Copper silicide/silicon nanowire heterostructures: in situ TEM observation of growth behaviors and electron transport properties.
Copper silicide has been studied in the applications of electronic devices and catalysts. In this study, Cu3Si/Si nanowire heterostructures were fabricated through solid state reaction in an in situ transmission electron microscope (TEM). The dynamic diffusion of the copper atoms in the growth process and the formation mechanism are characterized. We found that two dimensional stacking faults (SF) may retard the growth of Cu3Si. Due to the evidence of the block of edge-nucleation (heterogeneous) by the surface oxide, center-nucleation (homogeneous) is suggested to dominate the silicidation. Furthermore, the electrical transport properties of various silicon channel length with Cu3Si/Si heterostructure interfaces and metallic Cu3Si NWs have been investigated. The observations not only provided an alternative pathway to explore the formation mechanisms and interface properties of Cu3Si/Si, but also suggested the potential application of Cu3Si at nanoscale for future processing in nanotechnology.


A possible dopaminergic mechanism in the serotonergic antidepressant-induced sexual dysfunctions.
The administration of antidepressant serotoninergic medication is associated with the presentation of sexual dysfunctions. This seems to be mediated by the activation of the 5-HT2 receptors. Segraves (1995) has proposed that the inhibition of noradrenergic transmission by serotonin may be the mechanism which causes the antidepressant-induced sexual dysfunctions. The inhibition which the 5-HT2 receptors carry out on dopaminergic transmission leads us to propose this mechanism as also participating in the antidepressant-induced sexual dysfunctions.


Skeletal applications of videofluoroscopy.
The use of skeletal videofluoroscopy is spreading as new applications emerge for coupling the fluoroscope with the video cassette recorder to obtain detailed information on moving anatomy. This review compiles the findings of an extensive literature search and summarizes the current state of videofluoroscopy knowledge. It traces the development of this imaging tool, beginning with cineradiography and its early investigations into cervical spine motion in the 1950s. Videofluoroscopy is presently used to evaluate the entire spine and other areas of the skeletal system, as well as diverse systems throughout the body. Because it is the only imaging technique capable of visualizing actual joint motion in real time, it provides details on movement mechanics not available through other methods. Along with presenting current applications of videofluoroscopy, this review points to future research needs.


Long-term contamination of sink drains by carbapenemase-producing Enterobacterales in three intensive care units: characteristics and transmission to patients.
This study aimed to describe the contamination of sink drains (SDs) with carbapenemase-producing Enterobacterales (CPE) in three intensive care units (ICUs), and to assess the risk of transmission to hospitalized patients. All SDs were sampled monthly for CPE screening by culture. Rectal screening for CPE carriage was conducted weekly for hospitalized patients. CPE were isolated from 22% of SD samples. Some SDs remained colonized with the same strain for several months. No CPE acquisition occurred among hospitalized patients during the study. Certain strategies, such as systematic sampling of SDs in ICUs for screening for contamination by CPE, should be discouraged apart from during outbreaks.


Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases.
Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting.


[The optimum time interval for applying lidocaine containing adhesive tape is 6 to 8 hours for venipuncture pain relief].
Lidocaine containing adhesive tape (LT) is a pressure sensitive adhesive tape which contains 60% of lidocaine in base form. We investigated the optimum time interval for applying LT for venipuncture pain relief by using visual analogue scale (VAS). Six hundred seventeen cases were prospectively divided into 0.5, 1, 2, 3, 4, 6, 8, 12 hour groups. LT was applied on the dorsum of the hand and the vein was punctured with a 20 gauge polyurethane catheter (Insyte TM: Becton Dickinson, USA). The level of pin prick sensation was reduced in accordance with the duration of LT application. While the median of the pin prick sensation level was below 5% of control in the longer than 6 hour groups, the 90 percentile was 30% and 60% in 6 hour and 12 hour group, respectively. This suggested a possible poor skin contact of LT in the 12 hour group. VAS of venipuncture pain was significantly improved as the duration of LT application increased. When the punctures was smooth the median values of VAS in 6 and 8 hour groups were both less than 5%. Even with rough venipuncture, significant pain relief was observed in longer than 3 hour groups. We concluded that 6 to 8 hour applying of LT was optimum for pain relief of venipuncture.


A new form of RET rearrangement in thyroid carcinomas of children after the Chernobyl reactor accident.
Intrachromosomal rearrangements involving the RET and the adjacent H4 or ELE1 gene are very frequent events in thyroid cancer of children from Belarus after the Chernobyl reactor accident (Klugbauer et al., 1995). The fusion product between ELE1 and RET (RET/ PTC3) seems to be the prevailing type of rearrangement as shown in a recently published study using a novel RT multiplex PCR approach in combination with the identification of the rearrangement type by RT-PCR and direct sequencing. Now we found a new type of RET rearrangement: By the 5'RACE method we demonstrated in cDNA the fusion of the tyrosine kinase domain of RET with a truncated ELE1 gene shorter than the ELE1 in RET/PTC3. Sequencing of genomic DNA revealed a rearrangement breakpoint at position 41 of a new ELE1 intron (522 bp in length). The new oncogene RET/ delta PTC3 is shortened by one ELE1 exon of 144 bp in length. Structural considerations of the ele1 amino terminal of RET/ delta PTC3 suggest that the transforming activity of the fusion protein is apparently not affected by this truncation. The exon lacking in RET/ delta PTC3 was found to code in the reciprocal transcript RET/ delta ELE1 and increased its size by 144 bp. Obviously the new and possibly additional ELE/RET fusion molecules might even increase the high prevalence of ELE1/RET rearrangements in thyroid carcinomas of children after the Chernobyl reactor accident.


Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues.
Gangliosides are considered to be essential in the maintenance and repair of nervous tissues; however, the mechanisms for neurodegeneration caused by ganglioside defects are unknown. We examined gene expression profiles in double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes and showed that the majority of complement genes and their receptors were up-regulated in cerebellum in DKO mice. Inflammatory reactions were demonstrated in those tissues by measuring up-regulated inflammatory cytokines, indicating the presence of complement activation and inflammation as reported in Alzheimer's disease. Immunoblotting of fractionated membrane extracts by sucrose density gradient revealed that complement-regulatory molecules such as decay-accelerating factor and CD59 were dispersed from glycolipid-enriched microdomain/rafts in DKO cerebellum. Immunohistostaining of these molecules showed disordered membrane localization. These results suggested that dysfunction of complement-regulatory molecules may be due to abnormal glycolipid-enriched microdomain/rafts that triggered complement activation, subsequent inflammation, and neurodegeneration in DKO mice. Generation of the triple KO mice lacking complement activity in addition to the two glycosyltransferases suggested that complement activation is involved in the inflammatory reactions and neurodegeneration caused by the ganglioside deficiency.


Designing robust chitosan-based hydrogels for stem cell nesting under oxidative stress.
Introduction: Hydrogels are unique candidates for a wide range of biomedical applications including drug delivery and tissue engineering. The present investigation was designed to consider the impact of chitosan-based hydrogels as a scaffold on the proliferation of human bone marrow mesenchymal stem cells (hBM-MSCs) besides neutralization of oxidative stress in hBM-MSCs. Methods: Chitosan (CS) and CS-gelatin hydrogels were fabricated through ionic crosslinking using β-glycerophosphate. The hBM-MSCs were cultured on the prepared matrices and their proliferation was evaluated using DAPI staining and MTT assay. Furthermore, the effect of hydrogels on oxidative stress was assessed by measuring the expression of NQO1, Nrf2, and HO-1 genes using real-time PCR. Results: The developed hydrogels indicated a porous structure with high water content. The toxicity studies showed that the prepared hydrogels have a high biocompatibility/cytocompatibility. The expression of intracellular antioxidant genes was studied to ensure that stress is not imposed by the scaffold on the nested cells. The results showed that Nrf2 as a super transcription factor of antioxidant genes and its downstream antioxidant gene, NQO1 were downregulated. Unexpectedly, the upregulation of HO-1 was detected in the current study. Conclusion: The prepared CS-based hydrogels with desired properties including porous structure, high swelling ability, and cytocompatibility did not show oxidative stress for the nesting of stem cells. Therefore, they could be attractive scaffolds to support stem cells for successful tissue engineering purposes.


Ferroelectric domain structure of SrBi2Nb2O9 epitaxial thin films.
The domain structure in a ferroelectric with well-defined crystallography and negligible ferroelastic distortion (<0.002%) is reported. In contrast to prototypical ferroelectrics in which long-range elastic strain dictates the domain structure, in SrBi2Nb2O9 the elastic term is insignificant, allowing dipole-dipole interactions and domain wall energies to dominate in determining the domain structure. Electron microscopy reveals ferroelectric domains that are irregularly shaped and highly curved. Out-of-phase boundary defects are shown to be weakly correlated with 90 degrees ferroelectric domain structure.


Solvent effects on electrophilicity.
Continuum solvent effect on the electrophilicity index recently proposed by Parr and co-workers (Parr, R. G.; von Szentpaly, L.; Liu, S. J. Am. Chem. Soc. 1999, 121, 1922) is discussed in detail. Solvent effect is introduced using the self-consistent isodensity polarized continuum model (SCI-PCM). A linear relationship is found between the change in electrophilicity index and the solvation energy as represented in the frame of the reaction field theory. The effect of a polarizable environment on the global electrophilicity is examined for a series of 18 well-known electrophiles presenting a wide diversity in structure and bonding properties. It is found that solvation enhances the electrophilicity power of neutral electrophilic ligands but attenuates this power in charged and ionic electrophiles.


