate about the universal conceptualization of nursing's distinctive professional and scientific knowledge.


[Multi-species and multi-scale patterns and species associations of sand-fixing plantations].
Taking three sand-fixing plantations Hedysarum scoparium and Calligonum mongolicum, Haloxylon ammodendron on the oasis verges in northeast Ulanbuhe desert irrigated by Huanghe River as test objects, the multi-species and multi-scale patterns and the species associations of the plantations were investigated by contiguous quadrats transects method, with the natural vegetation nearby as the control. The results showed that 74.29% of the natural vegetation was dominated by single species pattern of Artemisia ordosica, and 24. 99% was dominated by single species pattern of Nitraria tangutorum. The sand-fixing plantations gradually became close-to-natural vegetation. Compared with natural vegetation, the sand-fixing plantations had higher pattern intensity, and played important role in sand-fixing and in accelerating the regeneration and succession of natural sand-fixing plants. However, with the succession, artificially planted shrubs would decline, while natural plants would be dominant. Therefore, it should be better to make use of the native dominated species in sand-fixing engineering. Under the almost same conditions, pattern scale was highly correlated with the characters and the associations of dominated species. The species association was correlated with the patch scale and species composition, as well as the species contribution to the patch.


Hopping time of a hard disk fluid in a narrow channel.
We use Monte Carlo (MC) and molecular dynamics (MD) methods to study the self-diffusion of hard disk fluids, confined within a narrow channel. The channels have a pore radius of Rp, above the passing limit of hard disk diameter (sigma(hd)). We focus on the average time (tau(hop)) needed for a hard disk to hop past a nearest neighbor in the longitudinal direction. This parameter plays a key role in a recent theory of the crossover from single-file diffusion to the bulk limit. For narrow channels near the hopping threshold (Rp=1 in units of sigma(hd)), both MC and MD results for tau(hop) diverge as approximately (Rp-1)(-2). Our results indicate that the scaling law exponent does not appear to be dependent on the differences between the two dynamics. This exponent is consistent with the prediction of an approximate transition state theory.


Physiology and pharmacology of corticothalamic stimulation-evoked responses in rat somatosensory thalamic neurons in vitro.
Whole cell current- and voltage-clamp recording techniques were employed in a rat thalamocortical slice preparation to characterize corticothalamic stimulation-evoked responses in thalamic neurons. Three types of corticothalamic stimulation-evoked responses were observed in thalamic neurons. Of thalamic neurons, 57% responded to corticothalamic stimulation with purely excitatory synaptic responses, whereas 27% had inhibitory synaptic responses and 16% had mixed excitatory/inhibitory responses. This suggested corticothalamic activation of multiple distinct synaptic circuits, presumably involving both nucleus reticularis thalami (NRT) and thalamus, because the rat ventrobasal complex is virtually devoid of GABAergic interneurons. Corticothalamic-stimulation-evoked excitatory postsynaptic currents (EPSCs) were predominantly slow rising currents that showed nonlinear voltage dependence, characteristics of an N-methyl-D-aspartate (NMDA)-receptor-mediated synaptic current. These slow rising EPSCs were blocked by the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV). A minority of corticothalamic EPSCs had faster kinetics, and were blocked by 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX). Corticothalamic stimulation of varying frequency optimally activated burst responses in thalamic neurons at low frequencies (3-6 Hz). The optimal 3- to 6-Hz response was reduced by ethosuximide, by APV, and by detaching the neocortex from the thalamocortical slice, suggesting that T current, NMDA receptors, and neocortical properties all contributed to generation of this 3- to 6-Hz frequency preference. In contrast to corticothalamic EPSCs, medial-thalamic-stimulation-evoked responses consisted of fast CNQX-sensitive EPSCs that were predominantly voltage insensitive, with no 3- to 6-Hz frequency preference. In thalamic neurons in which corticothalamic stimulation evoked predominantly inhibitory synaptic responses, this inhibitory postsynaptic potential (IPSP) had early and late phases, often followed by a rebound burst. The early IPSP reversed at -95 mV and was bicuculline sensitive, whereas the late IPSP reversed at -113 mV and was blocked by the gamma-aminobutyric acid-B (GABA(B)) antagonist 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzy lphoshinic acid (CGP-55845A). In thalamic neurons in which corticothalamic stimulation evoked a mixed excitatory postsynaptic potential (EPSP)/IPSP response, repetitive corticothalamic stimulation rapidly reduced IPSPs and enhanced EPSPs at higher frequencies. This resulted in burst firing being triggered in these mixed response neurons at frequencies >6 Hz. Corticothalamic feedback onto thalamic relay neurons activated diverse responses due to differing relative activation of NRT and "feedforward" inhibitory responses. These multiple in vitro corticothalamic responses differ from responses encountered in other in vitro thalamic preparations lacking a synaptically connected neocortex, but are similar to results evident in thalamic neurons in response to cortical stimulation in vivo. In addition, the thalamocortical 3- to 6-Hz frequency preference was conserved, suggesting that many factors critical for this emergent property of the thalamocortical system are maintained in vitro.


