[Global transition in health].
Global epidemiological transition reflected in changed patterns of death and diseases was first described by Omran; decreasing death and disease rates from infectious diseases, particularly in children and the young, are followed by decreased fertility rate and increased longevity, and by degenerative, and man-made diseases in ageing populations. Omran could not foresee the HIV/AIDS pandemic or the dramatic fall in longevity and fertility in, for example, Russia. But his model remains of value for health planners and politicians. We advocate for research in the interplay between diseases, populations and systems in a world in fast transition.


[The baseline EEG traits and the induced EEG changes by chronic antidepressant medication in patients with major depression. Early prediction of clinical outcomes solely based on quantification and mapping of EEG].
Forty patients of typical major depression (DSM-III-R) have been adopted for the present study. Hamilton Rating Scale for Depression (HAM-D) was used for the clinical assessment of depressive symptoms, and the patients were followed up at least for four weeks. All the patients were confirmed to be right-handed. The baseline EEGs were compared with age-matched normal subjects (N = 38; all right handed). The differences between depressive patients and normal subjects were less theta activity, more fast activity in anterior part of both hemispheres and in posterior part of the right hemisphere in the depressive patients than in the normal subjects. As a preliminary study, amitriptyline 25 mg was single dose administered and EEGs were recorded before and 1, 3 and 6 hours after the first drug administration in normal male volunteers (N = 6; right-handed). EEG changes of after the medication from the baseline were significant increase of theta and decrease of alpha activity, increase of beta activity was not significant changes. Particularly EEG changes of after 3 hour's administration showed the typical thymoleptic reaction type. EEG changes in patients from the baseline EEG after the first medication were similar to normal subjects. The patients (N = 21) were divided into two groups based on the changes of HAM-D score during four-weeks' treatment; therapy-responsive and therapy-resistant groups. EEG changes after the first single dose administrations in the former were compared with the latter of two patients' groups. Both groups have shown an increase of theta and a decrease of alpha activity. There was more evident alpha increase in therapy-responsive patients than in therapy-resistant ones. However, there were significant differences in amitriptyline-induced EEG changes particularly in beta frequency band; therapy-responsive group showed an increase of beta activity, while therapy-resistant showed no or little change. Using discriminant analysis, the overall hitting ratio of the EEG prediction for therapy-responsive and therapy-resistant group was calculated as 85% at 3 hours after the initiation of antidepressant medication. If EEG mapping, particularly the mapping of differences between pre- and post-drug EEGs, is used to illustrate the EEG responses against antidepressant medication, it will be quite useful to discriminate therapy-resistant patients from therapy-responsive ones in very early stage of the drug treatment.


The Anti-Migraine Effects of M2000 (β-D-Mannuronic Acid) on a Patient with Rheumatoid Arthritis: Case Report.
Rheumatoid arthritis (RA) and migraine are both common disorders which are caused by a faulty immune system and autonomic nervous system dysfunction, respectively. Although current treatment outlook has shown a great improvement in these two diseases, however many side effects have been reported. We reported a case of 43-years-female that has suffered from rheumatoid arthritis for 3 years with a 6 years history of migraine. She had used different types of medication for both rheumatoid arthritis and migraine but during these 6 years no improvement had been observed and even migraine progression in this patient became worse. She was admitted to the hospital for 12 weeks follow-up to evaluate the effect of β-D-mannuronic acid (M2000) on her RA disease. During 12 weeks of M2000 therapy, the signs and symptoms of migraine along with RA indices including Disease Activity Score (DAS28), simple disease activity index (SDAI) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP) and blood determinants were measured. The patient achieved a strong clinical improvement after 12 weeks of M2000 therapy in DAS28, SDAI and laboratory parameters. Moreover, M2000 showed a significant effect on the severity and the duration of migraine pain as well as times of migraine attack. In the present case, both rheumatoid arthritis and migraine as two different inflammatory diseases were diagnosed. Therefore, reducing the inflammation could be a valuable target to decrease the signs and symptoms of migraine and rheumatoid arthritis and help to the treatment process. M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property is able to treat migraine in addition to its potent efficacy on treatment of rheumatoid arthritis.


Response of Paracoccidioides lutzii to the antifungal camphene thiosemicarbazide determined by proteomic analysis.
To perform the proteomic profile of Paracoccidioides lutzii after treatment with the compound camphene thiosemicarbazide (TSC-C) in order to study its mode of action. Proteomic analysis was carried out after cells were incubated with TSC-C in a subinhibitory concentration. Validation of the proteomic results comprised the azocasein assay, western blot and determination of the susceptibility of a mutant to the compound. Proteins related to metabolism, energy and protein fate were regulated after treatment. In addition, TSC-C reduces the proteolytic activity of the protein extract similarly to different types of protease inhibitors. TSC-C showed encouraging antifungal activity, working as a protease inhibitor and downregulating important pathways impairing the ability of the fungi cells to produce important precursors.


Attentional disregulation: a benefit for implicit memory.
The authors investigated the effect of age and time of testing on the ability to control attention and addressed the possibility that older adults' susceptibility to distraction may sometimes facilitate performance on a later cognitive task. Using a modification of a G. Rees, C. Russell, C. D. Frith, and J. Driver (1999) procedure, the authors asked the participants to make same or different judgments on line drawings superimposed with task-irrelevant letter strings. Memory for the distractors was subsequently tested with an implicit memory task. Both older and young adults demonstrated greater memory for distractors at nonoptimal times of day than at optimal times of day; however, older adults showed considerably better memory for the distractors than did young adults.


Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics.
Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.


Delivering on the Promise of CLER: A Patient Safety Rotation That Aligns Resident Education With Hospital Processes.
Residency programs must provide training in patient safety. Yet, significant gaps exist among published patient safety curricula. The authors developed a rotation designed to be scalable to an entire residency, built on sound pedagogy, aligned with hospital safety processes, and effective in improving educational outcomes. From July 2015 to May 2017, each second-year resident completed the two-week rotation. Residents engaged the foundational science asynchronously via multiple modalities and then practiced applying key concepts during a mock root cause analysis. Next, each resident performed a special review of an actual adverse patient event and presented findings to the hospital's Special Review Committee (SRC). Multiple educational outcomes were assessed, including resident satisfaction and attitudes (postrotation survey), changes in knowledge via pre- and posttest, quality of the residents' written safety analyses and oral presentations (per survey of SRC members), and organizational changes that resulted from the residents' reviews. Twenty-two residents completed the rotation. Most components were rated favorably; 80% (12/15 respondents) indicated interest in future patient safety work. Knowledge improved by 44.3% (P < .0001; pretest mean 23.7, posttest mean 34.2). Compared to faculty, SRC members rated the quality of residents' written reviews as superior and the quality of the rated oral presentations as either comparable or superior. The reviews identified a variety of safety vulnerabilities and led to multiple corrective actions. The authors will evaluate the curriculum in a controlled trial with better measures of change in behavior. Further tests of the curriculum's scalability to other contexts are needed.


Spatiotemporal expression of Wnt3a during striated muscle complex development in rat embryos with ethylenethiourea-induced anorectal malformations.
Numerous patients with anorectal malformations (ARMs) continue to experience fecal incontinence and constipation following surgical procedures. One of the most important factors that influences defecation is the striated muscle complex (SMC). Wnt signaling regulates the expression of myogenic regulatory factors, which serve an important role in muscle development. Therefore, the present study aimed to investigate the expression pattern of Wnt3a protein (by immunohistochemistry and western blot analysis) and mRNA [by reverse transcription‑quantitative polymerase chain reaction (RT-qPCR)] in the SMC of ARM model rats that were exposed to ethylenethiourea. Immunostaining revealed that the expression of Wnt3a exhibits space‑ and time‑dependent changes in the developing SMC of ARM model rat embryos. Immunohistochemistry demonstrated that on embryonic day 17 (E17), Wnt3a‑positive cells were observed in the SMC in normal embryos, and expression levels gradually increased as the rat embryos developed. Similar changes in Wnt3a protein expression were detected in ARM model rat embryos; however, the expression of Wnt3a was significantly reduced compared with the normal rat embryos. Western blotting and RT‑qPCR also revealed lower expression levels of Wnt3a protein and mRNA, respectively, in the SMC of ARMs model rat embryos compared with normal rat embryos. These data revealed that the expression of Wnt3a in ARM embryos was notably reduced, indicating a potential role for Wnt3a in the maldevelopment of the SMC in patients with ARMs.


Solving multicomponent chiral separation challenges using a new SFC tandem column screening tool.
A tool for improved tandem column chiral supercritical fluid chromatography (SFC) method development screening was prepared by modification of a commercial analytical SFC instrument with two different software-controllable, six position high-pressure column selection valves, each controlling a bank of five different columns and a pass through line. The resulting instrument, which has the ability to screen 10 different individual columns and 25 different tandem column arrangements, is a useful tool for facilitating the screening of tandem column SFC arrangements for separation of complex mixtures of stereoisomers or other multicomponent mixtures. Strategies for optimal use of the instrument are discussed, and several examples of the use of the instrument in developing tandem SFC methods for resolution of multicomponent mixtures are presented.


Application of magnetic graphitic carbon nitride nanocomposites for the solid-phase extraction of phthalate esters in water samples.
Magnetic graphitic carbon nitride nanocomposites were successfully prepared in situ and used to develop a highly sensitive magnetic solid-phase extraction method for the preconcentration of phthalate esters such as di-n-butyl phthalate, butyl phthalate, dihexyl phthalate, and di-(2-ethyl hexyl) phthalate from water. The adsorption and desorption of the phthalate esters on magnetic graphitic carbon nitride nanocomposites were investigated and the parameters affecting the partition of the phthalate esters, such as adsorption, desorption, recovery, were assessed. Under the optimized conditions, the proposed method showed excellent sensitivity with limits of detection (S/N = 3) in the range of 0.05-0.1 μg/L and precision in the range of 1.1-2.6% (n = 5). This method was successfully applied to the analysis of real water samples, and good spiked recoveries over the range of 79.4-99.4% were obtained. This research provides a possibility to apply this nanocomposite for adsorption, preconcentration, or even removal of various carbon-based ring or hydrophobic pollutants.