Recent Advances of Chitosan and its Derivatives in Biomedical Applications.
Chitosan is the second-most abundant natural polysaccharide. It has unique characteristics, such as biodegradability, biocompatibility, and non-toxicity. Due to the existence of its free amine group and hydroxyl groups on its backbone chain, chitosan can undergo further chemical modifications to generate Chitosan Derivatives (CDs) that permit additional biomedical functionality. Chitosan and CDs can be fabricated into various forms, including Nanoparticles (NPs), micelles, hydrogels, nanocomposites and nano-chelates. For these reasons, chitosan and CDs have found a tremendous variety of biomedical applications in recent years. This paper mainly presents the prominent applications of chitosan and CDs for cancer therapy/diagnosis, molecule biosensing, viral infection, and tissue engineering over the past five years. Moreover, future research directions on chitosan are also considered.


Performance demands in the selection of objects for counting.
This paper considers the visual processes in object counting among children. Experiment 1 presented identical objects to 7- and 8-year-old children and found that spatially random configurations were counted more quickly than linear arrays, illustrating the difficulty of isolating objects grouped together in rows. However, the younger children were more prone to miscounting these random arrays than rows. The study also established a spatial proximity effect, with a dense arrangement of items being difficult to count. Experiment 2 revealed that this proximity effect can be removed by differentiating objects by color, providing further evidence that object counting involves overcoming Gestalt grouping forces and arguing against fine-motor control as a limiting factor in counting.


Do people believe combined hazards can present synergistic risks?
The risk attributable to some hazard combinations can be greater than the sum of the risk attributable to each constituent hazard. Such "synergistic risks" occur in several domains, can vary in magnitude, and often have harmful, even life-threatening, outcomes. Yet, the extent to which people believe that combined hazards can present synergistic risks is unclear. We present the results of two experimental studies aimed at addressing this issue. In both studies, participants examined synergistic and additive risk scenarios, and judged whether these were possible. The results indicate that the proportion of people who believe that synergistic risks can occur declines linearly as the magnitude of the synergistic risk increases. We also find that people believe, despite scientific evidence to the contrary, that certain hazard combinations are more likely to present additive or weakly synergistic risks than synergistic risks of higher magnitudes. Furthermore, our findings did not vary as a simple function of hazard domain (health vs. social), but varied according to the characteristics of the specific hazards considered (specified vs. unspecified drug combinations). These results suggest that many people's beliefs concerning the risk attributable to combined hazards could lead them to underestimate the threat posed by combinations that present synergistic risks, particularly for hazard combinations that present higher synergistic risk magnitudes. These findings highlight a need to develop risk communications that can effectively increase awareness of synergistic risks.


Plasmin--alpha 2-antiplasmin complex as an indicator of in vivo fibrinolysis.
alpha 2-Antiplasmin is the principal plasma inhibitor of plasmin, with which it rapidly and irreversibly forms a complex. The simple technique of crossed immunoelectrophoresis against antiserum to alpha 2-antiplasmin has been applied to detect plasmin-alpha 2-antiplasmin complex in plasma. The presence of this complex is demonstrated in patients in whom overactive fibrinolysis was the only or major contributor to severe haemorrhagic disorders arising spontaneously.


[Localization of beta-n-acetylhexosaminidase in stallion epididymis (author's transl)].
The localization of beta-N-acetylhexosaminidase activity in 6 different segments of the epididymis was investigated in 8 stallions using biochemical and histochemical methods. The highest enzyme activity was found in segment D while the other segments displayed a much weaker reaction There was no or only low enzyme activity present in the epididymal fluid of the proximal 3 segments, whereas it was high in the distal 3 segments. The biological function of beta-N-acetylhexosaminidase in the epididymis is discussed briefly.


[Epidemiology of pleural mesothelioma in Japan].
We describe the trend in pleural mesothelioma mortality rates since 1995, when the International Statistical Classification of Disease and Related Health Problems came into effect in Japan, and outline the risk factors for the disease. The number of pleural mesothelioma cases has been increasing in both genders, although male deaths predominated over female ones every year. In 2007, the latest year for which data are available, 652 deaths occurred among men and 130 among women, which was only one-fifth of that among men. The annual death rates were 0.88 and 0.20 per 10(5), respectively. The distribution of 5-year age-specific deaths was skewed toward younger age, with a single peak at 70-74 years in men but at 75-79 years in women. Birth cohort analysis showed that age-specific death rates from the disease became higher with younger birth year in men. Asbestos exposure causes pleural mesothelioma. Some cohort studies clarified the high mortality rate from the disease, which was reported to reach 0.5 x 10(3)/year among those with occupational asbestos exposure. Depending on the amount and variety of asbestos used in industrial plants, the range at which neighborhood asbestos exposure can increase the risk of residents developing pleural mesothelioma can be as much as 2,000 meters from an emission point.


Community management of peripherally inserted central catheters.
Peripherally inserted central catheters (PICCs) are increasingly being used in the UK to allow patients requiring medium-to-long term venous access for a range of therapies, including ambulatory chemotherapy, to receive their treatment at home, away from the hospital setting. This article provides information for community nurses on the background of PICC lines in the UK, and practical advice on how to clinically maintain and manage these lines. Complications relating to PICCs are discussed, including how to recognize and deal with these complications in the community, and when to refer back to the specialist centre. The author leads at a nurse-managed PICC insertion service at a major cancer centre in Wales. The ongoing success of this service relies heavily on the skill and expertise of the community nurses who support the service.


Gated recurrence enables simple and accurate sequence prediction in stochastic, changing, and structured environments.
From decision making to perception to language, predicting what is coming next is crucial. It is also challenging in stochastic, changing, and structured environments; yet the brain makes accurate predictions in many situations. What computational architecture could enable this feat? Bayesian inference makes optimal predictions but is prohibitively difficult to compute. Here, we show that a specific recurrent neural network architecture enables simple and accurate solutions in several environments. This architecture relies on three mechanisms: gating, lateral connections, and recurrent weight training. Like the optimal solution and the human brain, such networks develop internal representations of their changing environment (including estimates of the environment's latent variables and the precision of these estimates), leverage multiple levels of latent structure, and adapt their effective learning rate to changes without changing their connection weights. Being ubiquitous in the brain, gated recurrence could therefore serve as a generic building block to predict in real-life environments.


High-Performance and Reliable White Organic Light-Emitting Fibers for Truly Wearable Textile Displays.
Light-emitting fibers have been intensively developed for the realization of textile displays and various lighting applications, as promising free-form electronics with outstanding interconnectivity. These advances in the fiber displays have been made possible by the successful implementation of the core technologies of conventional displays, including high optoelectronic performance and essential elements, in the fiber form-factor. However, although white organic light-emitting diodes (WOLEDs), as a fundamental core technology of displays, are essential for realizing full-color displays and solid-state lighting, fiber-based WOLEDs are still challenging due to structural issues and the lack of approaches to implementing WOLEDs on fiber. Herein, the first fiber WOLED is reported, exhibiting high optoelectronic performance and a reliable color index, comparable to those of conventional planar WOLEDs. As key features, it is found that WOLEDs can be successfully introduced on a cylindrical fiber using a dip-coatable single white-emission layer based on simulation and optimization of the white spectra. Furthermore, to ensure durability from usage, the fiber WOLED is encapsulated by an Al2 O3 /elastomer bilayer, showing stable operation under repetitive bending and pressure, and in water. This pioneering work is believed to provide building blocks for realizing complete textile display technologies by complementing the lack of the core technology.


Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.
Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06-1.66), P=0.01), bacterial infections (HR 1.33 (1.05-1.67), P=0.02), fungal infections (HR 1.86 (1.28-2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39-3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46-2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.


Familial Wolff-Parkinson-White Syndrome: a disease of glycogen storage or ion channel dysfunction?
Wolff-Parkinson-White (WPW) syndrome is the most common cause of ventricular pre-excitation, a condition where, due to defects in the conduction pathway, all or part of the ventricle is excited earlier than would normally be expected, often leading to ventricular fibrillation and sudden cardiac death. It was recently discovered that many of the underlying mutations responsible for the familial form of WPW syndrome are located in the gene encoding for the regulatory gamma(2)-subunit (PRKAG2) of the AMP-activated protein kinase. The cellular mechanisms for the observed arrhythmias are currently being studied and may involve glycogen storage with associated hypertrophy as well as alterations in the properties of cardiac ion channels such as voltage-gated sodium channel. It is the aim of this review to discuss our current knowledge of the cellular disturbances underlying the induction of arrhythmias in patients with PRKAG2 mutations.


Hormonal treatment before and after artificial insemination differentially improves fertility in subpopulations of dairy cows during the summer and autumn.
Reduced conception rate (CR) during the hot summer and subsequent autumn is a well-documented phenomenon. Intensive use of cooling systems can improve summer and autumn reproductive performance, but is unable to increase CR to winter and spring levels. We examined whether combined hormonal treatments--to increase follicular turnover before artificial insemination (AI) and progesterone supplementation post-AI--might improve fertility of cooled cows during the summer and autumn. The experiment was conducted from July to November in 3 commercial herds in Israel and included 707 Holstein cows at 50 to 60 d in milk (DIM). Cows were hormonally treated to induce 2 consecutive 9-d cycles, with GnRH administration followed by PGF2α injection 7 d later, followed by an intravaginal insert containing progesterone on d 5 ± 1 post-AI for 14 d. Both untreated controls (n=376) and treated cows (n=331) were inseminated following estrus, and pregnancy was determined by palpation 42 to 50 d post-AI. First-AI CR data revealed a positive interaction between treatment and cows previously diagnosed with postpartum uterine disease [odds ratio (OR) 2.24]. Interaction between treatment and low body condition score tended to increase the probability of first-AI CR (OR 1.95) and increased pregnancy rate at 90 DIM (OR 2.50) and at 120 DIM (OR 1.77). Low milk production increased the probability of being detected in estrus at the end of synchronization within treated cows (OR 1.67), and interacted with treatment to increase probability of pregnancy at 90 DIM (OR 2.39) relative to control counterparts. It is suggested that when administered with efficient cooling, combined hormonal treatment in specific subgroups of cows, that is, those previously diagnosed with postpartum uterine disease or those with low body condition score or low milk yield might improve fertility during the summer and autumn. Integration of such an approach into reproductive management during the hot seasons might improve treatment efficiency and reduce expenses.