Chemical Identification of Interlayer Contaminants within van der Waals Heterostructures.
van der Waals heterostructures (vdWHs) leverage the characteristics of two-dimensional (2D) material building blocks to create a myriad of structures with unique and desirable properties. Several commonly employed fabrication strategies rely on polymeric stamps to assemble layers of 2D materials into vertical stacks. However, the properties of such heterostructures frequently are degraded by contaminants, typically of unknown composition, trapped between the constituent layers. Such contaminants, therefore, impede studies of the intrinsic properties of heterostructures and hinder their application. Here, we use the photothermal induced resonance (PTIR) technique to obtain infrared spectra and maps of the contaminants down to a few attomoles and with nanoscale resolution. Heterostructures comprised of WSe2, WS2, and hexagonal boron nitride layers were found to contain significant amounts of poly(dimethylsiloxane) (PDMS) and polycarbonate, corresponding to the stamp materials used in their construction. Additionally, we verify that an atomic force microscope-based "nanosqueegee" technique is an effective method for locally removing contaminants by comparing spectra within as-fabricated and cleaned regions. Having identified the source of the contaminants, we demonstrate that cleaning PDMS stamps with isopropyl alcohol or toluene prior to vdWH fabrication reduces PDMS contamination within the structures. The general applicability of the PTIR technique for identifying the sources corrupting vdWHs provides valuable guidance for devising mitigation strategies (e.g., stamp cleaning or pre-/post-treatments) and enhances capabilities for producing materials with precisely engineered properties.


First Contact: interprofessional education based on medical students' experiences from their nursing internship.
The aim of the course "interprofessional communication and nursing" is to reflect medical students' experiences from the nursing internship. The content of the course focuses on barriers and support of interprofessional communication as a foundation for teamwork between nursing professionals and physicians. The nursing internship is for most medical students the first contact with nursing professionals and can lead to perceptions about the other group that might hinder interprofessional teamwork and consequently harm patients. To meet the demographic challenges ahead it is important to emphasize interprofessional education in the study of medicine and better prepare future physicians for interprofessional collaboration. The design of the course includes an assessment of a change in the students' perceptions about nursing and interprofessional communication. The first class meeting presents the starting point of the assessment and visualizes students' perceptions of nursing and medicine. The content of the following class meetings serve to enhance the students' knowledge about nursing as a profession with its own theories, science and scholarship. In addition, all students have to write a research paper that entails to interview one nursing professional and one physician about their ideas of interprofessional communication and to compare the interviews with their own experiences from the nursing internship. To access what students learned during the course a reflective discussion takes place at the last meeting combined with an analysis of the students' research papers. The assessment of the students' perceptions about the nursing profession and the importance of successful interprofessional communication showed a new and deeper understanding of the topic. They were able to identify barriers and support measures of interprofessional communication and their own responsibilities as part of a team. Interprofessional education is an important part of medical education and should be a topic from the beginning. The assessment of the course shows that it is possible and important to integrate the topic early in the curriculum.


Primary pediatric brain tumors: statistics of Taipei VGH, Taiwan (1975-2004).
The purpose of the current study was to investigate a hospital series of 986 cases of primary pediatric brain tumors in Taiwan. The authors reviewed the database of primary pediatric brain tumors in patients < 18 years of age collected in Taipei Veterans General Hospital (Taipei VGH) from 1975 to May 2004. Age and gender distribution, location, and classification of brain tumors were analyzed. Intracranial tumors with diagnostic imaging were included. Nontumoral lesions, cysts, and vascular malformations were excluded. The mean age of these 986 patients was 7.8 years, and the male to female ratio was 1.4:1. Supratentorial (including pineal-quadrigeminal) located tumors (58.3%) was predominant to infratentorial tumors (41.1%). In these series, 886 patients had either histologic diagnosis (842 patients) or clinical diagnosis (44 patients). The most common 5 categories of tumors were astrocytic tumors (31.1%), germ cell tumors (14.0%), medulloblastomas (13.3%), craniopharyngiomas (8.3%), and ependymal tumors (5.8%). Atypical teratoid/rhabdoid tumors (AT/RTs), a rare but highly malignant tumor, were 2.1%. The high incidence of primary intracranial germ cell tumors correlated with reported series from Japan and Korea. For the remaining 100 patients without diagnostic classifications, the majority were most likely astrocytic tumors in brain stem. The authors analyzed a large hospital series of primary brain tumors in children. Both histologically verified and unverified tumors were recruited to avoid selective bias. Although it was not a study of a population-based brain tumor registry, it could still be representative of primary pediatric brain tumors in Taiwan.


Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents.
We sought to define the incidence of late clinical events and late stent thrombosis in patients treated with drug-eluting (DES) versus bare-metal stents (BMS) after the discontinuation of clopidogrel as well as their timing and outcome. There is growing concern that delayed endothelialization after DES implantation may lead to late stent thrombosis and related myocardial infarction (MI) or death. However, event rates and outcomes after clopidogrel discontinuation versus BMS are unknown. A consecutive series of 746 nonselected patients with 1,133 stented lesions surviving 6 months without major events were followed for 1 year after the discontinuation of clopidogrel. Patients were assigned randomly 2:1 to DES versus BMS in BASKET (Basel Stent Kosten Effektivitäts Trial). The primary focus of this observation was cardiac death/MI. Rates of 18-month cardiac death/MI were not different between DES and BMS patients. However, after the discontinuation of clopidogrel (between months 7 and 18), these events occurred in 4.9% after DES versus 1.3% after BMS implantation. Target vessel revascularization remained lower after DES, resulting in similar rates of all clinical events for this time period (DES 9.3%, BMS 7.9%). Documented late stent thrombosis and related death/target vessel MI were twice as frequent after DES versus BMS (2.6% vs. 1.3%). Thrombosis-related events occurred between 15 and 362 days after the discontinuation of clopidogrel, presenting as MI or death in 88%. After the discontinuation of clopidogrel, the benefit of DES in reducing target vessel revascularization is maintained but has to be balanced against an increase in late cardiac death or nonfatal MI, possibly related to late stent thrombosis.


Peniproline A, a new 1-phenylamino-2-pyrrolidone metabolite from the endophytic fungus Penicillium decumbens CP-4.
One new (named peniproline A, 1) and 11 known compounds were isolated from a culture of the endophytic fungus Penicillium decumbens CP-4. The structure of 1, featuring a phenylamine unit coupled with 2-pyrrolidone by forming a distinctive nitrogen-nitrogen bond, was elucidated based on extensive spectroscopic methods. Compound 1 was found to have cytotoxic effects against Bel-7402 and Hela cell lines with IC50 values of 8.1 and 15.5 μM, respectively.


Surgical Outcomes of Anterior Versus Posterior Fusion in Lenke Type 1 Adolescent Idiopathic Scoliosis.
Retrospective study. To describe surgical results in two and three dimensions and patient-reported outcomes of scoliosis treatment for Lenke type 1 idiopathic curves with an open anterior or posterior approach. Different surgical techniques have been described to prevent curve progression and to restore spinal alignment in idiopathic scoliosis. The spine can be accessed via an anterior or a posterior approach. However, the surgical outcomes, especially in three dimensions, for different surgical approaches remain unclear. Cohorts of Lenke curve type 1 idiopathic scoliosis patients, after anterior or posterior spinal fusion were recruited, to measure curve characteristics on conventional radiographs, before and after surgery and after 2 years follow-up, whereas the vertebral axial rotation, true mid-sagittal anterior-posterior height ratio of individual structures, and spinal height differences were measured on 3D reconstructions of the pre- and postoperative supine low-dose computed tomography (CT) scans. Additionally, the intraoperative parameters were described and the patients completed the Scoliosis Research Society outcomes and the 3-level version of EuroQol Group questionnaires postoperatively. Fifty-three patients with Lenke curve type 1 idiopathic scoliosis (26 in the anterior cohort and 27 in the posterior cohort) were analyzed. Fewer vertebrae were instrumented in the anterior cohort compared with the posterior cohort (P < 0.001), with less surgery time and lower intraoperative blood loss (P < 0.001). The Cobb angle correction of the primary thoracic curve directly after surgery was 57 ± 12% in the anterior cohort and 73 ± 12% in the posterior cohort (P < 0.001) and 55 ± 13% and 66 ± 12% (P = 0.001) at 2 years follow-up. Postoperative 3D alignment restoration and questionnaires showed no significant differences between the cohorts. This study suggests that Lenke type 1 curves can be effectively managed surgically with either an open anterior or posterior approach. Each approach, however, has specific advantages and challenges, as described in this study, which must be considered before treating each patient. 3.