Comparison of electron irradiation diets and gamma irradiation diets for reproductive effects on rats.
Rats were maintained on 50 kGy electron irradiation diets. Effects of the diets on reproductive performance of parents and developmental performance of fetuses (F1 and F2) were studied by comparison with data in rats maintained on gamma irradiation diets, as control animals, and the background data of our facility. As the result, no specific changes were observed in the group maintained on electron irradiation diets. Electron irradiation diets sterilized under the condition of 50 kGy irradiation in the present study, as well as the existing gamma irradiation diets, were found to be useful for breeding and nursing rats.


Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges.
Stable aneuploid genomes with nonrandom numerical changes in uneven ploidy ranges define distinct subsets of hematologic malignancies and solid tumors. The idea put forward herein suggests that they emerge from interactions between diploid mitotic and G0/G1 cells, which can in a single step produce all combinations of mono-, di-, tri-, tetra- and pentasomic paternal/maternal homologue configurations that define such genomes. A nanotube-mediated influx of interphase cell cytoplasm into mitotic cells would thus be responsible for the critical nondisjunction and segregation errors by physically impeding the proper formation of the cell division machinery, whereas only a complete cell fusion can simultaneously generate pentasomies, uniparental trisomies as well as biclonal hypo- and hyperdiploid cell populations. The term "somatic sex" was devised to accentuate the similarities between germ cell and somatic cell fusions. A somatic cell fusion, in particular, recapitulates many processes that are also instrumental in the formation of an abnormal zygote that involves a diploid oocyte and a haploid sperm, which then may further develop into a digynic triploid embryo. Despite their somehow deceptive differences and consequences, the resemblance of these two routes may go far beyond of what has hitherto been appreciated. Based on the arguments put forward herein, I propose that embryonic malignancies of mesenchymal origin with these particular types of aneuploidies can thus be viewed as the kind of flawed somatic equivalent of a digynic triploid embryo.


Different dependence of lithium and valproate on PI3K/PKB pathway.
Acute treatment with valproate (VPA) or lithium (Li+) protects cerebellar granule cells (CGC) against apoptosis induced by low potassium (K+) (5 mM). As the protection induced by VPA is absolutely dependent on insulin, in contrast to the observed effects of Li+, we decided to study the different role of the PI3K/PKB pathway in the neuroprotective effects of both drugs. We have studied the neuroprotection elicited by Li+ or VPA in cultures of rat CGC. We induced the apoptosis by switching to a medium with a low concentration of K+ or by adding C2-ceramide to the cultures. We studied the effect of Li+ and VPA on viability and on the regulation of the PI3K/PKB pathway. Insulin also protects against low K(+)-induced apoptosis in CGC, probably through its interaction with an insulin-like growth factor receptor. Moreover, whereas Li+ protects against the apoptosis induced by C2-ceramide, VPA cannot, probably due to the inhibition of protein kinase B (PKB) caused in this apoptotic stimulus. These results suggest that VPA protects against low K(+)-induced apoptosis by acting on the PI3K/PKB pathway; however, VPA does not affect the increase of PKB activity caused by insulin in these cells. The protection by Li+ is independent of this transduction pathway. Moreover, Li+ blocks the caspase 3 activation induced by low K+, whereas neither VPA nor insulin affects this activation.


SSBP3 Interacts With Islet-1 and Ldb1 to Impact Pancreatic β-Cell Target Genes.
Islet-1 (Isl1) is a Lin11, Isl1, Mec3 (LIM)-homeodomain transcription factor important for pancreatic islet cell development, maturation, and function, which largely requires interaction with the LIM domain-binding protein 1 (Ldb1) coregulator. In other tissues, Ldb1 and Isl1 interact with additional factors to mediate target gene transcription, yet few protein partners are known in β-cells. Therefore, we hypothesize that Ldb1 and Isl1 participate in larger regulatory complexes to impact β-cell gene expression. To test this, we used cross-linked immunoprecipitation and mass spectrometry to identify interacting proteins from mouse β-cells. Proteomic datasets revealed numerous interacting candidates, including a member of the single-stranded DNA-binding protein (SSBP) coregulator family, SSBP3. SSBPs potentiate LIM transcription factor complex activity and stability in other tissues. However, nothing was known of SSBP3 interaction, expression, or activity in β-cells. Our analyses confirmed that SSBP3 interacts with Ldb1 and Isl1 in β-cell lines and in mouse and human islets and demonstrated SSBP3 coexpression with Ldb1 and Isl1 pancreas tissue. Furthermore, β-cell line SSBP3 knockdown imparted mRNA deficiencies similar to those observed upon Ldb1 reduction in vitro or in vivo. This appears to be (at least) due to SSBP3 occupancy of known Ldb1-Isl1 target promoters, including MafA and Glp1r. This study collectively demonstrates that SSBP3 is a critical component of Ldb1-Isl1 regulatory complexes, required for expression of critical β-cell target genes.


Synthesis and application of thiocarbamates via thiol-dioxazolone modified Lossen rearrangement.
Thiocarbamates could be synthesized in green solvents via thiol-dioxazolone modified Lossen rearrangement under transition-metal free, additive free, and mild conditions. Polythiocarbamates were further prepared with excellent self-healing and shape-memory properties, showing great potential in the development of functional materials.


Vosaroxin in relapsed/refractory acute myeloid leukemia: efficacy and safety in the context of the current treatment landscape.
Treatment for acute myeloid leukemia (AML) generally consists of a combination of cytarabine and an anthracycline. Although induction therapy leads to complete remission (CR) for most patients, refractoriness to chemotherapy or relapse after initial response is associated with poor outcomes. The 1-year survival rates after first relapse have been reported at 29%, declining to 11% at 5 years. Prognosis is particularly poor among older patients whose higher prevalence of unfavorable cytogenetics and high frequency of comorbidities diminish their ability to tolerate intensive chemotherapy. There is no standard of care for relapsed/refractory (R/R) AML, and no new therapies have shown consistently superior outcomes in this setting in over two decades. Vosaroxin is an anticancer quinolone derivative (AQD) that was evaluated in combination with cytarabine for the treatment of R/R AML in the randomized, double-blind, placebo-controlled, phase III VALOR study (n = 711). Compared with placebo/cytarabine, the vosaroxin/cytarabine regimen demonstrated favorable CR rates and survival in patients ⩾60 years of age, with toxicities similar to other AML regimens. Here we review outcomes of recent studies of commonly used chemotherapy regimens for the treatment of R/R AML and evaluate the results of the VALOR trial in the context of the current treatment landscape.


Effects of antidepressants and antihistaminics on catalepsy induced by intracerebroventricular administration of histamine in mice.
The intracerebroventricular (icv) administration of histamine but not N-telemethylhistamine and 1-methyl-4-imidazole acetic acid induced catalepsy in mice. Histamine H1-receptor blockers such as cyproheptadine, mepyramine and diphenhydramine reduced histamine-induced catalepsy. However, astemizole which is known to be without central effects, did not reduce histamine-induced catalepsy. The icv pretreatment with histamine H2-receptor blockers, such as metiamide and cimetidine, also had no effect. Moreover, various antidepressants, both imipramine- and atypical-type drugs antagonized histamine-induced catalepsy to various degrees in this experiment. Thus, the induction of catalepsy by icv administration of histamine was mediated through histamine H1-receptors, and suggested that antidepressants reduced histamine-induced catalepsy via this mechanism. Histamine-induced catalepsy is a possible new animal model of depression which can also be used for evaluation of atypical antidepressants.


Paediatric environmental health history taking: why bother?
Environmental health history taking is often not part of standard medical history taking for clinical physicians. During recent years attention has been placed on home environments and asthma and allergies, high caloric intake and obesity and type 2 diabetes mellitus, yet environmental health history taking still remains relatively uncharted terrain for the clinical physicians of today. While the reasons for this are certainly varied, ignorance of environmental influences, ignorance of environmental pollutants, politics and prejudices will certainly play a role. We suggest a simple manner of environmental health history taking, and discuss the importance of the subject in our modern-day clinical practice.


[Suppurative hidradenitis].
An obese woman aged 18 years had been suffering for several years from axillary hidradenitis suppurativa. Repeated incision and drainage never gave lasting results and the patient became socially isolated. Hidradenitis suppurativa is a chronic suppurative inflammation of skin areas containing apocrine glands: the skin of the axillae, of the breasts and of the anogenital region. Treatment in the first instance consists of general hygienic measures. Pharmaceuticals used include antibiotics, antiandrogens and oestrogens. Surgery is performed when the condition is at an advanced stage, with cellulitis and scarring; ample excision is necessary to reduce the risk of recurrence. CO2 laser therapy is a new method of treatment that shows good results in incipient and advanced lesions.