Photocatalytic activity of nano and microcrystalline TiO(2) hybrid systems involving phthalocyanine or porphyrin sensitizers.
Hybrid photocatalysts based on TiO(2)-anatase matrix, representing the both micro- and nano-structures, impregnated with selected lanthanide diphthalocyanine and metalloporphyrin sensitizers, were compared to evaluate their activity and effectiveness in a water suspension catalytic system designed to degrade 4-nitrophenol (4-NP) in a UV-stimulated reaction. Either type of the anatase catalyst was proved to be effective in mineralizing of 4-NP. However, kinetic studies confirmed that the composite's efficiency basically depends on the nature of the macromolecular sensitizer and to a minor extent on the dimensions (micro/nano) of the TiO(2) particles. The apparent higher activity observed for the micro-TiO(2) catalysts indicates improvement of the electron transfer between the sensitizer and the micro-crystalline structure of TiO(2)-anatase in contrast to the nano-crystalline matrix. The mechanistic aspects of the observed catalytic performances have been discussed.


Specificity of insertion sequence-based PCR assays for mycobacterium tuberculosis complex.
To determine the specificity of different insertion sequence-targeted polymerase chain reaction (PCR) tests for Mycobacterium tuberculosis complex. One M. bovis BCG strain, two M. tuberculosis strains and ten species of mycobacteria other than tuberculosis (MOTT) were tested by three PCR assays based on the repetitive elements IS6110, IS1081 and IS990 under variable amplification conditions (different temperatures of primer annealing and numbers of reaction cycles). DNA amplifications based on the three insertion sequences yielded fragments of expected sizes only in DNA from M. tuberculosis complex strains when the tests were conducted at high stringency (65 degrees C). At the annealing temperature of 60 degrees C the PCR assay with IS6110-specific primers yielded a 245 bp fragment also in nine MOTT strains tested. This could result from previously reported homology between non-tuberculous mycobacteria and a central region of IS6110. Amplification assays based on IS1081 and IS990 gave false-positive results in some MOTT isolates only under very low stringency (55 degrees C), which could be due to non-specific priming of the target DNA at that temperature. Repetitive elements IS1081 and IS990 may represent a more reliable alternative to the more widely used IS6110 PCR target for tuberculosis diagnosis.


The mTOR pathway in breast cancer.
There is currently a wealth of information regarding the mutations that contribute to cancer development. Most of these mutations alter the expression and activity of signal transduction proteins. The current goal in cancer therapy is to use our knowledge of the molecular alterations in a cancer cell to choose the most appropriate signal transduction inhibitor for an individual patient. The topic of this review is the mammalian target of rapamycin (mTOR) kinase signaling pathway, which is aberrantly activated in many types of human cancer. We will discuss the mTOR pathway and the potential mechanisms that contribute to its activation in cancer, together with data relating to the potential for inhibitors targeting the mTOR-signaling pathway to impact on breast cancer therapy.


Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate.
Treatment of paroxysmal atrial fibrillation with flecainide acetate resulted in a 4-fold increase in ventricular capture thresholds. The detailed time course of the threshold increase and decrease was documented using the AutoCapture algorithm and graphic summary.


Achieving Access Parity for Inpatient Psychiatric Care Requires Repealing the Medicaid Institutions for Mental Disease Exclusion Rule.
Approximately 3.4% of Americans have a mental health condition and suicide is the 10th leading cause of death. While the rate of mental health conditions has slightly increased for adult populations, America's youth has experienced a significant rise in depression. From 2008 to 2017, occurrence of depression in the adolescent population increased from 8.3% to 13.3%. As adolescents mature into adults; it is likely the rate of mental health conditions for the adult population will rise as well as it is the common thread that binds the diseases of despair: drug abuse, alcoholism, and suicide. Arising out of the deinstitutionalization movement of the 1960s, the Medicaid Institutions for Mental Disease (IMD) Exclusion Rule (§1905(a)(B) of the Social Security Act) prohibits reimbursement for Medicaid recipients ages 21 to 64 years receiving inpatient care at a psychiatric hospital with 16 or more beds. Consequently, the rule limits payment for psychiatric treatment to general hospitals and smaller, nonspecialized centers, which blocks patients from receiving inpatient care and transfers the financial burden of care onto psychiatric hospitals. The IMD Rule is approaching its 55th anniversary. It requires reevaluation. Although a state waiver process is available, use of this option has the potential to increase the incidence of racial and ethnic disparities across states. Full repeal of the IMD Exclusion Rule could help provide immediate access to inpatient care that is consistent nationwide and be a vital step toward creating financial, treatment and ethical parity for mental health services.


Evaluation of image quality metrics for the prediction of subjective best focus.
Seven existing and three new image quality metrics were evaluated in terms of their effectiveness in predicting subjective cycloplegic refraction. Monochromatic wavefront aberrations (WA) were measured in 70 eyes using a Shack-Hartmann based device (Complete Ophthalmic Analysis System; Wavefront Sciences). Subjective cycloplegic spherocylindrical correction was obtained using a standard manifest refraction procedure. The dioptric amount required to optimize each metric was calculated and compared with the subjective refraction result. Metrics included monochromatic and polychromatic variants, as well as variants taking into consideration the Stiles and Crawford effect (SCE). WA measurements were performed using infrared light and converted to visible before all calculations. The mean difference between subjective cycloplegic and WA-derived spherical refraction ranged from 0.17 to 0.36 diopters (D), while paraxial curvature resulted in a difference of 0.68 D. Monochromatic metrics exhibited smaller mean differences between subjective cycloplegic and objective refraction. Consideration of the SCE reduced the standard deviation (SD) of the difference between subjective and objective refraction. All metrics exhibited similar performance in terms of accuracy and precision. We hypothesize that errors pertaining to the conversion between infrared and visible wavelengths rather than calculation method may be the limiting factor in determining objective best focus from near infrared WA measurements.


Dendritic systems based on dinuclear ruthenium or rhodium units generating peripheral catalytic sites.
A series of dendritic cations 1-4 containing Ru(2)S(3) or Rh(2)S(3) units, either in the core or in the dendrons, has been synthesized and characterized. The X-ray crystal structure analysis of 2-Cl shows a trigonal bipyramidal Rh(2)S(3) core with propeller-like para-hydroxyphenyl substituents at the sulfur atoms. Reaction of the peripheral OH groups with diphenylphosphino benzoic acid results in the formation of phosphine-functionalized dendritic cations 5-8. The ruthenium-containing cation 5, with three PPh(2) functions at the periphery, acts as ligand for rhodium(I) and enhances significantly the catalytic activity of [[Rh(CO)(2)Cl](2)] for the carbonylation of methanol.


Smart nanovehicles based on pH-triggered disassembly of supramolecular peptide-amphiphiles for efficient intracellular drug delivery.
A novel type of nanovehicle (NV) based on stimuli-responsive supramolecular peptide-amphiphiles (SPAs, dendritic poly (L-lysine) non-covalently linked poly (L-leucine)) is developed for intracellular drug delivery. To determine the pH-dependent mechanism, the supramolecular peptide-amphiphile system (SPAS) is investigated at different pH conditions using a variety of physical and chemical approaches. The pH-triggered disassembly of SPAS can be attributed to the disappearance of non-covalent interactions within SPAs around the isoelectric point of poly (L-leucine). SPAS is found to encapsulate guest molecules at pH 7.4 but release them at pH 6.2. In this way, SPAS is able to act as a smart NV to deliver its target to tumor cells using intracellular pH as a trigger. The DOX-loaded NVs are approximately 150 nm in size. In vitro release profiles and confocal laser scanning microscopy (CLSM) images of HepG2 cells confirm that lower pH conditions can trigger the disassembly of NVs and so achieve pH-dependent intracellular DOX delivery. In vitro cytotoxicity of the DOX-loaded NVs to HepG2 cells demonstrate that the smart NVs enhance the efficacy of hydrophobic DOX. Fluorescence-activated cell sorting (FACS) and CLSM results show that the NVs can enhance the endocytosis of DOX into HepG2 cells considerably and deliver DOX to the nuclei.


Morphological study of liver in patients of chronic hepatitis C treated with interferon.
The effect of interferon therapy on liver morphology was assessed in ten patients with serologically proven chronic hepatitis C. All these patients received 3 million units of alpha interferon three times a week. Six patients received therapy for 6 months, two patients for 12 months, one patient each for 3 and 9 months. All patients underwent a second liver biopsy 1 to 6 months after cessation of therapy. Alanine aminotransferase levels were determined before, during and after therapy. Each biopsy was assessed histologically by revised classification of chronic hepatitis proposed by Desmet et al and Kondell histological activity index was determined. Four patients showed significant reduction in the necroinflammatory activity with decrease in the HAI and normalisation of ALT level. Three patients showed partial reduction in the necroinflammatory activity with partial reduction of ALT levels. Two patients did not show any change in the grade of disease while one patient showed worsening of necroinflammatory activity with rising ALT levels. One patient showed a significant reduction in fibrosis with conversion of early developing cirrhosis into bridging fibrosis. A second liver biopsy is extremely useful for assessing the response of interferon treatment, however, it must be done at a suitable time after cessation of therapy.