Privacy and Security within Biobanking: The Role of Information Technology.
Along with technical issues, biobanking frequently raises important privacy and security issues that must be resolved as biobanks continue to grow in scale and scope. Consent mechanisms currently in use range from fine-grained to very broad, and in some cases participants are offered very few privacy protections. However, developments in information technology are bringing improvements. New programs and systems are being developed to allow researchers to conduct analyses without distributing the data itself offsite, either by allowing the investigator to communicate with a central computer, or by having each site participate in meta-analysis that results in a shared statistic or final significance result. The implementation of security protocols into the research biobanking setting requires three key elements: authentication, authorization, and auditing. Authentication is the process of making sure individuals are who they claim to be, frequently through the use of a password, a key fob, or a physical (i.e., retinal or fingerprint) scan. Authorization involves ensuring that every individual who attempts an action has permission to do that action. Finally, auditing allows for actions to be logged so that inappropriate or unethical actions can later be traced back to their source.


Genomic cloning and characterization of a Pto-like gene SsPto-2 from Solanum surattense.
A Pto-like gene (designated as SsPto-2) was isolated from Solanum surattense by using genomic walker technology which encoded a cytoplasmically localized serine-threonine protein kinase. Analysis of the 2365 bp segment revealed a gene including a 905 bp 5' flanking region, a 924 bp open reading frame (ORF) and a 536 bp 3' flanking region. The deduced amino acid sequence of the SsPto-2 gene shared high homology with other known Ptos. The deduced SsPto-2 protein contained no signal peptide with a calculated molecular weight of 34.61 kDa. The analysis of SsPto-2 promoter region and terminator region was also presented. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that SsPto-2 transcripts were up-regulated by defense-related factors such as gibberellic acid (GA(3)), salicylic acid (SA) and down-regulated by darkness. The cloning of the SsPto-2 gene will allow us to further study its potential role in disease resistance.


How do type of preoperative P2Y12 receptor inhibitor and withdrawal time affect bleeding? Protocol of a systematic review and individual patient data meta-analysis.
In order to reduce the risk of bleeding in patients on P2Y12 receptor inhibitors presenting for non-emergent coronary artery bypass grafting (CABG), current guidelines recommend a preoperative discontinuation period of at least three, five and seven days for ticagrelor, clopidogrel and prasugrel, respectively, to allow for recovery of platelet function. However, there is still substantial interinstitutional variation in preoperative management and relevant covariates of CABG-related bleeding are largely elusive so far. We will search PubMed (July 2013 to November 2021) and EMBASE (January 2014 to November 2021) using the following terms, MeSH terms and their synonyms: clopidogrel, prasugrel, ticagrelor, dual antiplatelet, P2Y12 receptor inhibitor, CABG, bleeding, haemorrhage. Two independent reviewers will screen all abstracts and full papers for eligibility. Disagreements will be solved by consulting with a third reviewer.The primary outcome is the incidence of Bleeding Academic Research Consortium type-4 bleeding depending on type of P2Y12 receptor inhibitor and preoperative withdrawal period. The secondary outcomes are mortality and ischaemic events according to the Academic Research Consortium 2 Consensus Document. We will perform an individual patient data meta-analysis (IPD-MA) with drug-specific preoperative withdrawal time and adjust for demographic and procedural variables. Subgroup analyses will be performed for anaemic patients and patients undergoing non-emergent versus urgent/emergent surgery. This IPD-MA consists of secondary analyses of existing non-identifiable data and meets the criteria for waiver of ethics review by the local Research Ethics Committee. Data sharing and transfer will be subject to a confidentiality agreement and a data use agreement. Findings will be disseminated through peer-reviewed publication and conference presentation. CRD42022291946.


Hepatitis C virus life cycle and lipid metabolism.
Hepatitis C Virus (HCV) infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus life cycle is intimately connected to lipid metabolism. In this review, we present an update on the lipids and apolipoproteins that are involved in the HCV infectious cycle steps: entry, replication and assembly. Moreover, the result of the assembly process is a lipoviroparticle, which represents a peculiarity of hepatitis C virion. This review illustrates an example of an intricate virus-host interaction governed by lipid metabolism.