Estimating inbreeding from the Faculty Office Registers, 1534-1540.
Estimates of inbreeding are rather scarce for British populations. A number of studies, especially of Scottish island populations, have focused on pedigree analysis, whilst others have used survey methods or inference from isonymy. By comparison with continental Europe, however, little is known of the historical development of inbreeding. This is undoubtedly due to the lack of evidence from dispensations to marry blood relatives, which are routinely available in the records of marriage of the Roman Catholic church. The paper uses as its data source the Faculty Office Registers, 1534-1540, which were the product of a new system of issuing dispensations following the Dispensations Act of 1533, and which are among the earliest administrative records of the Church of England, founded as a result of Henry VIII's breach with Rome. Dispensations are recorded in the Faculty Office until 1540, when all prohibitions on marriage beyond the proscribed relationships laid down in Leviticus were lifted. The data suggest surprisingly low levels of consanguineous marriage, including a lack of first-cousin marriages. These findings are discussed in terms of the reliability of the archive, and of the social and religious views attending marriage between blood relatives in the medieval and early modern periods.


Motivation to reduce alcohol consumption and subsequent attempts at reduction and changes in consumption in increasing and higher-risk drinkers in England: a prospective population survey.
To assess how far motivation to reduce alcohol consumption in increasing and higher-risk drinkers in England predicts self-reported attempts to reduce alcohol consumption and changes in alcohol intake during the following 6 months. This study used self-reported data from 2928 higher-risk drinkers in the Alcohol Toolkit Study (ATS): a series of monthly cross-sectional household surveys of adults aged 16+ years of age in England. Alcohol consumption was measured in an initial survey and in a 6-month telephone follow-up interview using the Alcohol Use Disorders Identification Test (AUDIT)-C questionnaire. Motivation was measured in the initial survey using the Motivation to Reduce Alcohol Consumption (MRAC) scale. Attempts to reduce alcohol consumption during the past 6 months were recorded at follow-up. Data were analysed using repeated-measures difference-in-differences and logistic regression models. Participants with higher initial motivation to reduce alcohol consumption were more likely to report that they had made an attempt to reduce consumption at follow-up [adjusted odds ratio (ORadj ) = 2.39, 95% confidence interval (CI) = 1.75-3.29]. There was an overall reduction in alcohol consumption between initial survey and follow-up (ORadj = 0.72, 95% CI = 0.65-0.79), but there was insufficient evidence of an additional effect of motivation to reduce consumption on subsequent changes in alcohol consumption, with the difference-in-differences effect instead suggesting an average increase (ORadj = 1.37, 95% CI = 1.00-1.88). Increasing and higher-risk drinkers in England who report greater motivation to reduce their consumption are more likely to report making an attempt to reduce during the next 6 months, but this may not be associated with a reduction in alcohol consumption.


Several synthetic chemicals inhibit progesterone receptor-mediated transactivation in yeast.
The human progesterone receptor (hPR) B-form and a progesterone-sensitive reporter were expressed in yeast and used to screen a library of synthetic chemicals for their ability to function as agonists or antagonists of hPR. The transcriptional activity of hPR was not increased in the presence of over 40 individual chemicals. Seven chemicals decreased progesterone-dependent activity in yeast. The most effective chemicals were 6-hydroxychrysene, 1-hydroxypyrene, 4-hydroxy, 2',4',6'-trichloro biphenyl, and 4-hydroxy, 2',3',4',5'-tetrachloro biphenyl. The decrease of progesterone-mediated transactivation strongly correlated with their displacement of [3H]progesterone from hPR. The absence of the hydroxyl group on the above chemicals completely abolished their inhibitory activity. The other chemicals which decreased progesterone activity were endosulfan II, endosulfan sulfate, and lindane. These chemicals did not inhibit [3H]progesterone binding, suggesting that they inhibit progesterone action by interacting with a region of hPR distinct from binding [3H]progesterone or by a mechanism independent of hPR. These results highlight the utility of yeast for screening hormonally-active chemicals. In addition, hydroxylation appears to be essential for the interaction of some chemicals with hPR.


The effect of RANTES on human sperm chemotaxis.
Follicular fluid (FF) is a powerful stimulator of human sperm hyperactivation and the acrosome reaction. FF causes sperm accumulation by way of chemotaxis. The chemoattractant in FF has not yet been identified in the human. It is well known that some types of chemokine such as RANTES (Regulated on Activation Normal T Expressed and Secreted Chemokine) exist in genital tract fluids (for example, FF, seminal plasma and uterine fluid). Few reports appear to exist concerning the direct effect of chemokines on the function of human sperm. The chemotactic effect of RANTES on human sperm were investigated by capillary and double-chamber assays, while the chemokinetic effect was investigated using computer-assisted sperm analysis. Both the capillary and double-chamber assays demonstrated a significant chemotactic effect of RANTES on human sperm. Anti-RANTES rabbit IgG partially neutralized the chemotactic effect of FF. In contrast, no statistically significant chemokinetic effect was observed in any motility parameter. Here, it was demonstrated that mRNA for the RANTES receptors CCR-1 and CCR-5 are present in human sperm. Furthermore, RANTES is involved in the chemotactic effect of FF in vitro.


Highly Engaged Video-Watching Pattern in Asynchronous Online Pharmacology Course in Pre-clinical 4th-Year Medical Students Was Associated With a Good Self-Expectation, Understanding, and Performance.
Online video-based learning is more common in higher education. Investigating students' viewing behaviors while watching online video lectures is essential for instructors to understand their learning status so that the course content, structure, and media selection can be improved continuously. The current study identified the engagement level of the learners based on their online video-watching behaviors, and tested the correlation between the engagement level and learning outcome. The action logs of watching online video lectures in 2020 Spring Pharmacology of the 4th-year medical students of the 6-year course and their feedbacks by questionnaires after each exam during the semester were provided anonymously. The data were analyzed and visualized for an efficient way to comprehend and interpret. To define the student's engagement level in his or her video-based learning journey, three viewing criteria, "Completion," "Pausing," and "Repeated watching" were identified. We evaluated the association between the engagement level and the students' learning outcomes, including their learning satisfaction, knowledge acquisition progresses based on assessment results, and the grades measured by the instructors. The graphs and the charts demonstrate whether the students allocated enough time to finish the video lectures (completion), paused for a while, then resumed the video (pausing), or replayed the specific sections of video content (repeated watching). The engagement level with video lectures, evaluated by pre-defined thresholds for "Completion," "Pausing," and "Repeated watching" had a positive correlation with the learning outcomes. We suggested that an engagement dashboard containing real-time visualized information on students' online video-watching behaviors can be developed to help instructors to monitor students' learning progress and improve teaching in a timely fashion. It can also help each student to re-feel the stimulation of peers, prompt self-monitoring, improve their learning attitudes and disciplines for better learning outcomes. This innovative way of assessing student's engagement during online video-based learning can also be used for quality assurance purposes.


The Cancer-Immune Set Point in Oesophageal Cancer.
Immunotherapy has achieved long-term disease control in a proportion of cancer patients, but determinants of clinical benefit remain unclear. A greater understanding of antitumor immunity on an individual basis is needed to facilitate a precision oncology approach. A conceptual framework called the "cancer-immune set point" has been proposed to describe the equilibrium between factors that promote or suppress anticancer immunity and can serve as a basis to understand the variability in clinical response to immune checkpoint blockade. Oesophageal cancer has a high mutational burden, develops from pre-existing chronic inflammatory lesions and is therefore anticipated to be sensitive to immune checkpoint inhibition. However, both tumour- and patient-specific factors including the immune microenvironment, the microbiome, obesity, and host genetics contribute to an immune set point that confers a lower-than-expected response to checkpoint blockade. Immunotherapy is therefore currently confined to latter lines of treatment of advanced disease, with no reliable predictive biomarker of response. In this review, we examine oesophageal cancer in the context of the cancer-immune set point, discuss factors that contribute to response to immunotherapeutic intervention, and propose areas requiring further investigation to improve treatment response.


Genetic susceptibility and the role of hypertension in diabetic nephropathy.
Evidence exists to suggest that some individuals with diabetes have a genetic predisposition to diabetic nephropathy. Cases of nephropathy cluster in families and a parental history of hypertension, cardiovascular disease and diabetes is more common in patients with diabetic nephropathy. Current evidence favours a role for hypertension in the genetic susceptibility to diabetic nephropathy. This review focuses on the recent evidence for genetic susceptibility, the role and mechanisms of hypertension in the predisposition to nephropathy and the potential of a novel sib-pair approach to identify susceptibility genes.


Theory of the Kapitza-Dirac diffraction effect.
We treat the Kapitza-Dirac diffraction effect observed recently by Batelaan et al. using a newly developed nonperturbative quantum-field scattering theory. Our theory shows that an electron beam passing perpendicularly through a focused standing light wave can produce diffraction patterns. Our theory predicts (1) the minimum value of the ponderomotive energy is (Planck's over 2 pi omega)(2)/m(e)c(2), (2) the critical laser intensity above which the first pair of electron diffraction peaks will occur, and (3) the existence of sidebands in the electron spectra separated far from the central band by a momentum of several hundred photons. Our theory provides a unified explanation of the experimental results of Bucksbaum et al. and Batelaan et al.


Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy.
Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.


Astronomical demonstration of an optical vortex coronagraph.
Using an optical vortex coronagraph and simple adaptive optics techniques, we have made the first convincing demonstration of an optical vortex coronagraph that is coupled to a star gazing telescope. We suppressed by 97% the primary star of a resolvable binary system, Cor Caroli. The stars had an angular separation of 1.9lambda/D at our imaging camera. The secondary star suffered no suppression from the vortex lens.


An outbreak of Cyclospora infection on a cruise ship.
In 2010, an outbreak of cyclosporiasis affected passengers and crew on two successive voyages of a cruise ship that departed from and returned to Fremantle, Australia. There were 73 laboratory-confirmed and 241 suspected cases of Cyclospora infection reported in passengers and crew from the combined cruises. A case-control study performed in crew members found that illness was associated with eating items of fresh produce served onboard the ship, but the study was unable conclusively to identify the responsible food(s). It is likely that one or more of the fresh produce items taken onboard at a south-east Asian port during the first cruise was contaminated. If fresh produce supplied to cruise ships is sourced from countries or regions where Cyclospora is endemic, robust standards of food production and hygiene should be applied to the supply chain.


Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma.
Purpose of this study has been the assessment of nuclear factor-kappaB (NF-kappaB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-kappaB activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm. In HMC and MMe cells, NF-kappaB nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor-alpha (TNF-alpha). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated. Here, we show that NF-kappaB activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-kappaB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo. Inhibition of NF-kappaB constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe.


[Assessment on anti-nociception and anti-inflammation pharmacodynamics of Asarum heterotropoides var. mandshuricum and Asarum sieboldii].
To assess the anti-nociception and anti-inflammation pharmacodynamics of Asarum heterotropoides var. mandshuricum and A. sieboldii. Both the writhing test and hot plate test were conducted to assess the anti-nociceptive effect of Asarum and Xylene-induced mouse ear edema was conducted to assess the anti-inflammatory effect of Asarum. Twelve samples of A. heterotropoides var. mandshuricum and A. sieboldii from different producing areas showed anti-nociceptive and anti-inflammatory effects. Specifically, 27% to 61% of the seven samples of A. heterotropoides var. mandshuricum showed anti-nociceptive effect and while 34% to 48% of A. sieboldi showed anti-nociceptive effect. The inflammatory inhibition rate of A. heterotropoides var. mandshuricum produced in six producing areas (38%-57%) is higher than that of A. heterotropoides var. mandshuricum produced in five producing areas (34%-48%). The same kind of Asarum produced in different areas showed significant differences. A. heterotropoides var. mandshuricum produced in Jilin province (38%-57%) showed better anti-nociceptive effect than sample produced in Heilongjiang province (34%) in writhing test. A. heterotropoides var. mandshuricum produced in Heilongjiang (43%) province showed a better anti-nociceptive effect than samples produced in Liaoning province (29%-36%) in hot plate test. A. sieboldii produced in Shaanxi province (47%-49%) showed a better anti-nociceptive effect than samples produced in Hubei province (40%) in writhing test. A. sieboldii produced in Shaanxi province (45%-59%) showed better anti-nociceptive effect than samples produced in Chongqing (40%) in hot plate test. A. heterotropoides var. mandshuricum produced in Jilin province (51%-63%) showed better anti-inflammatory effect than samples produced in Heilongjiang province (50%). In totality, the results from analysis of geoherbalism showed that famous-region A. heterotropoides var. mandshuricum and A. sieboldii had a better anti-nociception effect than Asarum produced in other producing areas, famous-region A. heterotropoides var. mandshuricum had a better effect than those produced in other producing areas in anti-inflammation. But famous-region A. sieboldii showed no obvious difference from those produced in other producing areas in anti-inflammation. All samples of Asarum showed anti-nociceptive and anti-inflammatory effects, but with significant differences among Asarum produced in different areas, indicating the eoherbalism to some extent.


Quantum cryptography as a retrodiction problem.
We propose a quantum key distribution protocol based on a quantum retrodiction protocol, known as the Mean King problem. The protocol uses a two way quantum channel. We show security against coherent attacks in a transmission-error free scenario, even if Eve is allowed to attack both transmissions. This establishes a connection between retrodiction and key distribution.


From Simplicity to Complexity in Grafting Dawson-Type Polyoxometalates on Porphyrin, Leading to the Formation of New Organic-Inorganic Hybrids for the Investigation of Third-Order Optical Nonlinearities.
Four new organic-inorganic hybrids, [N(C4H9)4]5H[{HNC2O(CH2O)3P2V3W15O59}C44N4H29O3] (TPPOH-1POM), [N(C4H9)4]10H2[{HNC2O(CH2O)3P2V3W15O59}2C44N4H28O2] (TPPOH-2POM trans), [N(C4H9)4]10H2[{HNC2O(CH2O)3P2V3W15O59}2C44N4H28O2] (TPPOH-2POM cis), and [N(C4H9)4]15H3[{HNC2O(CH2O)3P2W15V3O59}3C44N4H27O] (TPPOH-3POM), have been synthesized by covalently grafting the Dawson-type polyoxometalate (POM) [N(C4H9)4]5[H4P2W15V3O62] onto new porphyrins N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]-4-[10,15,20-tris(4-hydroxyphenyl)porphyrin-5-yl]benzamide (TPPOH-1Tris), 4,4'-[5,15-bis(4-hydroxyphenyl)porphyrin-10,20-diyl]bis[ N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]benzamide] (TPPOH-2Tris trans), 4,4'-[10,15-bis(4-hydroxyphenyl)porphyrin-5,20-diyl]bis[ N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]benzamide] (TPPOH-2Tris cis). and 4,4',4″-[20-(4-hydroxyphenyl)porphyrin-5,10,15-triyl]tris[ N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]benzamide] (TPPOH-3Tris), respectively, in N, N-dimethylacetamide under nitrogen. The hybrid compounds were thoroughly characterized by elemental analysis, FT-IR, NMR (1H, 2D NOESY, 31P, and 51V), ESI-MS, MALDI-TOF-MS, UV-vis, and fluorescence spectroscopy. All porphyrins and their corresponding hybrids exhibited remarkable third-order nonlinear-optical responses under laser irradiation, with the intensity of light at focus E0 being 4.2 μJ at wavelength 532 nm, pulse duration τ = 6 ns, and repetition rate 10 Hz. The molecular second hyperpolarizability (γ) values of the hybrids (TPPOH-1POM, TPPOH-2POM trans, TPPOH-2POM cis, TPPOH-3POM) were calculated to be 8.48 × 10-28 esu, 8.94 × 10-28 esu, 10.16 × 10-28 esu, and 8.93 × 10-28 esu, while the molecular second hyperpolarizability (γ) of their corresponding porphyrin precursors (TPPOH-1Tris, TPPOH-2Tris trans, TPPOH-2Tris cis, and TPPOH-3Tris) were 7.19 × 10-28 esu, 8.09 × 10-28 esu, 9.07 × 10-28 esu, and 7.24 × 10-28 esu, respectively. The γ values of the cis forms were found to be superior to those of all other compounds, indicating the significant role of the greater dipole moment and low symmetry of the cis form compared to other compounds. It was also found that the fluorescence intensity was decreased by 81.52%, 90.37%, 93.93%, and 84.62% for the hybrids TPPOH-1POM, TPPOH-2POM trans, TPPOH-2POM cis, and TPPOH-3POM with respect to their corresponding precursors, respectively, which reveals the Dawson-type POM as a strong quencher. This quenching phenomenon not only indicates again unequivocally the formation of hybrid compounds but also may imply a photoinduced electron/energy-transfer process favored from a porphyrin moiety to a Dawson-type POM moiety.


Our findings, my method: Framing science in televised interviews.
The public communication of science and technology largely depends on their framing in the news media, but scientists' role in this process has only been explored indirectly. This study focuses on storied accounts told by scientists when asked to present their research or provide expert advice in the course of a news interview. A total of 150 items from a current affairs talk show broadcast in the Israeli media were explored through a methodology combining narrative and conversation analysis. Using the concept of framing as originally proposed by Erving Goffman, we show that researchers use personal accounts as a way of reframing news stories introduced by the program hosts. Elements of method and rationale, which are usually considered technical and are shunned in journalistic reports, emerged as a crucial element in the accounts that experts themselves provided. The implications for framing research and science communication training are discussed.


A marine anthraquinone SZ-685C overrides adriamycin-resistance in breast cancer cells through suppressing Akt signaling.
Breast cancer remains a major health problem worldwide. While chemotherapy represents an important therapeutic modality against breast cancer, limitations in the clinical use of chemotherapy remain formidable because of chemoresistance. The HER2/PI-3K/Akt pathway has been demonstrated to play a causal role in conferring a broad chemoresistance in breast cancer cells and thus justified to be a target for enhancing the effects of anti-breast cancer chemotherapies, such as adriamycin (ADR). Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. In this context, SZ-685C, an agent that has been previously shown, as such, to suppress Akt signaling, is expected to increase the efficacy of chemotherapy. Our current study investigated whether SZ-685C can override chemoresistance through inhibiting Akt signaling in human breast cancer cells. ADR-resistant cells derived from human breast cancer cell lines MCF-7, MCF-7/ADR and MCF-7/Akt, were used as models to test the effects of SZ-685C. We found that SZ-685C suppressed the Akt pathway and induced apoptosis in MCF-7/ADR and MCF-7/Akt cells that are resistant to ADR treatment, leading to antitumor effects both in vitro and in vivo. Our data suggest that use of SZ-685C might represent a potentially promising approach to the treatment of ADR-resistant breast cancer.


Severe drug-induced interstitial lung disease successfully treated with corticosteroid plus recombinant human soluble thrombomodulin.
There is no established therapeutic option for corticosteroid (CS) refractory drug-induced interstitial lung disease (DILD). We report a case of CS refractory severe DILD successfully treated with recombinant human soluble thrombomodulin (rhTM). A 64-year-old Japanese man was admitted with symptoms of fever, dry cough and dyspnoea. A chest radiograph showed bilateral infiltrations. DILD from Nijutsutou, a Chinese medicine, was suspected based on a history of similar interstitial lung disease after its administration 4 years prior and a positive drug-induced lymphocyte stimulation test. Nijutsutou was promptly discontinued and high doses of CS administered, but the patient's bilateral infiltrations remained unimproved. Since coagulation tests also indicated a rapid aggravation of coagulopathy, rhTM was added to the CS therapy. The patient's lung infiltration ameliorated and plasma levels of D-dimer and high morbidity group box 1 (HMGB1) decreased. rhTM may be an alternative agent for CS refractory DILD. Further study is necessary to confirm this.