[When people born in French overseas departments return home to retire. A survey of intentions].
"Almost half of...over-45s born in French overseas departments and living in mainland France had plans to return overseas by the year 2000. The desire to return is more clear-cut among the 50 to 54 year olds. The younger people have yet to think seriously about retirement, whilst a number of the oldest individuals have already made definite plans." Data are from a survey carried out in 1992. (SUMMARY IN ENG AND GER AND SPA)


Do different types of nurses give different triage decisions in NHS Direct? A mixed methods study.
To determine whether nurses with different clinical backgrounds make different triage decisions in NHS Direct, the 24-hour telephone helpline staffed by nurses. Mixed methods including semistructured interviews with 24 nurses and a multilevel analysis of 60 794 calls triaged by 296 nurses. Nurse accounts helped to identify nurse characteristics that might affect decision-making. The proportion of calls triaged to self-care was 40% (24 049/60 794), varying by individual nurse from a 10th centile of 22% to a 90th centile of 60%, after adjustment for the age and sex of the patient and the time of the call. Variability was partly explained by the length of clinical experience of nurses and the type of software used: nurses with more than 20 years clinical experience were more likely to triage callers to self-care than those with less than ten years experience (42% versus 36%, respectively; odds ratio = 1.41, 95% confidence interval 1.13, 1.78). Proportions triaged to selfcare differed by the type of clinical decision support software used: 31%, 37% and 44%. There was no evidence that the clinical background of nurses (hospital or community), their length of experience in NHS Direct, the range of their experience, or their gender affected triage decisions. Interviews identified that nursing characteristics affected individual nurses in different ways and helped to generate a hypothesis for future research - that individual nurses' approaches to risk may influence triage decisions. There is no likely benefit in narrowing nurse recruitment to particular clinical backgrounds. The appropriateness of triage decisions still needs to be evaluated.


[The recent progress in chemoradiotherapy of lung cancer].
This is a review of the recent progress in chemoradiotherapy of locally advanced lung cancer. In the limited disease stage of small cell lung cancer, a meta-analysis showed patients treated with a combination of chemotherapy and radiotherapy have a statistically significantly longer survival than those with chemotherapy alone. However, the timing of the combination of radiation and chemotherapy has not been clarified. One study favored late over early use of radiotherapy for survival. Another randomized study and a meta-analysis revealed earlier radiotherapy had a better prognosis. JCOG performed a randomized phase III study comparing concurrent chemoradiotherapy with chemotherapy followed by radiotherapy, and the final results will be published in the near future. In the past, radiotherapy alone had been considered standard therapy for inoperable locally advanced non-small cell lung cancer. Several randomized studies and meta-analyses demonstrated the combination of chemotherapy and radiotherapy produced better survival rates than by radiotherapy alone. Our randomized study indicated the addition of radiotherapy after chemotherapy is superior in long-term survival to chemotherapy alone. The West Japan Lung Cancer Group conduct a phase III randomized study comparing concurrent and sequential chemoradiotherapy, and the determination of survival is now in the follow-up stage. The role of induction chemoradiotherapy before surgical resection, comparison of chemoradiotherapy with induction chemoradiotherapy followed by surgery, and the effects and safety of the combination of new drugs and radiotherapy are now under investigation.


A malignant neoplasm with features of both squamous cell carcinoma and malignant melanoma.
A case of a malignant neoplasm with features suggestive of both malignant melanoma and squamous cell carcinoma is reported. The neoplastic cells were positive for both S-100 protein and keratin when stained by the indirect peroxidase-antiperoxidase method. The literature on other instances of bi- or multidirectional differentiation of neoplastic cells is reviewed. The significance of these findings for terminology of neoplasms is discussed.


Laser microdissection of plant tissue: what you see is what you get.
Laser microdissection (LM) utilizes a cutting or harvesting laser to isolate specific cells from histological sections; the process is guided by microscopy. This provides a means of removing selected cells from complex tissues, based only on their identification by microscopic appearance, location, or staining properties (e.g., immunohistochemistry, reporter gene expression, etc.). Cells isolated by LM can be a source of cell-specific DNA, RNA, protein or metabolites for subsequent evaluation of DNA modifications, transcript/protein/metabolite profiling, or other cell-specific properties that would be averaged with those of neighboring cell types during analysis of undissected complex tissues. Plants are particularly amenable to the application of LM; the highly regular tissue organization and stable cell walls of plants facilitate the visual identification of most cell types even in unstained tissue sections. Plant cells isolated by LM have been the starting point for a variety of genomic and metabolite studies of specific cell types.


Optical Detection of Stereoselective Interactions with DNA-Wrapped Single-Wall Carbon Nanotubes.
DNA-wrapped carbon nanotubes have been explored increasingly as sensitive near-infrared fluorescence probes for biomolecules. However, notably missing in previous studies is an inquiry on stereoselective interactions between DNA-wrapped carbon nanotubes and biomolecules. Here, enantiopure (+) and (-)(6,5), and (-)(8,3) as well as achiral (11,0) carbon nanotubes wrapped with specific resolving DNA sequences are used to demonstrate their stereoselective detection of amino acid enantiomers. Furthermore, stereoselective sensing abilities are found to be retained by dispersions containing a multitude of chiral nanotube structures. The fluorescence response profiles of six different DNA-wrapped carbon nanotube dispersions to nine standard amino acids, and their enantiomers, demonstrate that DNA-wrapped carbon nanotubes are exquisitely sensitive to the stereoconfiguration and side-chain functionality of amino acids in a manner that is dependent on both DNA sequence and nanotube chirality. Implications of our findings are discussed in the context of developing a machine learning-aided multiplexed biosensing scheme called a molecular perceptron.


Conference Scene: biomarkers: discovery technologies and novel disease applications.
This conference was organized by EuroSciCon and its unifying theme was the application of technology to discover and monitor biomarkers of disease. The meeting was arranged to promote interaction of presenters, and delegates and, in addition to formal presentations, an ask the panel question and answer session was included. Presentations, given by representatives from academia and companies, highlighted the requirement for the use of techniques combining exquisite sensitivity and specificity for application at the genomic and proteomic level in solid and fluid biosamples.


Reducing the lifetime risk of cancer from spinal radiographs among people with adolescent idiopathic scoliosis.
Data from a retrospective cohort study of people with adolescent idiopathic scoliosis were combined with information on full-spinal radiographs to estimate contemporary x-ray doses and lifetime risks for development of cancer. To project the lifetime risk for development of cancer from diagnostic radiographs for people with adolescent idiopathic scoliosis. Although a twofold excess risk for breast cancer has been reported for women treated for scoliosis between 1925 and 1965, information on the cancer risks associated with scoliosis management today is sparse. Specifically, there is a lack of up-to-date information on the number of spinal radiographs taken, the organ-specific x-ray doses from current radiographic techniques, and the projected cancer risks. The cohort consisted of subjects with adolescent idiopathic scoliosis who were referred to the scoliosis clinic of a large pediatric hospital between 1965 and 1979 in Montreal, Quebec, Canada. Based on radiographic equipment and practices implemented in 1982, organ-specific x-ray doses to the thyroid gland, female breast, respiratory organs, digestive organs, and bone marrow were calculated using Monte Carlo methods. These doses were incorporated into a life table procedure to calculate theoretic lifetime cancer risks. For all organs except the thyroid gland, dose-response models from the United States National Academy of Sciences Fifth Committee on the Biological Effects of ionizing Radiation were used. For thyroid cancer, a risk model was derived from a study of thyroid cancer incidence after x-ray treatment for tinea capitis. The average number of spinal radiographs was 12 for women (80% anteroposterior or posteroanterior) and 10 for men (78% anteroposterior or posteroanterior). Cumulative x-ray doses were in general higher in adolescents who were referred as younger teenagers than at later ages, and doses increased with the size of the spinal curve. Depending on the age at referral and curve size, the total excess lifetime cancer risks were calculated to range from 42 to 238 cases per 100,000 women and 14 to 79 cases per 100,000 men. For subjects who underwent surgery (those exposed to the highest doses), the lifetime number of cancer cases over and above background was almost as great as the number of thyroid cancers that would occur in the absence of radiation exposure. If the anteroposterior view was replaced by the posteroanterior view, a three- to sevenfold reduction in cumulative doses to the thyroid gland and the female breast would be achieved, yielding three- to fourfold reductions in the lifetime risk of breast cancer and a halving of the lifetime risk of thyroid cancer. The cancer risks from full-spinal radiographs for scoliosis are not negligible and can be reduced from one half to three quarters if the anteroposterior view is replaced with the posteroanterior view.


Modelling the degradation of low concentration pollutants in membrane bioreactors.
This paper deals with the development of a description of membrane bioreactor systems, focussing on wastewater treatment and removal of specific low concentration persistent organic pollutants (e.g. persistent polar pollutants--P3 compounds). In the present work we offer a basic model, adapted to Membrane Bioreactor (MBR) conditions, which reflects the biodegradation of recalcitrant (organic) substances. We put a particular focus on organic aromatic pollutants and demonstrate a model parameter estimation approach, with experiments carried out for linear alkylbenzene sulphonates (LAS).