Prothrombin time international normalized ratio monitoring by self-testing.
The increasing numbers of patients on oral anticoagulants may challenge the traditional organization of patient monitoring. The availability of portable coagulometers capable of measuring prothrombin time (PT) international normalized ratio (INR) in a drop of capillary blood facilitates decentralization of monitoring by self-testing. This article reviews the literature on use of portable coagulometers. Numerous studies have evaluated the reliability of portable coagulometers in testing the PT-INR. This has been assessed by statistically as well as clinically relevant criteria. Other studies have been devoted to developing calibration models fulfilling the criteria recommended by the World Health Organization (WHO) for the calibration of INR measuring systems. Finally, studies have assessed the value of schemes for patient training and for the long-term quality assurance of portable coagulometers. It can be concluded from the published studies that PT-INR self-testing may be considered as a suitable alternative to conventional laboratory testing. For the PT-INR to be reliable, manufacturers of portable coagulometers should calibrate their devices against international standards for thromboplastin with procedures similar to those recommended by WHO for conventional measuring systems. Training of patients and implementation of appropriate quality assessment schemes are also essential prerequisites for the success of PT-INR self-testing.


A hexamer peptide ligand that binds selectively to staphylococcal enterotoxin B: isolation from a solid phase combinatorial library.
By screening a solid-phase combinatorial peptide library, a short peptide ligand, YYWLHH, has been discovered that binds with high affinity and selectivity to staphylococcal enterotoxin B (SEB), but only weakly to other SEs that share sequence and structural homology with SEB. Using column affinity chromatography with an immobilized YYWLHH stationary phase, it was possible to separate SEB quantitatively from Staphylococcus aureus fermentation broth, a complex mixture of proteins, carbohydrates and other biomolecules. The immobilized peptide was also used to purify native SEB from a mixture containing denatured and hydrolyzed SEB, and showed little cross-reactivity with other SEs. To our knowledge this is the first report of a highly specific short peptide ligand for SEB. Such a ligand is a potential candidate to replace antibodies for detection, removal and purification strategies for SEB.


Cd adsorption properties of components in different freshwater surface coatings: the important role of ferromanganese oxides.
Surface coatings developed in different natural waters were used to study the role of the composition of surface coatings in controlling Cd adsorption in aquatic environments. To investigate the adsorption property of each component, the method of extraction techniques followed by Cd adsorption and statistical analysis were employed. Hydroxylamine hydrochloride was used to remove Mn oxides selectively, sodium dithionite was used to remove Mn and Fe oxides, and oxalic acid was used to remove most metal oxides and part of the organic material. Adsorption of Cd to surface coatings was measured before and after extraction under controlled laboratory conditions. The observed Cd adsorptions to unextracted and extracted surface coatings were analyzed using nonlinear least-squares fitting to estimate the adsorption property of each surface coating constituent. In different waters, the relative contribution to Cd adsorption of each component was different, but in all the waters studied, ferromanganese oxides contributed most with lesser roles indicated for organic phase and Al oxides. The Cd adsorption ability of manganese oxides was significantly higher than that of the other components.


Prediction of structures of multidomain proteins from structures of the individual domains.
We describe the development of a method for assembling structures of multidomain proteins from structures of isolated domains. The method consists of an initial low-resolution search in which the conformational space of the domain linker is explored using the Rosetta de novo structure prediction method, followed by a high-resolution search in which all atoms are treated explicitly and backbone and side chain degrees of freedom are simultaneously optimized. The method recapitulates, often with very high accuracy, the structures of existing multidomain proteins.


Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice: natural killer cell activity in cultured spleen leukocytes concomitant with T-cell-dependent immune interferon production.
The characteristics and specificities of spleen and peritoneal cytotoxic cells generated during lymphocytic choriomeningitis virus (LCMV) infection of C3H/St mice were examined. Activated natural killer (NK) cell activity was identified in fresh leukocyte populations from the 2nd to 8th days postinfection, whereas virus-specific cytotoxic T-cell activity was detected from the 6th to 14th days. When leukocytes were cultured overnight at 37 degrees C before assay, T-cell activity was still observed, but nonspecific activated NK cell-like cytotoxicity was only detected on the 6th and to a lesser degree the 8th day postinfection. Overnight culture of leukocytes taken earlier in the infection eliminated their NK cell activity. Similar activities were seen with spleen cell, plastic-adherent peritoneal cell, and nonadherent peritoneal cell populations. The virus-specific cytotoxicity observed with adherent peritoneal cells was due to contamination with cytotoxic T cells, as shown by H-2-restricted cytotoxicity and sensitivity to anti-theta antibody and complement. The nonspecific cultured day 6 effector cell from either the spleen or peritoneum displayed killing specificities and other physical properties identical to those of activated NK cells, but had sensitivities to anti-theta antibody and complement intermediate between activated day 3 NK cells and cytotoxic T cells. Culture stable NK-like cells were not found in athymic nude mice, suggesting a T-cell-dependent mechanism. Whereas LCMV spleen homogenates contained 10-fold-higher levels of interferon at day 2 than at day 6 postinfection, substantially more (nearly 20-fold) interferon was made in cultures of day 6 cells than day 2 cells. Spleen interferon was predominantly type I, whereas the culture interferon was predominantly type II, as shown by acid lability studies. Significant levels of interferon were produced by nylon-wool-passed day 6 spleen cells, and virtually all interferon production was eliminated by treatment of either day 2 or day 6 cells with antibody to theta antigen and complement, suggesting that T cells produced the interferon in vitro. Furthermore, athymic nude mice had no culture-stable NK cells 6 days postinfection, and spleen cells from them failed to produce significant levels of interferon in vitro. Addition of interferon (type I, fibroblast) to cultured C3H spleen cells affect the already elevated levels of cytotoxicity in day 6 cultures, suggesting that the NK cells in the day 6 culture were already activated. Our results suggest that T cells responding to LCMV infection secrete interferon type II which causes the continued activation of NK cells in culture. The resulting population of activated NK cells therefore appears to be relatively stable in culture and to express more theta antigen because of this T-cell dependence. Although one could mistakenly or allospecific cytotoxic T cells or cytotoxic macrophages, more careful examination shows that they are most likely activated NK cells...


Bilateral central serous chorioretinopathy associated with estrogen modulator diindolylmethane.
Central serous chorioretinopathy (CSCR) is an idiopathic disease associated with states of hypercortisolism that causes fluid to collect under the retina resulting in visual impairment. The authors describe an otherwise healthy female patient who presented with headaches and blurry vision after a 2-month history of excessive daily consumption of diindolylmethane (DIM), an over-the-counter estrogen modulator medication used to treat facial acne. Imaging demonstrated asymmetric, bilateral CSCR with active leakage in the left eye. She was instructed to discontinue DIM and reported that visual improvement began 2 weeks after, with resolution to baseline after 8 weeks.


Identifying opportunities to support patient-centred care for ductal carcinoma in situ: qualitative interviews with clinicians.
Women with ductal carcinoma in situ (DCIS) report poor patient-clinician communication, and long-lasting confusion and anxiety about their treatment and prognosis. Research shows that patient-centred care (PCC) improves patient experience and outcomes. Little is known about the clinician experience of delivering PCC for DCIS. This study characterized communication challenges faced by clinicians, and interventions they need to improve PCC for DCIS. Purposive and snowball sampling were used to recruit Canadian clinicians by specialty, gender, years of experience, setting, and geographic location. Qualitative interviews were conducted by telephone. Data were analyzed using constant comparison. Findings were mapped to a cancer-specific, comprehensive PCC framework to identify opportunities for improvement. Clinicians described approaches they used to address the PCC domains of fostering a healing relationship, exchanging information, and addressing emotions, but do not appear to be addressing the domains of managing uncertainty, involving women in making decisions, or enabling self-management. However, many clinicians described challenges or variable practices for all PCC domains but fostering a healing relationship. Clinicians vary in describing DCIS as cancer based on personal beliefs. When exchanging information, most find it difficult to justify treatment while assuring women of a good prognosis, and feel frustrated when women remain confused despite their efforts to explain it. While they recognize confusion and anxiety among women, clinicians said that patient navigators, social workers, support groups and high-quality information specific to DCIS are lacking. Despite these challenges, clinicians said they did not need or want communication interventions. Findings represent currently unmet opportunities by which to help clinicians enhance PCC for DCIS, and underscore the need for supplemental information and supportive care specific to DCIS. Future research is needed to develop and test communication interventions that improve PCC for DCIS. If effective and widely implemented, this may contribute to improved care experiences and outcomes for women diagnosed with and treated for DCIS.