Hydroxamic acid content and toxicity of rye at selected growth stages.
Rye (Secale cereale L.) is an important cover crop that provides many benefits to cropping systems including weed and pest suppression resulting from allelopathic substances. Hydroxamic acids have been identified as allelopathic compounds in rye. This research was conducted to improve the methodology for quantifying hydroxamic acids and to determine the relationship between hydroxamic acid content and phytotoxicity of extracts of rye root and shoot tissue harvested at selected growth stages. Detection limits for an LC/MS-MS method for analysis of hydroxamic acids from crude aqueous extracts were better than have been reported previously. (2R)-2-beta-D-Glucopyranosyloxy-4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA-G), 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA), benzoxazolin-2(3H)-one (BOA), and the methoxy-substituted form of these compounds, (2R)-2-beta-D-glucopyranosyloxy-4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA glucose), 2,4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA), and 6-methoxy-benzoxazolin-2(3H)-one (MBOA), were all detected in rye tissue. DIBOA and BOA were prevalent in shoot tissue, whereas the methoxy-substituted compounds, DIMBOA glucose and MBOA, were prevalent in root tissue. Total hydroxamic acid concentration in rye tissue generally declined with age. Aqueous crude extracts of rye shoot tissue were more toxic than extracts of root tissue to lettuce (Lactuca sativa L.) and tomato (Lycopersicon esculentum Mill.) root length. Extracts of rye seedlings (Feekes growth stage 2) were most phytotoxic, but there was no pattern to the phytotoxicity of extracts of rye sampled at growth stages 4 to 10.5.4, and no correlation of hydroxamic acid content and phytotoxicity (I50 values). Analysis of dose-response model slope coefficients indicated a lack of parallelism among models for rye extracts from different growth stages, suggesting that phytotoxicity may be attributed to compounds with different modes of action at different stages. Hydroxamic acids may account for the phytoxicity of extracts derived from rye at early growth stages, but other compounds are probably responsible in later growth stages.


Reduced Insecticide Susceptibility in Aedes vexans (Diptera: Culicidae) Where Agricultural Pest Management Overlaps With Mosquito Abatement.
Mosquito abatement programs in Midwestern communities frequently exist within landscapes dominated by agriculture. Although separately managed, both agricultural pests and mosquitoes are targeted by similar classes of insecticides. As a result, there is the potential for unintended insecticide exposure to mosquito populations from agricultural pest management. To determine the impact that agricultural management practices have on mosquito insecticide susceptibility we compared the mortality of Aedes vexans (Meigen; Diptera: Culicidae) between populations sampled from locations with and without mosquito abatement in South Dakota, a region dominated by agricultural production. Collection locations were either within towns with mosquito abatement programs (n = 2; Brookings and Sioux Falls, SD) or located > 16 km from towns with mosquito abatement programs (n = 2; areas near Harrold and Willow Lake, SD). WHO bioassays were used to test susceptibly of adults to differing insecticide classes relative to their respective controls; 1) an organochlorine (dieldrin 4%), 2) an organophosphate (malathion 5%), and 3) a pyrethroid (lambda-cyhalothrin 0.05%). Corrected mortality did not significantly differ between locations with or without abatement; however, when locations were analized by proportion of developed land within the surrounding landscape pyrethroid mortality was significantly lower where crop production dominated the surrounding landscape and mosquito abatement was present. These data suggest that agricultural pest management may incidentally contribute to reduced mosquito susceptibility where overlap between agricultural pest management and mosquito abatement exists. Decoupling insecticide classes used by both agricultural and public health pest management programs may be necessary to ensure continued efficacy of pest management tools.


"Onion" flap: a novel technique for reconstruction of burn nail deformities.
Nail fold deformities from burn injury frequently result in eponychial retraction, proximal nail exposure, pain, and distal phalangeal function impairment. Secondary nail abnormalities including longitudinal ridges, surface cracks, and fragility are common sequelae to nail fold deformities. Surgical management of postburn nail fold deformity is challenging because of scar contractures involving the dorsum of digits and lack of surrounding healthy tissues that can be used as source of soft tissue for reconstruction. Previous reports have discussed several methods for reconstruction of these deformities. However, all of these methods are associated with significant donor site morbidities. From August 2008 to January 2010, "onion" flap reconstruction was performed for postburn nail fold contractures and deformities on 32 fingers of eight patients (five men and three women; average age, 44.4 years; age range, 23-54 years). This novel technique was used to release scar contractures in the eponychial area and allow soft tissue restoration by redraping the eponychium in a single-step procedure. All 32 fingers received single-stage "onion" flap reconstruction for their nail fold deformities at least 6 months after the initial injury. The follow-up period, with an average of 7.8 months, revealed that all nails had good esthetic and functional results. All experienced amelioration of nail abnormalities. The "onion" advancement flap had effectively released the scar contracture around the nail fold and simultaneously restored the eponychial fold. The "onion" flap technique provides superior results compared with those from conventional techniques. We recommend it as the mainstay of treatment for reconstruction of the postburn eponychial deformities. V, therapeutic study.


Complement activation in relation to protective function of antibodies to Escherichia coli O antigens.
The relation between complement activation in an indirect hemolysis assay of E. coli O antibodies and their protective function in experimentally infected mice was analyzed. The antibody amounts and avidities were estimated in antisera and in IgG and IgM antibody fractions by the ammonium sulphate precipitation (ASP) technique of Farr. The protection obtained was due to both IgG and IgM antibodies and showed a close relation to the quantity of antibodies measured by the ASP technique. No link between complement activation capacity of the antibodies and their protective function could be seen. In the system used, the IgM antibodies showed a correlation between antibody avidity and complement activating efficiency, whereas the IgG antibodies activated complement poorly. The results do not indicate a major function of the complement in antibody-mediated protection against E. coli in this experimental system in mice.


How Employee's Leadership Potential Leads to Leadership Ostracism Behavior: The Mediating Role of Envy, and the Moderating Role of Political Skills.
Recently, research on the leadership potential of employees has gradually attracted the attention of scholars. However, further exploration is required to better understand the upward influence of employee's leadership potential on their leaders. This study examined the mechanisms behind the impact of employee's leadership potential on leadership ostracism behavior. Moreover, the mediating role of leader's envy and the moderating role of employee's political skills in the relationship between employee's leadership potential and leadership ostracism behavior were investigated. The results of an empirical analysis of 221 employee-leader pairs, studied over multiple periods, are as follows: employee's leadership potential had a significant positive impact on leader's envy and leadership ostracism behavior; leader's envy had a significant positive impact on leadership ostracism behavior; and leader's envy mediated the relationship between leadership potential and leadership ostracism behavior. In addition, employee's political skills negatively moderated the indirect effect of leadership potential on leadership ostracism behavior through leader's envy. The leadership potential of employees with more political skills appeared to have less influence on organizational ostracism via leader's envy. This study explored the "dark-side" of employee's leadership potential by understanding its impact on their leaders; the findings have theoretical and practical significance for companies.


Association of plasma nitric oxide concentration and endothelial nitric oxide synthase T-786C gene polymorphism in coronary artery disease.
Nitric oxide (NO) is synthesized from l-arginine by endothelium nitric oxide synthase (NOS3) and plays important roles in many physiologic and pathologic processes. NO involved in the pathogenesis of coronary atherosclerosis. In the present study we hypothesized that polymorphisms of NOS gene might be associated with increased risk of coronary artery disease (CAD) and plasma NO concentrations. The eNOS gene polymorphism was investigated in 241 unrelated CAD patients with positive coronary angiograms and 261 ages matched control subjects without a history of symptomatic CAD. The NOS3 gene polymorphisms were analyzed by RFLP. Plasma NO, lipid profile and other risk factors were also assessed. The genotype frequencies for T-786C polymorphism differed significantly between CAD patients and controls (p=0.041). The mean plasma NO(x) concentrations showed significant differences according to genotypes of T-786C polymorphism in total population only. The mean plasma NO(x) increased in those individuals that are homozygote for C allele in promoter compared with those individuals are heterozygote for this allele and homozygote for T allele in total population and Controls, but no in CAD patients. The present study provides evidences that T-786C polymorphism of the NOS3 gene is associated with CAD. T-786C polymorphism was not associated with increased plasma NO in CAD patients.


Association of the m6 A reader IGF2BP3 with tumor progression and brain-specific metastasis in breast cancer.
This study aimed to determine the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an N6 -methyladinosine reader, in the progression and distant metastasis of breast cancer. IGF2BP3 expression was assessed in 152 pairs of breast cancer and adjacent normal tissue (ANT) by real-time quantitative polymerase chain reaction and in 561 cases of breast cancer and 163 cases of ANT by immunohistochemistry. Survival curves were estimated using the Kaplan-Meier method and then compared statistically using the log-rank test. The prognostic role of IGF2BP3 was determined by Cox regression analysis. Analysis of public gene data sets revealed that IGF2PB3 predicted distant metastasis in breast cancer and was highly correlated with brain metastasis. In the clinical retrospective cohort, the positive rate of IGF2BP3 increased gradually with breast cancer progression. Positive IGF2BP3 expression was related to poor distant metastasis-free survival (DMFS, p = .030) and Cox regression analysis identified IGF2BP3 as an independent risk factor for DMFS (hazard ratio, 1.876; 95% confidence interval, 1.128-3.159; p = .019). Positive IGF2BP3 expression was markedly related to breast cancer brain metastasis (p = .011) but not to lung and bone metastasis. Moreover, patients with IGF2BP3-positive brain metastasis had lower survival than patients with IGF2BP3-negative brain metastasis (p = .041). Gene expression profiling results indicated that high IGF2BP3 expression was associated with the PD-1 checkpoint pathway, HER2-HER3 signaling, and epithelial-mesenchymal transition. IGF2BP3 may serve as a novel predictive biomarker and a potential therapeutic target for breast cancer brain metastasis, which warrants further investigation. As an m6 A reader, IGF2BP3 is dysregulated and implicated in various cancers but its role in breast cancer has not been fully clarified. In this study, we found that IGF2BP3 was upregulated in breast cancer and IGF2BP3 expression increased gradually during breast cancer progression. IGF2BP3 expression exerted no effect on the overall survival and breast cancer-specific survival of breast cancer patients; however, IGF2BP3-positive patients were more likely to develop distant metastasis than IGF2BP3-negative patients. In addition, IGF2BP3 was associated with brain-specific metastasis in breast cancer patients. These findings warrant further investigation because they provide a rationale for novel predictive or therapeutic approaches.