Fine-Tuning Native Promoters of Synechococcus elongatus PCC 7942 To Develop a Synthetic Toolbox for Heterologous Protein Expression.
The cyanobacterium Synechococcus elongatus PCC 7942 is a potential photosynthetic cell-factory. In this study, two native promoters from S. elongatus PCC 7942 driving the expression of abundant cyanobacterial proteins phycocyanin (P cpcB7942) and RuBisCO (P rbc7942) were characterized in relation to their sequence features, expression levels, diurnal behavior, and regulation by light and CO2, major abiotic factors important for cyanobacterial growth. P cpcB7942 was repressed under high light intensity, but cultivation at higher CO2 concentration was able to recover promoter activity. On the other hand, P rbc7942 was repressed by elevated CO2 with a negative regulatory region between 300 and 225 bp. Removal of this region flipped the effect of CO2 with Rbc225 being activated only at high CO2 concentration, besides leading to the loss of circadian rhythm. The results from this study on promoter features and regulation will help expand the repertoire of tools for pathway engineering in cyanobacteria.


Toxic Combustion Product Yields as a Function of Equivalence Ratio and Flame Retardants in Under-Ventilated Fires: Bench-Large-Scale Comparisons.
In large-scale compartment fires; combustion product yields vary with combustion conditions mainly in relation to the fuel:air equivalence ratio (Φ) and the effects of gas-phase flame retardants. Yields of products of inefficient combustion; including the major toxic products CO; HCN and organic irritants; increase considerably as combustion changes from well-ventilated (Φ < 1) to under-ventilated (Φ = 1⁻3). It is therefore essential that bench-scale toxicity tests reproduce this behaviour across the Φ range. Yield data from repeat compartment fire tests for any specific fuel show some variation on either side of a best-fit curve for CO yield as a function of Φ. In order to quantify the extent to which data from the steady state tube furnace (SSTF [1]; ISO TS19700 [2]) represents compartment fire yields; the range and average deviations of SSTF data for CO yields from the compartment fire best-fit curve were compared to those for direct compartment fire measurements for six different polymeric fuels with textile and non-textile applications and for generic post-flashover fire CO yield data. The average yields; range and standard deviations of the SSTF data around the best-fit compartment fire curves were found to be close to those for the compartment fire data. It is concluded that SSTF data are as good a predictor of compartment fire yields as are repeat compartment fire test data.


Antibiotic use for respiratory syncytial virus in the Middle East: A surveillance study in hospitalized Jordanian children.
In developing countries where point-of-care testing is limited, providers rely on clinical judgement to discriminate between viral and bacterial respiratory infections. We performed a cross-sectional cohort study of hospitalized Jordanian children to evaluate antibiotic use for respiratory syncytial virus (RSV) infections. Admitting diagnoses from a prior viral surveillance cohort of hospitalized Jordanian children were dichotomized into suspected viral-like, non-pulmonary bacterial-like, and pulmonary bacterial-like infection. Stratifying by sex, we performed a polytomous logistic regression adjusting for age, underlying medical condition, maternal education, and region of residence to estimate prevalence odds ratios (PORs) for antibiotic use during hospitalization. Sensitivity and specificity of admission diagnoses and research laboratory results were compared. Children with a suspected viral-like admission diagnosis, compared to those with suspected non-pulmonary bacterial-like, were 88% and 86% less likely to be administered an empiric/first-line antibiotic (male, aPOR: 0.12; female, aPOR: 0.14; p-value = <0.001). There were slight differences by sex with males having a lower prevalence than females in being administered an expanded coverage antibiotic; but they had a higher prevalence of macrolide administration than males with non-pulmonary bacterial-like infection. Overall, children with RSV had a 34% probability (sensitivity) of being assigned to a suspected viral-like diagnosis; whereas RSV-negative children had a 76% probability (specificity) of being assigned to a suspected pulmonary bacterial-like diagnosis. Hospitalized children with a suspected viral-like admission diagnosis were less likely to receive an empiric/first-line and expanded coverage antibiotic compared to suspected non-pulmonary and pulmonary infections; however, when evaluating the accuracy of admission diagnosis to RSV-laboratory results there were considerable misclassifications. These results highlight the need for developing antibiotic interventions for Jordan and the rest of the Middle East.


Cognition-emotion integration in the anterior insular cortex.
Both cognitive and affective processes require mental resources. However, it remains unclear whether these 2 processes work in parallel or in an integrated fashion. In this functional magnetic resonance imaging study, we investigated their interaction using an empathy-for-pain paradigm, with simultaneous manipulation of cognitive demand of the tasks and emotional valence of the stimuli. Eighteen healthy adult participants viewed photographs showing other people's hands and feet in painful or nonpainful situations while performing tasks of low (body part judgment) and high (laterality judgment) cognitive demand. Behavioral data showed increased reaction times and error rates for painful compared with nonpainful stimuli under laterality judgment relative to body part judgment, indicating an interaction between cognitive demand and stimulus valence. Imaging analyses showed activity in bilateral anterior insula (AI) and primary somatosensory cortex (SI), but not posterior insula, for main effects of cognitive demand and stimulus valence. Importantly, cognitive demand and stimulus valence showed a significant interaction in AI, SI, and regions of the frontoparietal network. These results suggest that cognitive and emotional processes at least partially share common brain networks and that AI might serve as a key node in a brain network subserving cognition-emotion integration.


Liver necrosis induced by acute intraperitoneal ethanol administration in aged rats.
It is generally agreed that the deleterious pathophysiological effects of ethanol are caused, at least partially by an increase in free radical production. However, little attention has been directed to the effects of ethanol upon elderly organisms. Male Wistar rats at ages 3, 6, 12, 18 and 24 months were treated either with a single i.p. dose of 35% ethanol (v/v) at 3 g ethanol/kg body weight or an isovolumetric amount of 0.9% saline solution. We then assessed the plasma levels of transaminases and hepatic levels of oxidative stress-related parameters, followed by liver histological evaluation. The younger rats (3 months old) were not affected by the treatment with ethanol with respect to any of the studied parameters except for a lowering of total hepatic GSH and an increase in hepatic thiobarbituric acid reactants (TBARS) formation, while animals older than 3 months were increasingly more affected by the treatment. Acute ethanol treatment elicited the similar responses to those in the 3 months-old group, plus a decrease in the hepatic and plasma levels of beta-carotene and the plasma level of alpha-tocopherol, as well as an increase in the activity of plasma transaminases. In the 12,18 and 24 months old groups, there was increasing liver necrosis. These findings suggest that liver damage induced by acute ethanol administration in elderly rats may involve a lack of antioxidants.


Predicting the Relation between Biopsychosocial Factors and Type of Childbirth using the Decision Tree Method: A Cohort Study.
With the growing rate of cesarean sections, rising morbidity and mortality thereafter is an important health issue. Predictive models can identify individuals with a higher probability of cesarean section, and help them make better decisions. This study aimed to investigate the biopsychosocial factors associated with the method of childbirth and designed a predictive model using the decision tree C4.5 algorithm. In this cohort study, the sample included 170 pregnant women in the third trimester of pregnancy referring to Shahroud Health Care Centers (Semnan, Iran), from 2018 to 2019. Blood samples were taken from mothers to measure the estrogen hormone at baseline. Birth information was recorded at the follow-up time per 30-42 days postpartum. Chi square, independent samples t test, and Mann-Whitney were used for comparisons between the two groups. Modeling was performed with the help of MATLAB software and C4.5 decision tree algorithm using input variables and target variable (childbirth method). The data were divided into training and testing datasets using the 70-30% method. In both stages, sensitivity, specificity, and accuracy were evaluated by the decision tree algorithm. Previous method of childbirth, maternal body mass index at childbirth, maternal age, and estrogen were the most significant factors predicting the childbirth method. The decision tree model's sensitivity, specificity, and accuracy were 85.48%, 94.34%, and 89.57% in the training stage, and 82.35%, 83.87%, and 83.33% in the testing stage, respectively. The decision tree model was designed with high accuracy successfully predicted the method of childbirth. By recognizing the contributing factors, policymakers can take preventive action.It should be noted that this article was published in preprint form on the website of research square (https://www.researchsquare.com/article/rs-34770/v1).


Ku80 removal from DNA through double strand break-induced ubiquitylation.
The Ku70/Ku80 heterodimer, or Ku, is the central component of the nonhomologous end joining (NHEJ) pathway of double strand break (DSB) repair. Because Ku forms a ring through which the DSB threads, it likely becomes topologically attached to DNA during repair. The mechanism for its removal was unknown. Using a method to identify proteins recruited to DSBs in Xenopus laevis egg extract, we show that DSB-containing DNAs accumulate members of the Skp1-Cul1-F-box complex and K48-linked polyubiquitylated proteins in addition to known repair proteins. We demonstrate that Ku80 is degraded in response to DSBs in a ubiquitin-mediated manner. Strikingly, K48-linked polyubiquitylation, but not proteasomal degradation, is required for the efficient removal of Ku80 from DNA. This removal is DNA length dependent, as Ku80 is retained on duplex oligonucleotides. Finally, NHEJ completion and removal of Ku80 from DNA are independent from one another. We propose that DSB-induced ubiquitylation of Ku80 provides a mechanism to efficiently eliminate Ku from DNA for pre- and postrepair processes.


Lignocaine to aid the insertion of the laryngeal mask airway with thiopentone. A comparison between topical and intravenous administration.
Conditions for insertion of a laryngeal mask airway in 90 unpremedicated adult were patients were assessed in a randomised, single-blinded trial. Each patient received fentanyl 1 microgram.kg-1 and thiopentone 5 mg.kg-1, and this was preceded either by lignocaine 0.5 mg.kg-1 intravenously (group 1), lignocaine 1.5 mg.kg-1 intravenously (group 2) or 40 mg of topical lignocaine spray to the posterior pharyngeal wall (group 3). Conditions for laryngeal mask airway insertion were recorded. The group receiving topical lignocaine had a lower incidence of laryngospasm (p < 0.05), required fewer attempts for successful insertion of the laryngeal mask (p < 0.05) and coughed or gagged less frequently than either group receiving lignocaine intravenously (p > 0.05). Overall, the conditions for laryngeal mask airway insertion were better in the topical group (p < 0.05). There were no significant differences in haemodynamic response and apnoea between the three groups. Topical lignocaine spray prior to thiopentone provides conditions for insertion of a laryngeal mask that are superior to those provided by lignocaine and thiopentone intravenously.