[Smoking cessation in smokers with chronic obstructive pulmonary disease].
One out of two smokers who smoke throughout their lifetime will die from a disease related to smoking. Tobacco smoking therefore represents a major global public health issue. Smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Projections for 2020 indicate that by then, COPD will have become the third cause of death and the fifth cause of disability worldwide. Stopping smoking reduces the risk of developing COPD and is an essential treatment for this inflammatory disease. Smoking cessation decreases the prevalence of respiratory symptoms, number of hospitalizations, and decline in FEV1, as well as exacerbation frequency and overall mortality. Among the patients, 38-77% with COPD are smokers. Their daily cigarette consumption and level of nicotine dependence are often high. The combination of high intensity behavioral interventions and medication treatments (nicotine replacement therapy, varenicline, bupropion) is the most effective strategy for smokers with COPD. In contrast, behavioral interventions without medication are not more effective than simple advice to stop. Two factors seem to predict the success of the attempt to quit in smokers with COPD: a strong motivation to quit and the use of smoking cessation medications.


Robot-assisted radical nephrectomy using novel surgical robot platform, hinotori: Report of initial series of 13 cases.
The aims of the present study were to describe the perioperative findings of the first series of patients undergoing robot-assisted radical nephrectomy (RARN) with a newly launched platform, the hinotori surgical robot system, and compare the findings with a similar set receiving RARN with the existing system, da Vinci. This study included 34 patients, consisting of 13 and 21 undergoing RARN using the hinotori and da Vinci robotic systems, respectively. As a rule, RARN was performed via an intraperitoneal approach employing 3 robotic arms, irrespective of the robotic systems. In the hinotori group, the median age, body mass index and tumor diameter were 65 years, 23.3 kg/m2 and 50 mm, respectively. All surgical procedures with hinotori could be completed by a purely robotic approach. In the hinotori group, the median operative time, time using the robotic system, estimated blood loss and length of hospital stay were 157, 83 min, 11 mL and 6 days, respectively, and major perioperative complications did not occur. In this group, 3, 1 and 9 patients were pathologically diagnosed with pT1a, pT1b and pT3a tumors, respectively. No significant differences in baseline characteristics were noted between the hinotori and da Vinci groups, and there were also no significant differences in perioperative findings between them. Despite a case series with a small sample size, this is the first report evaluating RARN using the hinotori surgical robot system, which could be safely conducted and achieved perioperative outcomes similar to that using the da Vinci system.


Interpolymer complex between hydroxypropyl cellulose and maleic acid-styrene copolymer: phase behavior of semi-dilute solutions.
The phase behavior of a water/hydroxypropyl cellulose/maleic acid-styrene copolymer (H2O/HPC/MAc-S) system was investigated in the semi-dilute range by turbidimetry, rheology, and optical microscopy. The two polymers under investigation form interpolymer complexes via hydrogen bonding. In the case of a total polymer concentration of cpol = 5 mg . mL(-1) a second phase segregates upon heating the homogeneous ternary system. By applying a constant shear rate (gamma = 50 s(-1)) the phase separation temperature of the system is 10-15 degrees C lower than for an unsheared one. For cpol = 10 mg . mL(-1) phase separation has already occurred at room temperature when the two binary polymer solutions are mixed. The distribution of the partners among the coexisting phases was examined by FT-IR spectroscopy. The stoichiometry of the interpolymeric complex (IPC) was estimated to be HPC/MAc-S = 40:60 (w/w) independent of cpol.


Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis.
We previously reported that a novel combretastatin A-4 derivative, AC7700, has remarkable antitumour effects because of an irreversible stasis of tumour blood flow (TBF) and subsequent loss of nutrient supply to tumour tissue. Since early 2002, under the new designation AVE8062, AC7700 has undergone clinical trials in Europe and the US. Questions remain, however, concerning how AC7700 blocks TBF and why the TBF stasis does not recover. In this study, using a rat tumour LY80, a variant of Yoshida sarcoma, we examined whether TBF cessation after AC7700 administration is due to a direct action of the agent on tumour blood vessels. We constructed electrodes that can drop a small quantity of the drug solution directly at the site of blood flow measurement and inserted them subcutaneously and into the tumour. We compared the blood flow responses of normal vessels and tumour vessels after administration of 10-microl doses of various concentrations (0.2, 1, 10, and 50 mg ml(-1)) of the AC7700 solution. In addition, we assessed TBF stasis after i.v. and intra-arterial 10 mg x kg(-1) AC7700 administration in an LY80-induced kidney tumour. To determine why the TBF stasis is irreversible, we observed AC7700-induced changes in host arterioles and the tumour vascular network of the Sato lung carcinoma using a vital microscopic rat transparent chamber. Since an increase in tumour interstitial fluid pressure brings about a decrease in TBF, we also measured 10 mg x kg(-1) AC7700-induced changes in this pressure. The sensitivity of the blood flow response after intratumoral application of AC7700 was markedly higher in normal vessels relative to tumour vessels. Intra-arterial administration of AC7700 did not have stronger effects on TBF stasis than did i.v. administration. Intravital microscopy showed that AC7700 induced a powerful and long-lasting constriction of host arterioles, so that complete stasis of blood flow occurred in downstream vessels, which supplied blood to tumours. Owing to this stasis, the lumens of numerous tumour vessels narrowed or completely disappeared, and numerous erythrocytes stagnated in drainage vessels of the tumour vascular network. Haemolysis of these erythrocytes occurred after 2-3 h, resulting in complete thrombosis. There was no indication of reperfusion in vessels showing haemolysis. This haemolysis is thought to be the main cause for the irreversibility of TBF stasis. Since the tumour interstitial fluid pressure decreased after i.v. AC7700 administration, the possibility of stasis of TBF being caused by tumour vascular compression was excluded. All these results strongly suggest that the main target of AC7700 is host arterioles and that the stasis of TBF induced by AC7700 is not triggered by a direct action of the drug on tumour vessels.


Alpha1- and alpha2-adrenoreceptor antagonist profiles of 1- and 2-[omega-(4-arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles.
A series of pharmacologically interesting 1- and 2-[omega-(4-arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles, compounds 1-27, were synthesized (Scheme) and subjected to various biological studies to identify structure-activity relationships (SAR). The new compounds were found to exhibit good non-selective binding affinity towards the alpha1-adrenoreceptor (Table 1). In several cases, high functional antagonism was observed towards the alpha1A-, alpha1B-, and alpha1D-adrenoreceptor subtypes (Table 2). The selectivity for these three subtypes was comparable with or superior to that displayed by the standard drug prazosin. The most-common selectivity rank order was alpha1D > alpha1B > alpha1A, followed by alpha1B > alpha1D > alpha1A. In functional experiments, antagonism towards the alpha2-adrenoreceptor was generally low; however, a few compounds were endowed with significant antagonist properties (pA2 values of up to 7.87).


Chiral Manganese Aminopyridine Complexes: the Versatile Catalysts of Chemo- and Stereoselective Oxidations with H2 O2.
In the last decade, manganese(II) complexes with N-donor tetradentate aminopyridine ligands emerged as efficient catalysts of enantioselective epoxidation of olefins and direct selective oxidation of C-H groups in complex organic molecules, with environmentally benign oxidant hydrogen peroxide. In this personal account, we summarize the progress of these catalysts with regard to ligands design, structure-reactivity correlations, evaluation of the substrate scope, as well as mechanistic studies, shedding light on the nature of active sites and the mechanisms of selective oxygenations. Several practically promising catalytic syntheses with the aid of Mn aminopyridine catalysts are exemplified.


Predictors of speech and swallowing function following primary surgery for oral and oropharyngeal cancer.
To examine the association between the speech and swallowing aspect of health-related quality of life (HRQOL) and selected clinical parameters, and particularly to determine those that are predictive of good outcomes at 1 year after surgery. Prospective questionnaire and clinical study. Regional Maxillofacial Unit. A total of 278 consecutive patients undergoing primary surgery for squamous cell carcinoma between 1995 and 1999. HRQOL was assessed using the University of Washington Quality of Life questionnaire (UW-QOL) pre-surgery, and post-surgery at 6 months, 1 year and later (median 39 months). Presentation of results was mainly descriptive, involving percentages and mean scores. Association of clinico-demographic factors with tumour site, and with UW-QOL swallowing and speech after 12 months, was tested with Fisher's exact or chi-squared tests as appropriate and modelled using logistic regression methods. Univariate relationships were seen between speech and swallowing scores and with tumour size, T staging, radiotherapy, type of surgery (primary closure or free tissue transfer), tumour site, extent of resection of posterior tongue and soft palate, and UW-QOL taste and saliva scores. Multiple logistic regression showed that no radiotherapy (P<0.001) and primary surgical closure/laser surgery (P=0.003) were the main predictors of good swallowing, and primary surgical closure/laser surgery was the main predictor of good speech (P<0.001) at 1 year. A number of clinical parameters can influence the speech and swallowing aspect of quality of life in these patients and when feasible, primary closure results in a better outcome than free flap reconstruction.