Population pharmacokinetics of vancomycin in Chinese pediatric patients .
This study was conducted to develop a population pharmacokinetic (PopPK) model for vancomycin and to detect the significant covariates that influence the PopPKs to facilitate individualized therapy for Chinese pediatric patients. Patients ≤ 10 years old who received vancomycin for ≥ 72 hours between 2007 and 2010 were analyzed using a nonlinear mixed-effects modeling approach (-NONMEM). A one-compartment model with first-order elimination was chosen to depict the data. Stepwise covariate modeling (SCM) was employed to detect significant covariates and obtain a final model. Internal validation methods, including bootstrapping and visual predictive checks (VPC), were applied to evaluate the robustness and predictive power of the final model. The analysis included 54 pediatric inpatients with 128 serum concentration samples. The mean age (range) was 124.30 (1.29 - 541.4) weeks, the mean weight was 10.36 (1.4 - 33.5) kg, and the mean baseline serum creatinine (Scr) level was 0.39 (0.15 - 1.32) mg/dL. Pneumonia was the most common indication for vancomycin therapy (33.33%), followed by bacteremia (25.93%), and meningitis (22.22%). A PopPK model of vancomycin in Chinese pediatric patients was developed. Postnatal age (PNA) significantly affected the vancomycin clearance (CL) of pediatric patients, and the influence was described using the sigmoid maximum effect (Emax) model. The effect of body weight (WT) on CL and volume of distribution (V) was investigated using an allometric scaling equation. The final model parameters were CL(L/h) = 11.75×[PNA0.4672/(PNA0.4672+33.30.4672)]×(WT/70)0.75×e0.362 and V(L) = 54.49×WT/70×e0.6711. The model evaluation results suggested robustness and good predictability of the final model. A PopPK model of vancomycin for Chinese pediatric patients was developed in this study. The significant covariates distinguished in the final model can provide helpful information to facilitate individualized therapy for Chinese pediatric patients. .


Reducing lead exposure by surveillance system: the Taiwan experience.
To evaluate the performance of a lead-surveillance program in reducing blood lead levels of workers in Taiwan, the authors conducted prospective and cross-sectional studies. A total of 6 905 workers, whose job titles indicated a direct exposure to lead in 1995, were included in this surveillance system. In this study, the authors compared the mean blood lead levels in 1994 (i.e., year of onset of surveillance) with that in 1995 in workers of major industries. Lead-exposed workers had a statistically significant decrease (i.e., average of 1.8 microg/dl) in blood lead levels during this 1-y period. The decrease was particularly obvious in individuals who worked in chemical products manufacturing, ship building/repairing, and plastic products manufacturing. The significant decreases in blood lead levels in these workers indicated that this surveillance system was effective. Surveillance, combined with control measures, might be an important means by which occupational lead exposure can be reduced.


How regular visits and preventive programs affect onset of adult caries.
If it is to be effective, preventive dental treatment must be based on an individual's risk of caries and periodontal disease. However, hitherto, preventive treatment has been generally conducted without proper caries-risk assessment because of lack of knowledge about an individual's caries risk. This study sought to identify high-risk adult patients and examine the effectiveness of preventive programs. Data for 442 patients from a single general practice who met the inclusion criteria were analyzed. Multiple logistic-regression analysis showed that high levels of mutans streptococci (SM) correlated with the onset of primary and secondary caries, with odds ratios of 2.34 (95%CI: 1.15-4.76, p = 0.019) and 2.22 (95%CI: 1.06-4.62, p = 0.034), respectively. Lactobacilli (LB) also correlated with secondary caries, with an odds ratio of 3.34 (95%CI: 1.35-6.85, p = 0.007). When the patients were checked after three years of a preventive program, the correlation with SM and LB disappeared. Survival analyses by Cox regression models and Kaplan-Meier methods showed that secondary caries was difficult to control by conventional preventive programs alone in patients with high levels of cariogenic bacteria. In conclusion, cariogenic bacteria play an important role in the incidence of caries, and additional intensive preventive treatment should be considered for high-risk patients.


[Allergic airway response associated with the intestinal microflora disruption induced by antibiotic therapy].
Over the past several decades, there has been a significant increase in allergy and asthma in the world, which correlates with alterations in microflora and widespread use of antibiotics. The authors have developed a mouse model of antibiotics-induced microbiota disruption. In that model, mice were challenged by intranasal exposure to Aspergillus fumigatus allergens to explore the relation of allergic airway response and intestinal microflora disruption. Sixty female BALB/c mice were divided at random into 6 groups with 10 mice in each. (1) First antibiotic therapy group: the mice were given oral cefoperazone for 7 days, on day 7, mice were inoculated with Candida albicans (10(9)/ml, 50 microl) orally. (2) First control group: the mice were treated as first antibiotic therapy group, but cefoperazone and Candida albicans were replaced by saline. The mice in groups (1) and (2) were sacrificed on day 8, and cecal contents were collected for quantitative analysis of the intestinal bacterial flora. (3) Antibiotic therapy and challenge group: the mice were treated as the first antibiotic therapy group, then challenged (day 9 and 16) by intranasal exposure to Aspergillus fumigatus allergen. (4) Second antibiotic therapy group: the mice were treated as the first antibiotic therapy group, then challenged (day 9 and 16) by intranasal exposure to saline. (5) Challenge group: the mice were treated as the first control group, then challenged (day 9 and 16) by intranasal exposure to Aspergillus fumigatus allergen. (6) Second control group: the mice were treated as the first control group, then challenged (day 9 and 16) by intranasal exposure to saline. The mice in (3) - (6) group were killed for analysis of allergic airway response on day 19. The quantity of Enterobacteriaceae, Enterococcus, Bifidobacterium and Lactobacillus in first antibiotic therapy group was significantly lower than that in the first control group, the quantity of Candida albicans increased in the first antibiotic therapy group as compared with the first control group. Mice intestinal microflora were disrupted with weight reduction and increased moisture in feces. After challenging with Aspergillus fumigatus allergens via intranasal inhalation, the total cell count, eosinophils, lymphocytes and neutrophils increased in BALF, especially in bronchoalveolar lavage fluid (BALF) from the mice in antibiotic therapy and challenge groups. IL-4 level in BALF from antibiotic therapy and challenge group (45.35 +/- 2.36) pg/ml was higher than that in the second control group (35.32 +/- 2.53) pg/ml. The expression of GATA-3 mRNA in the mice lung tissue (0.569 +/- 0.023) was higher than that in the second control group (0.410 +/- 0.020), and the ratios of T-bet/GATA-3 (0.578 +/- 0.021) decreased as compared with that in the second control group (0.804 +/- 0.035). IFN-gamma level in BALF from any group was not significantly different. In the absence of antibiotics, mice exposed to Aspergillus fumigatus allergen did not develop an allergic response in the airways. The allergic (Th2) immune response can be induced by airway challenge with Aspergillus fumigatus allergen in the mice in which the intestinal microflora disruption resulted from antibiotic therapy, this result suggests that the intestinal microflora disruption resulted from antibiotic therapy is a risk factor for allergy and asthma.


On the biochemical nature of the 'Sm' nucleoplasmic antigen.
The nucleoplasmic autoantigens RNP and Sm are of particular interest because of their associations with certain symptoms of mixed connective tissue disease and systemic lupus erythematosus. The RNP is generally thought to be a ribonucleoprotein and there is evidence that its RNA may be single-stranded. Experiments presented in this report are in support of the concept that the Sm-antigen may also be an RNA protein. Purified Sm-anti-Sm precipitates were shown to have high RNA contents and treatment of Sm-antigen with RNAase in a hypotonic medium strongly reduced in antigenicity. The latter effect indicates that the Sm-antigen may in contrast to the RNP contain double-stranded RNA, a possibility also suggested by the finding that the Sm-antigen was soluble in 2 M LiCl. The Sm-antigen was found further to differ from RNP in being selectively absorbed in BD-Sephadex, while RNP remained active in the supernatant. Cytochemical studies involving stimulation and inhibition experiments with lectins and RNA polymerase inhibitors showed that the Sm-antigen was, in distinction to RNP, sensitive to rifampicin but not to alpha-amanitine. This suggests that the RNAs of the nucleoplasmic antigens may be synthesized by different RNA polymerases.