[Screening for precursors of colorectal cancer].
Screening has been proven to be effective for the control of colorectal cancer (CRC). The target of CRC screening is shifting from CRC to colorectal neoplasia (CN), the precursors of CRC. Based on the the latest national guideline, the Consensus of Screening for CRC and CN, and the recent research of precursors both at home and abroad. This paper summarizes the progress in the research of risk factors, risk prediction model, screening strategy optimization, colonoscopy quality control, sessile serrated adenoma identification and follow up as well as the recognition of precursors.


Research trends in Jiang-flavor baijiu fermentation: From fermentation microecology to environmental ecology.
Chinese baijiu is one of the six major distilled spirits worldwide and is widely enjoyed because of its unique flavor. Among typical baijiu, Jiang-flavor baijiu is gaining popularity. However, the fermentation mechanisms of baijiu remain unclear due to its open inoculation environment and complex brewing process. In recent years, advances in high-throughput sequencing and multi-omics technologies have yielded meaningful information regarding fermentation microbiome. Therefore, this paper reviews recent developments in the investigation of the diversity, stability, and metabolism of the Jiang-flavor baijiu microbial community. Furthermore, the importance of protecting the ecology of the production environment is proposed based on the putative contribution of environmental factors to the fermentation microbiome and baijiu characteristics. Finally, this paper discusses current research challenges that need to be addressed, including the limitations of sequencing technologies and difficulties unveiling the mechanisms of microbial interaction between the fermentation microbiome and the environmental ecology. The findings of this review will promote further understanding of the Jiang-flavor baijiu fermentation process and provide valuable information for the research and development of traditional baijiu and other naturally fermented foods. PRACTICAL APPLICATION: Baijiu, a transparent strong alcoholic drink, is the world's largest consumed and the most valuable spirit in the market. However, the fermentation mechanisms of baijiu remain unclear due to its open inoculation environment and complex brewing process. Therefore, if we can summarizes the current advances and research challenges of microbial fermentation in baijiu, it will deepen the reader's understanding of the complex fermentation process and fermentation mechanism in baijiu. Furthermore, based on the putative contribution of environmental factors to the fermentation process, the importance of protecting the ecology of the production environment is proposed in future research trends, which will provide valuable information for the research and development of other traditional naturally fermented foods. This will not only achieve breakthroughs in academic value, but also bring higher practical value to fermented foods.


Nationally representative levels of selected volatile organic compounds in Canadian residential indoor air: population-based survey.
A comprehensive, population-based national indoor air survey was conducted in 2009-2011 in Canada. A total of 84 volatile organic carbons (VOCs) from 3218 houses, 546 apartments, and 93 other dwelling types were measured using passive sampling followed by thermal desorption GC/MS. A total of 12 VOCs were measured in both this study and the 1992 Canadian national study. Arithmetic means of VOCs in this study were 2-5 times lower than those in the 1992 study with the exception of a higher styrene level (1.13 μg · m(-3)). Comparing the geometric means of the 24 VOCs showed that levels for the VOCs in this study were comparable to those reported in Europe. They were generally within a factor of 2; 1,4-dichlorobenzene (0.21 μg · m(-3)) and 1,2,4-trimethylbenzene (0.51 μg · m(-3)) were noticeably lower in this study than in the European studies. There were 47 VOCs detected in more than 50% of Canadian households; 33 of them were higher in houses than in apartments for all nonsmoking homes, while only 4 were lower in houses than in apartments. A total of 11 of 47 VOCs were higher in smoking homes compared to nonsmoking homes, while the rest had similar levels. Principal component analysis identified several groups of VOCs with possible common sources.


Single molecule spectroscopy studies of diffusion in mesoporous silica thin films.
Single molecule spectroscopy is applied in studies of diffusion and surface adsorption in sol-gel-derived mesoporous silica thin films. Mesoporous films are obtained by spin casting surfactant-templated sols onto glass substrates. Small-angle X-ray diffraction results are consistent with hexagonally ordered mesophases in as-synthesized (i.e., surfactant-containing) films. Upon calcination, a 30% contraction and disordering of these structures occurs. Nile Red is used as a fluorescent probe of both the as-synthesized and calcined films. It is loaded into the samples at subnanomolar levels either prior to spin casting or after calcination. Fluorescence imaging and single-point fluorescence time transients show the dye molecules to be relatively mobile in the as-synthesized samples. In contrast, the molecules appear entrapped at fixed locations in dry calcined films. In calcined films rehydrated under high humidity conditions, the Nile Red molecules again become mobile. Time transients obtained from the as-synthesized and rehydrated samples provide clear evidence for frequent reversible adsorption of the dye to the silica surfaces. Autocorrelations of the time transients provide quantitative data on the mean diffusion coefficients (D = 2.4 x 10(-10) and 2.6 x 10(-10) cm2/s) and mean desorption times (1/k = 25 and 40 s) for the as-synthesized and rehydrated films, respectively. The results prove both water and surfactant play important roles in governing matrix interactions and mass transport.


Serious infections under treatment with TNF-alpha antagonists compared to traditional DMARDs in patients with rheumatoid arthritis.
Biological treatments aiming to neutralize TNF-alpha (tumour necrosis factor alpha) (infliximab, adalimumab and etanercept) are increasingly used to treat rheumatoid arthritis (RA). Although increased frequency has not been observed in randomized clinical trials with TNF-alpha antagonist agents, postmarketing surveillance suggests that infections might be serious consequences of these therapies. Our aim was to compare infections in patients with RA under treatment with disease-modifying antirheumatic drugs (DMARDs) and TNF-alpha antagonists in a university outpatient rheumatology clinic in Turkey. A total of 130 RA patients treated with DMARDs and 48 treated with TNF-alpha antagonists were analysed for the incidence of infections. Patients taking TNF-alpha antagonists were also reviewed for infections before these therapies. The incidence of serious infections was 7/100 patient-years before TNF-alpha antagonists and 8.6/100 patient-years in DMARDs group. The incidence rose to 17/100 patient-years during therapy with TNF-alpha antagonists. In patients with RA on routine follow-up, treatment with TNF-alpha antagonists seems to carry an increased risk of infections compared to traditional DMARDs.


[The development of biosimilars in oncology].
With the extensive application in clinical practice, biological medicine plays a significant role in both treatment and supportive care in oncology. With the expiration of original drug patents, biosimilars emerge. The biosimilars are defined as biological drugs that are be highly similar but not identical to the biological reference. Their development and evaluation procedure are different from those of small molecular chemical generics. Biosimilars are expected to reduce the health care costs worldwide. The booming developments of biosimilars, such as rituximab, trastuzumab and bevacizumab in medical oncology can optimize the clinical strategies, offer patients more treatment options and reduce the medical expenditure. In this article, we review the advances in the field of biosimilars, especially focus on the challenges and opportunities of biosimilars in clinical oncology.


Role of PET imaging in adaptive radiotherapy for lymphoma.
Positron emission tomography/Computed tomography (PET/CT) is an essential part of modern radiotherapy for patients with lymphoma. PET/CT can be used to adapt treatment algorithms in Hodgkin lymphoma, reserving consolidation radiotherapy for patients with residual fluoro-D-glucose (FDG) avidity after treatment with intensive chemotherapy such as escalated BEACOPP and limiting the need for radiotherapy for some patients with complete metabolic response on PET if radiotherapy may be associated with increased toxicity. More importantly, PET/CT is now mandatory to define sites of initial disease for radiotherapy planning where smaller volumes are to be used rather than historical extended field treatments, such as mantle radiotherapy or even involved field radiotherapy. Involved node radiotherapy (INRT) treats only the initially involved nodes and is possible when the pretreatment PET/CT scan has been performed in the radiotherapy treatment position. Involved site radiotherapy (ISRT) builds in a margin for uncertainty when a pretreatment PET/CT is available, but has not been performed in the radiotherapy treatment position. Studies suggest that PET/CT changes radiotherapy volumes in approximately one third of patients by mapping the extent of initial disease better than using CT alone. PET/CT has also been used to adjust radiotherapy dose for patients who may be at increased risk of radioresistance, by virtue of residual FDG avidity post chemotherapy or patients with relapsed disease. This article will discuss the role of PET in selecting patients for radiotherapy, its influence on the choice of target volume and radiotherapy dose and the practicalities of how PET/CT scanning is incorporated into the radiotherapy planning process.


Geostatistical interpolation model selection based on ArcGIS and spatio-temporal variability analysis of groundwater level in piedmont plains, northwest China.
Based on the geo-statistical theory and ArcGIS geo-statistical module, datas of 30 groundwater level observation wells were used to estimate the decline of groundwater level in Beijing piedmont. Seven different interpolation methods (inverse distance weighted interpolation, global polynomial interpolation, local polynomial interpolation, tension spline interpolation, ordinary Kriging interpolation, simple Kriging interpolation and universal Kriging interpolation) were used for interpolating groundwater level between 2001 and 2013. Cross-validation, absolute error and coefficient of determination (R(2)) was applied to evaluate the accuracy of different methods. The result shows that simple Kriging method gave the best fit. The analysis of spatial and temporal variability suggest that the nugget effects from 2001 to 2013 were increasing, which means the spatial correlation weakened gradually under the influence of human activities. The spatial variability in the middle areas of the alluvial-proluvial fan is relatively higher than area in top and bottom. Since the changes of the land use, groundwater level also has a temporal variation, the average decline rate of groundwater level between 2007 and 2013 increases compared with 2001-2006. Urban development and population growth cause over-exploitation of residential and industrial areas. The decline rate of the groundwater level in residential, industrial and river areas is relatively high, while the decreasing of farmland area and development of water-saving irrigation reduce the quantity of water using by agriculture and decline rate of groundwater level in agricultural area is not significant.