Sensory denervation reduces visceral hypersensitivity in adult rats exposed to chronic unpredictable stress: evidences of neurogenic inflammation.
The purpose of this study is to provide evidence of neurogenic inflammation in chronic unpredictable stressed rats with the changes of visceral sensitivity, number of mast cells, and close proximity among mast cell-nerve-blood vessels. We found that (1) capsaicin denervation blocked stress-induced increase of visceral sensitivity, while doxantrazole presented a partial blocking; (2) capsaicin denervation blocked stress-induced enhancement of the proximity of mast cell-nerve fiber-blood vessels and blood vessel damage, while doxantrazole showed no effects on these; (3) doxantrazole blocked stress-induced increases of the MPO activity, the number and the degranulation of mast cells in the colon; (4) sensory denervation and doxantrazole had no effects on stress-induced behavioral inhibition. These results suggest that capsaicin-sensitive sensory fibers play a key role in stress-induced visceral hypersensitivity and the ultrastructural changes, mast cells play an important role in the generation of stress-induced colon inflammation.


Elevated transcription of the gene QSOX1 encoding quiescin Q6 sulfhydryl oxidase 1 in breast cancer.
The q arm of chromosome 1 is frequently amplified at the gene level in breast cancer. Since the significance of this is unclear we investigated whether 1q genes are overexpressed in this disease. The cDNA levels of 1q-located genes were analysed in a search for overexpressed genes. 26 genes mapping to the 1q arm show highly significant (P≤0.01) overexpression of transcripts in breast cancer compared to normal breast tissue. Amongst those showing the highest levels of overexpression in both expressed sequence tag (EST) and serial analysis of gene expression (SAGE) databases was enzyme quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We investigated QSOX1 cDNA derived from T47D breast carcinoma cells by RT-PCR and 3'-RACE PCR and identified a novel extended form of QSOX1 transcript, containing a long 3'UTR, nearly double the size of the previously reported QSOX1 cDNA, and confirmed its 3' end nucleotide sequence using RACE-PCR. We also used quantitative real-time PCR to analyse a panel of cDNAs derived from 50 clinically-graded normal and malignant breast tissue samples for the expression of QSOX1 mRNAs. QSOX1 transcription was elevated in an increasing proportion in the grade 2 and grade 3 tumours (graded according to the Nottingham prognostic index), with 10 of the 15 grade 3 tumours (67%) examined exceeding the normal range. There was a significant correlation between relative transcript level and clinical grade (P≤0.01) for all qPCR primer sets tested. QSOX1 mRNA levels, based on SAGE expression data, did not correlate with either Estrogen Receptor (ER) or Epidermal Growth Factor Receptor 2 (ErbB-2 or HER2/neu) expression. Our data indicate that QSOX1 is a potential new prognostic marker which may prove of use in the staging of breast tumours and the stratification of breast cancer patients.


Application of optical biosensors in small-molecule screening activities.
The last two decades have seen remarkable progress and improvements in optical biosensor systems such that those are currently seen as an important and value-adding component of modern drug screening activities. In particular the introduction of microplate-based biosensor systems holds the promise to match the required throughput without compromising on data quality thus representing a sought-after complement to traditional fluidic systems. This article aims to highlight the application of the two most prominent optical biosensor technologies, namely surface plasmon resonance (SPR) and optical waveguide grating (OWG), in small-molecule screening and will present, review and discuss the advantages and disadvantages of different assay formats on these platforms. A particular focus will be on the specific advantages of the inhibition in solution assay (ISA) format in contrast to traditional direct binding assays (DBA). Furthermore we will discuss different application areas for both fluidic as well as plate-based biosensor systems by considering the individual strength of the platforms.


Encouraging minority undergraduates to choose science careers: career paths survey results.
To explore the reasons for the dearth of minorities in Ph.D.-level biomedical research and identify opportunities to increase minority participation, we surveyed high-achieving alumni of an undergraduate biology enrichment program for underrepresented minorities. Respondents were asked to describe their career paths and to reflect on the influences that guided their career choices. We particularly probed for attitudes and experiences that influenced students to pursue a research career, as well as factors relevant to their choice between medicine (the dominant career choice) and basic science. In agreement with earlier studies, alumni strongly endorsed supplemental instruction as a mechanism for achieving excellence in basic science courses. Undergraduate research was seen as broadening by many and was transformative for half of the alumni who ultimately decided to pursue Ph.D.s in biomedical research. That group had expressed no interest in research careers at college entry and credits their undergraduate research experience with putting them on track toward a research career. A policy implication of these results is that making undergraduate research opportunities widely available to biology students (including "premed" students) in the context of a structured educational enrichment program should increase the number of minority students who choose to pursue biomedical Ph.D.s.


Comparing the effects of different dietary organic acids on the growth, intestinal short-chain fatty acids, and liver histopathology of red hybrid tilapia (Oreochromis sp.) and potential use of these as preservatives.
Dietary organic acids are increasingly being investigated as a potential means of improving growth and nutrient utilization in aquatic animals. A 9-week study was performed to compare equal amounts (2%) of different organic acids (sodium butyrate, acetate, propionate, or formate) on the growth, muscle proximate composition, fatty acid composition, cholesterol and lipid peroxidation, differential cell counts, plasma biochemistry, intestinal short-chain fatty acid (SCFA) level, and liver histopathology to red hybrid tilapia (Oreochromis sp.) (initial mean weight of 2.87 g). A second experiment was performed to determine their effects on lipid peroxidation and trimethylamine (TMA) when added at 1% to tilapia meat and left out for 24 h. The results of the first experiment showed no treatment effect to growth, feeding efficiencies, or muscle fatty acid composition, but all dietary organic acids significantly decreased intestinal SCFA. Dietary butyrate and propionate significantly decreased muscle lipid peroxidation compared to the control group, but the dietary formate treatment had the lowest lipid peroxidation compared to all treatments. Muscle crude protein and lipid in tilapia fed the formate diet were significantly lower and higher, respectively, and showed evidence of stress based on the differential cell counts, significantly higher plasma glucose and liver glycogen, as well as inflammatory responses in the liver. Although a potential benefit of dietary organic acids was a reduction to lipid peroxidation, this could be accomplished post-harvest by direct additions to the meat. In addition, inclusions of butyrate and propionate to tilapia meat significantly decreased TMA, which might be a more cost-effective option to improve the shelf life of tilapia products.


Psychosocial and functional contributors to personal recovery in serious mental illness.
Background: Although recovery-oriented services have been conceptualized to improve personal recovery, related research often focuses on measures of clinical recovery. Identifying the relationships between personal recovery, clinical recovery, and psychosocial variables will inform service components and outcome measurement in recovery-oriented services. Aims: This study sought to determine the connection between personal recovery and two sets of potential contributors: psychosocial variables (i.e., empowerment, resilience, and consumer involvement) and functional indicators of clinical recovery. Method: These relationships were examined by analyzing survey data collected from 266 consumers who are receiving public mental health services in the United States. Results: Empowerment, resilience and psychological involvement were associated with personal recovery. Clinical recovery did not uniquely contribute to personal recovery once psychosocial factors were accounted for. Interactions revealed that the relationship between psychological involvement and personal recovery was stronger for those who had been recently hospitalized, and for those with relatively greater resilience. Conclusions: Results indicate that personal recovery is an essential outcome measure for recovery-oriented services that cannot be replaced by clinical recovery outcome measurement. Additionally, empowerment, resilience, and consumer involvement are key components of recovery, which suggests that services and outcome measures should prioritize incorporation of these constructs.


Radiologic vignette: primary disorders of articular cartilage in childhood.
We discuss several less well recognized disorders of articular cartilage which may affect pediatric patients, including relapsing polychondritis, idiopathic chondrolysis of the hip and chondrolysis after slipped capital femoral epiphysis. Idiopathic osteolysis is not considered in our review because it has been well described previously.


Effects of delta-aminolevulinic acid and melatonin in the harderian gland of female Syrian hamsters.
Effects of delta-aminolevulinic acid (ALA) and melatonin were investigated in the female Syrian hamster Harderian gland. This is an organ physiologically exposed to strong oxidative stress due to the highest porphyrinogenic rates known in nature. Enzyme activities of porphyrin biosynthesis and of antioxidative protection, oxidative protein modification, and histological integrity were studied. In the porphyrin biosynthetic pathway, ALA and melatonin acted synergistically by downregulating ALA synthase (ALA-S) and stimulating product formation from ALA; the combination of ALA and melatonin suppressed ALA-S activity, down to about 1% of that in controls. While ALA effects on porphyrinogenesis can be interpreted in terms of homeostasis, melatonin's actions may be seen in relation to seasonality and/or reduction of oxidative stress. Among antioxidant enzymes, superoxide dismutase (SOD) and glutathione reductase (GR) activities were diminished by ALA, presumably due to the vulnerability of their active centers to free radicals, whereas melatonin moderately increased SOD. Both ALA and melatonin strongly stimulated catalase (CAT), thereby counteracting the oxidative stress induced by ALA and its metabolites. Nevertheless, exogenous ALA caused a strong net rise in protein carbonyl and considerable damage of tissue. When given together with ALA, melatonin antagonized these effects and largely protected the integrity of glandular structures.


The intense starburst HDF 850.1 in a galaxy overdensity at z ≈ 5.2 in the Hubble Deep Field.
The Hubble Deep Field provides one of the deepest multiwavelength views of the distant Universe and has led to the detection of thousands of galaxies seen throughout cosmic time. An early map of the Hubble Deep Field at a wavelength of 850 micrometres, which is sensitive to dust emission powered by star formation, revealed the brightest source in the field, dubbed HDF 850.1 (ref. 2). For more than a decade, and despite significant efforts, no counterpart was found at shorter wavelengths, and it was not possible to determine its redshift, size or mass. Here we report a redshift of z = 5.183 for HDF 850.1, from a millimetre-wave molecular line scan. This places HDF 850.1 in a galaxy overdensity at z ≈ 5.2, corresponding to a cosmic age of only 1.1 billion years after the Big Bang. This redshift is significantly higher than earlier estimates and higher than those of most of the hundreds of submillimetre-bright galaxies identified so far. The source has a star-formation rate of 850 solar masses per year and is spatially resolved on scales of 5 kiloparsecs, with an implied dynamical mass of about 1.3 × 10(11) solar masses, a significant fraction of which is present in the form of molecular gas. Despite our accurate determination of redshift and position, a counterpart emitting starlight remains elusive.