Efficacy of contrast-enhanced ultrasonography in radiofrequency ablation for hepatocellular carcinoma.
Local recurrence after radiofrequency ablation (RFA) is a major problem that needs to resolved to increase the survival rate of hepatocellular carcinoma (HCC). CE-US with Sonazoid(®), the second-generation contrast media, can detect smaller HCC lesions and the detection rate of ultrasonically unrecognized hypervascular HCC was improved by CE-US. The aim of the present study was to evaluate the role of CE-US with Sonazoid(®) in improving radicality and reducing local recurrence after RFA for HCC. A total of 102 nodules treated by RFA at our hospital from January 2006 to October 2009 were enrolled: 31 nodules were treated without CE-US, since CE-US was not yet available (Group A), and 71 nodules were treated with a combination of RFA and CE-US with Sonazoid(®) (Group B). The clinical characteristics (sex, virus marker, Child-Pugh grade, with or without transcatheter arterial infusion chemotherapy with lipiodol, and T factor) did not differ significantly between group A and group B. Mean age was significantly older and tumor size was significantly larger in group B. Group B had significantly better radicality compared with group A. The non-local recurrence rate was significantly higher in group B as compared with group A. CE-US with Sonazoid(®) greatly helps to improve RFA efficacy in HCC treatment. We suggest that the ability of CE-US with Sonazoid(®) to detect an accurate area of HCC before RFA and to immediately detect a residual tumor during RFA might contribute to an increase of the radicality and reduction of local recurrence after RFA.


[Adsorption and coprecipitation of dissolved metals with jarosite under conditions simulating sewage sludge bioleaching].
The inoculation of Acidithiobacillus ferrooxidans and the addition of Fe2+ as their substrates accelerated the solubilization of Zn, Cu and Cr from sewage sludge. However, a decrease in Cu removal from 91% to 60% with time elapse could be observed in the late process, which appeared simultaneously with the formation of jarosite resulting from hydrolysis of Fe3+. The tested jarosite was synthesized by using bacterial oxidation of Fe2+ by resting A. ferrooxidans in acid solution (pH 2.5) under conditions stimulating sludge bioleaching. Adsorption edge measurement showed that only less than 9% of Cu2+ was adsorbed onto jarosite in the pH range of 2.0-2.5, indicating that adsorption mechanism could not explain fully re-sorption of Cu2+ (about 31%) in the anaphase of bioleaching process. In the coprecipitation studies, when jarosite was precipitated in the presence of Cu2+ (10 mg x L(-1)), a significant amount of Cu (44.6%) was incorporated into the precipitate. Coprecipitation of jarosite with Cu2+ was the predominant process by which soluble Cu was partially re-sorpted by jarosite in the anaphase of bioleaching process.


[Preclinical and clinical researches of Denileukin Diftitox (Genetical Recombination) (Remitoro®), a novel agent for T-cell lymphoma].
Denileukin Diftitox (DD) is a recombinant fusion protein of diphtheria toxin (DT) fragments and human interleukin-2 (IL-2). DD binds to IL-2 receptor (IL-2R) expressed on tumor cells and is taken up into the cells. Subsequently, DT fragments with adenosine diphosphate ribosylation enzyme inhibit protein synthesis, then ultimately trigger cell death. DD binds to both high- and intermediate-affinity IL-2Rs via IL-2 domain and inhibits growth of human T-cell lymphomas cell lines. E7777, which contains DD as an active component, has improved purity and an increased percentage of active monomer compared with the approved drug E7272 (ONTAK in the US, not approved in Japan). In the phase I clinical study in Japanese patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), the maximum tolerated dose and recommended dose of E7777 were 9 μg/kg/day (administered on Days 1-5 of each cycle) based on the evaluation of dose-limiting toxicity. In the phase II clinical study, the objective response rate was 36.1%, showing comparable efficacy to existing therapies. E7777 showed anti-tumor activity observed across the range of CD25 expression. Grade 3 or higher adverse events (AE) occurred in 94.6%, and serious AE such as capillary leak syndrome and rhabdomyolysis were reported. Therefore, safety monitoring activities have been continued along with alerting related events. Based on these results, E7777 obtained a new drug approval in Japan in March 2021 for the indication of relapsed or refractory PTCL/CTCL.


Functional properties of Na,K-ATPase, and their structural implications, as detected with biophysical techniques.
A full understanding of the molecular mechanism of ion transport and energetics of the Na,K-ATPase will require both structural and functional data. During recent years biophysical methods have provided a number of important pieces of information on ion binding and release and the charge transfer process. This allows the formulation of kinetic models of the transport process. Although a breakthrough has not been obtained due to the lack of detailed knowledge on the three-dimensional structure with a resolution high enough to identify the ion-binding sites and the transport pathway, the functional information has structural implications that create constraints on possible mechanisms of active transport. Here we describe briefly contributions of some biophysical methods to our conceptual understanding of the ion transport process.


Transcatheter aortic and mitral valve implantations for failed bioprosthetic heart valves.
Restoring degenerated bioprosthetic valves by transcatheter valve implantation may obviate the need for redo surgery in carefully selected patients. We present our initial experience with valve-in-valve (VIV) procedures for failed aortic and mitral bioprosthetic valves. Data were collected for all patients who underwent VIV procedures at a tertiary medical center (n = 6). Findings were analyzed and compared with those for transcatheter valve implantation in native valves at the same center during the last 3 years (n = 84). Six patients of mean age 78.3 ± 13.8 years (range, 51-87) underwent VIV procedures with the CoreValve (n = 4) or Edwards-SAPIEN device (n = 2). Four (66%) had a failed prosthetic aortic valve, and 2 (33%) had a failed prosthetic mitral valve. Regurgitation accounted for valve failure in 83.3% of the VIV group versus 1.2% of the comparison group (p < 0.001). Procedural success and 30-day survival rates were 100%. Patient functional class improved significantly from 0% class I/II, 50% class III, and 50% class IV before the procedure to 66% class I, 33% class II, and 0% class III/IV after (p < 0.001). This preliminary experience demonstrates that in carefully selected cases, transcathether valve implants can be safely and effectively deployed in stenotic and/or regurgitant degenerated bioprosthetic valves. Further evaluations in larger series are needed.


Numerical and experimental analysis of balloon angioplasty impact on flow hemodynamics improvement.
The paper focuses on the numerical and experimental evaluation of the fluid flow inside chosen fragments of blood vessels. In the first stage of the study, the experimental tests were conducted using a research test stand, designed to be used in this evaluation. The study evaluated the blood flow through a silicone vessel with an implanted coronary stent. The PIV method was used in order to visualize the flow vectors inside a silicone vessel. Deformed vessel geometry implemented for computational fluid dynamics purposes was obtained owing to a non-linear simulation of the stent expansion (angioplasty process) in a silicone vessel. Additionally, a vessel model with a statistical 55% area stenosis and an irregular real vessel with an atherosclerotic plaque were also subjected to analysis from the hemodynamic flow point of view. A vessel with a statistical stenosis was also used to simulate the angioplasty process, which resulted in obtaining a flow domain for the vessel with an atherosclerotic plaque after the stent implantation. For each case, distributions of parameters such as OSI or TAWSS were also analyzed and discussed. The areas of low TAWSS values appear close to the stent struts. Stents with increased diameters, compared to the normal vessel diameter, create a higher risk of occurrence of the areas with low WSS values. Excessive stent deformation can cause inflammation by injuring the vessel and can initiate the restenosis and thrombotic phenomena through the increased vessel diameter.


Perspectives on child diarrhoea management and health service use among ethnic minority caregivers in Vietnam.
In Vietnam, primary government health services are now accessible for the whole population including ethnic minority groups (EMGs) living in rural and mountainous areas. However, little is known about EMGs' own perspectives on illness treatment and use of health services. This study investigates treatment seeking strategies for child diarrhoea among ethnic minority caregivers in Northern Vietnam in order to suggest improvements to health services for EMGs and other vulnerable groups. The study obtained qualitative data from eight months of field work among four EMGs in lowland and highland villages in the Northern Lao Cai province. Triangulation of methods included in-depth interviews with 43 caregivers of pre-school children (six years and below) who had a case of diarrhoea during the past month, three focus group discussions (FGDs) with men, and two weeks of observations at two Communal Health Stations (CHGs). Data was content-analyzed by ordering data into empirically and theoretically inspired themes and sub-categories assisted by the software NVivo8. This study identified several obstacles for EMG caregivers seeking health services, including: gender roles, long travelling distances for highland villagers, concerns about the indirect costs of treatment and a reluctance to use government health facilities due to feelings of being treated disrespectfully by health staff. However, ethnic minority caregivers all recognized the danger signs of child diarrhoea and actively sought simultaneous treatment in different health care systems and home-based care. Treatments were selected by matching the perceived cause and severity of the disease with the 'compatibility' of different treatments to the child. In order to improve EMGs' use of government health services it is necessary to improve the communication skills of health staff and to acknowledge both EMGs' explanatory disease models and the significant socio-economic constraints they experience. Broader health promotion programs should address the significant gender roles preventing highland mothers from seeking health services and include family elders and fathers in future health promotion programs. Encouraging existing child health care practices, including continued breastfeeding during illness and the use of home-made rehydration solutions, also present important opportunities for future child health promotion.


[Non-invasive determination of the quantity of pleural effusion and evaluation of the beneficial effect of pleuracentesis in patients with acute exacerbation of chronic congestive heart failure].
A non-invasive method to determine the quantity of pleural effusion and to evaluate the beneficial effect of pleuracentesis in patients with acute exacerbation of chronic congestive heart failure was evaluated. Twenty-three patients with pleural effusion due to acute exacerbation of chronic congestive heart failure were studied. The angle (x) formed by the diaphragm and lung (right side) or pericardium (left side) was measured by ultrasonography in the sitting position using the subscapular approach. Pleuracentesis was then performed in 15 patients, and the quantity of aspirated pleural effusion (y) was measured and compared with the angle x. There was significant relationship between y and x: y = 0.125 x 10(0.017x) (r = 0.77, p < 0.01). The 18 patients with more than 500 ml of estimated one-sided pleural effusion were divided into two groups; the nonpleuracentesis group (n = 8) and the pleuracentesis group (n = 10). The intravenous furosemide dose per increased body weight, and the term of oxygen supply and time to disappearance of edema were compared between the two groups. Intravenous furosemide dose was lower (p < 0.05) and the term of oxygen supply was shorter in the pleuracentesis group than in the nonpleuracentesis group (p < 0.05), whereas time to disappearance of edema was not significantly different. This non-invasive method can estimate the quantity of pleural effusion, and pleuracentesis had beneficial effect on patients with pleural effusion of greater than 500 ml (the angle x > 35 degrees ) in patients with acute exacerbation of chronic congestive heart failure.


Critical phenomena on k-booklets.
We define a "k-booklet" to be a set of k semi-infinite planes with -∞<x<∞ and y≥0, glued together at the edges (the "spine") y=0. On such booklets we study three critical phenomena: self-avoiding random walks, the Ising model, and percolation. For k=2, a booklet is equivalent to a single infinite lattice, and for k=1 to a semi-infinite lattice. In both these cases the systems show standard critical phenomena. This is not so for k≥3. Self-avoiding walks starting at y=0 show a first-order transition at a shifted critical point, with no power-behaved scaling laws. The Ising model and percolation show hybrid transitions, i.e., the scaling laws of the standard models coexist with discontinuities of the order parameter at y≈0, and the critical points are not shifted. In the case of the Ising model, ergodicity is already broken at T=T_{c}, and not only for T<T_{c} as in the standard geometry. In all three models, correlations (as measured by walk and cluster shapes) are highly anisotropic for small y.


Pedobacter aquatilis sp. nov., isolated from drinking water, and emended description of the genus Pedobacter.
A Gram-negative, rod-shaped, non-spore-forming bacterium (strain AR107(T)) was isolated from the drinking water distribution system of Seville (Spain). A polyphasic taxonomic study of the isolate resulted in its identification as a member of the genus Pedobacter. On the basis of 16S rRNA gene sequence comparisons, strain AR107(T) was shown to belong to the phylum Bacteroidetes, being related to members of the genus Pedobacter. It showed 95.2 % sequence similarity with respect to the type strains of Pedobacter heparinus and Pedobacter piscium, and 94.1 % similarity with respect to the type strain of Pedobacter himalayensis. The predominant fatty acids were iso-C(15 : 0), iso-C(17 : 0) 3-OH and summed feature 3 (iso-C(15 : 0) 2-OH and/or C(16 : 1)omega7c), which supports the affiliation of strain AR107(T) to the genus Pedobacter. The DNA G+C content of this strain was 38 mol%. On the basis of the phenotypic, phylogenetic and genotypic results, strain AR107(T) represents a novel species, for which the name Pedobacter aquatilis sp. nov. is proposed. The type strain is AR107(T) (=CCM 7347(T)=CECT 7114(T)=JCM 13454(T)).


Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models.
Pain and post-herpetic neuralgia (PHN) are common and highly distressing complications of herpes zoster that remain a significant public health concern and in need of improved therapies. Zoster results from reactivation of the herpesvirus varicella zoster virus (VZV) from a neuronal latent state established at the primary infection (varicella). PHN occurs in some one fifth to one third of zoster cases with severity, incidence, and duration of pain increasing with rising patient age. While VZV reactivation and the ensuing ganglionic damage trigger the pain response, the mechanisms underlying protracted PHN are not understood, and the lack of an animal model of herpes zoster (reactivation) makes this issue more challenging. A recent preclinical rodent model has developed that opens up the potential to allow the exploration of the underlying mechanisms and treatments for VZV-induced pain. Rats inoculated with live cell-associated human VZV into the hind paw reliably demonstrate thermal hyperalgesia and mechanical allodynia for extended periods and then spontaneously recover. Dorsal root ganglia express a limited VZV gene subset, including the IE62 regulatory protein, and upregulate expression of markers suggesting a neuropathic pain state. The model has been used to investigate treatment modalities and aspects of pain signaling and is under investigation by the authors to delineate VZV genetics involved in the induction of pain. This article compares human zoster-associated pain and PHN to the pain indicators in the rat and poses important questions that, if answered, could be the basis for new treatments.


Dynamic combinatorial chemistry.
Dynamic combinatorial chemistry is based on the reversible combination of initial building blocks to form dynamic combinatorial libraries. It has recently emerged as an efficient strategy to detect and to evaluate affinity between the library products and a target molecule. In this review, examples from various fields of chemistry and biochemistry are presented and extensively discussed. The last section deals with the practical aspects for implementing this approach.


Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity.
Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin.


Control of Pyrophosphated-Fructose-6-Phosphate 1-Phosphotransferase Activity in the Cotyledons of Citrullus lanatus.
After initiation of radicle elongation, the pyrophosphate:d-fructose-6-phosphate 1-phosphotransferase (PFP) activity sharply increases in the cotyledons of Citrullus lanatus. Removal of the radicle early during incubation prevents the increase in PFP activity in the cotyledons evident in the control. Removal of the radicle at any stage after germination results in a decrease in PFP activity in the cotyledons. Application of kinetin (0.5 micromolar) or 2-chlorophosphonic acid (0.1 micromolar) to isolated cotyledons replaces the effect of the radicle. Gibberellic acid (0.09 micromolar GA(3)) also partially mimics the presence of the radicle. Anaerobic conditions, as well as cycloheximide application (0.18 micromolar) to intact embryos or to kinetin and ethrel treated isolated cotyledons prevent the increase in PFP activity evident in the control.


Analysis of human immunodeficiency virus type 1 nef gene sequences among inmates from prisons in China.
To provide the hard-won information on HIV-1 polymorphism from inmates in prison and to study the genetic variation of HIV-1 strains, we analyzed the characterization of the nucleotide and corresponding protein sequences of naturally occurring nef sequences derived from 16 HIV-1-positive inmates from prisons in China. Nested PCR and DNA sequencing were used to determine nef sequences in peripheral blood mononuclear cells. Phylogenetic analysis revealed a distribution of the viral sequences among subtype B, CRF_BC, and CRF_AE, with subtype B accounting for more than half of the genotypes. When compared with the consensus sequence, a certain amino acid sequence variability was observed. However, most of the described nef functional motifs were relatively well conserved in the majority of the sequences analyzed. Our results indicate that HIV-1 strains found in our study subjects may have a common origin and the description of motifs will produce important information for further studies of nef function.


Adhesion of Corynebacterium pilosum by pili to epithelial cells of bovine vulva.
Piliated (P+) and nonpiliated (P-) clones of Corynebacterium pilosum were selected, and their adhesion to the epithelial cells of the bovine vulva and vaginal vestibule was examined. The number of P+ bacteria of C pilosum that adhered to vulval epithelial cells was greater than that of P- bacteria. The adhesion of P+ bacteria, but not P- bacteria, to the epithelial cells was inhibited by the antipilus antiserum; therefore, the adhesion of C pilosum to the epithelial cells of the vulva was primarily dependent on the pili. The number of C pilosum that adhered to the epithelial cells of the bovine vulva and of the vaginal vestibule increased by decreasing the pH.


Operative Treatment of Anterior Shoulder Instability A Network Meta-Analysis.
Traumatic anterior shoulder instability is a common clinical problem among athletic populations, with several surgical treatment options available. The optimal treatment remains undetermined. Currently the main current treatment options are the Latarjet procedure or open or arthroscopic Bankart repair. The purpose of this study was to network meta-analyze the recent evidence to ascertain if the open Latarjet procedure and open or arthroscopic Bankart repair result in lower recurrence rates and subsequent revision procedures. The results were ranked with the P-score. A literature search was performed based on the PRISMA guidelines. Cohort studies comparing any of the open Latarjet procedure and open or arthrosopic Bankart repair for anterior shoulder instability were included. Clinical outcomes were compared using a frequentist approach to network meta-analysis, with statistical analysis performed using R. Twenty-nine studies with 2,474 patients were included. The open Latarjet procedure resulted in lower rates of recurrent instability and revisions due to recurrence compared to both open and arthroscopic Bankart repairs. The open Latarjet procedure resulted in the highest rate of return to play. However, the open Latarjet procedure also resulted in the highest complication rate. Our network meta-analysis found the open Latarjet procedure had the lowest recurrence rates, lowest revisions rates, and highest rates of return to play in the surgical treatment of anterior shoulder instability. However, the Latarjet procedure has been shown to result in a higher complication rate, which needs to be considered when deciding which stabilization procedure to perform.


[Development of Efficient Synthetic Method for Tautomeric Dihydropyrimidines and Analysis of Their Functionality].
I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by 1H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC50 value of 341 nM.