Left and right bundle branch block, left anterior and left posterior hemiblock.
The data available on the prognosis of the intraventricular conduction disturbances--left and right bundle branch block (LBBB, RBBB) and left anterior and posterior hemiblock (LAH, LPH)--are uneven. However, there is no evidence to suggest that incomplete RBBB, established complete RBBB or established LAH carry other than a normal prognosis. Data on incomplete LBBB and on established LPH are insufficient to support conclusions. There are no adequate data on the risks of recently acquired LAH or LPH. Recently acquired isolated RBBB appears to carry little or no additional risk but the data are scant. It requires evaluation and may justify restriction to multi-crew operation. Established LBBB carries a small but definite increase in mortality risk, but subject to assessment it may be permissible in multi-crew operation. Recently acquired LBBB carries a substantial increase in mortality risk and should be disqualifying to fly.


[The impact of guidelines, standards and economic restrictions on clinical decision-making processes].
Guidelines aim at improving clinical decision-making. Contrary to textbooks and reviews that want to improve medical knowledge, guidelines try to influence medical behaviour. Scientific models of clinical decision-making such as the action theory and empirical data on the effects of guidelines suggest that guidelines will not always reach their goals but can instead even lead to a deterioration in the quality of medical care. Therefore there is a need for controlled clinical trials to investigate whether guideline-exposed physicians yield better patient outcomes than guideline-naïve physicians. Guidelines should only be regarded as evidence-based if their positive effects have been empirically demonstrated.


Rational Design of Two-Dimensional Binary Polymers from Heterotriangulenes for Photocatalytic Water Splitting.
On the basis of first-principles calculations, we report the design of three two-dimensional (2D) binary honeycomb-kagome polymers composed of B- and N-centered heterotriangulenes with a periodically alternate arrangement as in hexagonal boron nitride. The 2D binary polymers with donor-acceptor characteristics are semiconductors with a direct band gap of 1.98-2.28 eV. The enhanced in-plane electron conjugation contributes to high charge carrier mobilities for both electrons and holes, about 6.70 and 0.24 × 103 cm2 V-1 s-1, respectively, for the 2D binary polymer with carbonyl bridges (2D CTPAB). With appropriate band edge alignment to match the water redox potentials and pronounced light adsorption for the ultraviolet and visible range of spectra, 2D CTPAB is predicted to be an effective photocatalyst/photoelectrocatalyst to promote overall water splitting.


Pore space partition of a fragile Ag(i)-carboxylate framework via post-synthetic linker insertion.
The pore space partition approach via post-synthetic linker insertion was used to modulate the porosity of a fragile Ag(i)-carboxylate framework with potentially large pore space. The resulting Ag(i)-MOFs with partitioned pores showed enhanced permanent porosity compared with a nonpartitioned Ag(i)-carboxylate framework.


[A biochemical theory of schizophrenia].
In addition to the dopamine hypothesis, a glutamate hypothesis has been recently discussed in the biochemical theories on the cause of schizophrenia. In schizophrenic patients less glutamic acid has been found in the cerebrospinal fluid. Glutamate is probably the most important excitatory transmitter of the mammalian forebrain. The liberation of glutamic acid in the striatum is inhibited by dopamine, more specifically by the D2 receptor, which is also though to be responsible for the antipsychotic effects of neuroleptic drugs. It seems possible that schizophrenia may be primarily caused by underfunction of glutamatergic corticostriatal and corticomesolimbic neurons rather than by overfunction of the dopaminergic system. The negative cognitive symptoms associated with schizophrenia would fit in with this hypothesis. The classical and the new atypical neuroleptic drugs show differential effects on glutamate and GABA in the brain tissue of the striatum and in the cerebrospinal fluid. Whereas sulpiride diminishes glutamate in the striatum and enhances glutamate in the cerebrospinal fluid, tiapride does not affect either of them. Correspondingly, tiapride does not show any antipsychotic effects. Haloperidol, on the other hand, enhances the GABA level in the striatum in a dose-related manner. These findings may perhaps prompt experimental research to find antipsychotic drugs with fewer side effects.


T-Cell Cytokines as Predictive Markers of the Risk of Allograft Rejection.
Over the last decade, several biomarkers and surrogate markers have surfaced as promising predictive markers of risk of rejection in solid organ transplantation. The monitoring of these markers can help to improve graft and recipient care by personalizing immunomodulatory therapies. The complex immune system response against an implanted graft can change during long-term follow-up, and the dynamic balance between effector and regulatory T-cell populations is a crucial factor in antidonor response, risk of rejection, and immunosuppression requirements. Therefore, at any time before and after transplantation, T-effector activity, which is associated with increased production and release of proinflammatory cytokines, can be a surrogate marker of the risk of rejection and need for immunosuppression. In addition, immunosuppressive drugs may have a different effect in each individual patient. The pharmacokinetics and pharmacodynamics of these drugs show high interpatient variability, and pharmacodynamic markers, strongly associated with the specific mechanism of action, can potentially be used to measure individual susceptibility to a specific immunosuppressive agent. The monitoring of a panel of valid biomarkers can improve patient stratification and the selection of immunosuppressive drugs. After transplantation, therapy can be adjusted based on the prediction of rejection episodes (maintained alloreactivity), the prognosis of allograft damage, and the individual's response to the drugs. This review will focus on current data indicating that changes in the T-cell production of the intracellular cytokines interferon-γ and interleukin-2 could be used to predict the risk of rejection and to guide immunosuppressive therapy in transplant recipients.


Kaposi's sarcoma associated herpesvirus immune evasion strategies.
The battle between viruses and their hosts is beautiful in its complexity. The interplay between viral proteins and the immune system has taught researchers much about not just the virus, but also the molecular mechanisms underlying the immune response. With additional evasion strategies constantly being described, this avenue of research is still rich with potential discoveries. In this review, we examine a number of proteins encoded by Kaposi's sarcoma herpesvirus (HHV-8) and detail how they aid the virus in escape from immune system elimination. We include, where possible, examples from other homologous viral systems.


The role of prophylactic antibiotics in elective inguinal tension-free hernia repair: A systematic review and meta-analysis.
Whether to use antibiotics to prevent surgical site infection in elective inguinal tension-free hernia repair has been controversial. To systematically evaluate the effect of prophylactic antibiotic application in elective inguinal tension-free hernia repair, we identified all published randomised controlled trials of the effect of prophylactic antibiotic application on elective inguinal tension-free hernia repair were collected by computer retrieval from the China National Knowledge Infrastructure; VIP Database; Wanfang Database; China Biomedical Literature Database; and PubMed, EMBASE and Cochrane Library databases. Meta-analysis was performed by RevMan 5.3 software. The meta-analysis showed that the total incidence of surgical site infections [P = 0.003] and the incidence of superficial surgical site infections [P = 0.004] in the antibiotic group (AG) were lower than those in the non-antibiotic group (NAG). There was no significant difference in the total incidence of postoperative infections [P = 0.06], deep surgical site infections [P = 0.26] and seroma [P = 0.52] between the AG and the NAG. Based on current evidence, the application of prophylactic antibiotics in elective inguinal tension-free hernia repair can prevent the total incidence of surgical site infections and that of superficial surgical site infections but cannot prevent the total incidence of postoperative infection events, incidence of deep surgical site infections and incidence of seroma.


Structure and biological roles of Sinorhizobium fredii HH103 exopolysaccharide.
Here we report that the structure of the Sinorhizobium fredii HH103 exopolysaccharide (EPS) is composed of glucose, galactose, glucuronic acid, pyruvic acid, in the ratios 5∶2∶2∶1 and is partially acetylated. A S. fredii HH103 exoA mutant (SVQ530), unable to produce EPS, not only forms nitrogen fixing nodules with soybean but also shows increased competitive capacity for nodule occupancy. Mutant SVQ530 is, however, less competitive to nodulate Vigna unguiculata. Biofilm formation was reduced in mutant SVQ530 but increased in an EPS overproducing mutant. Mutant SVQ530 was impaired in surface motility and showed higher osmosensitivity compared to its wild type strain in media containing 50 mM NaCl or 5% (w/v) sucrose. Neither S. fredii HH103 nor 41 other S. fredii strains were recognized by soybean lectin (SBL). S. fredii HH103 mutants affected in exopolysaccharides (EPS), lipopolysaccharides (LPS), cyclic glucans (CG) or capsular polysaccharides (KPS) were not significantly impaired in their soybean-root attachment capacity, suggesting that these surface polysaccharides might not be relevant in early attachment to soybean roots. These results also indicate that the molecular mechanisms involved in S. fredii attachment to soybean roots might be different to those operating in Bradyrhizobium japonicum.


Lysosomal degradation of cell organelles. III. Uptake and disappearance in Kupffer cells of intravenously injected isotope-labeled mitochondria and microsomes in vivo and in vitro.
14C-leucine and 3H-glycerol-labeled microsomes and mitochondria were intravenously injected into a series of highly inbred rats. The uptake and disappearance of the organelles were followed in a crude liver lysosomal fraction and in serum. Approximately half of the injected dose was recovered in the liver, and only smaller amounts were found in lungs, kidneys, spleen, and heart. The clearance in serum was more rapid for microsomes (t1/2, 5 to 15 minutes) than for mitochondria (t1/2 30 to 60 minutes). Both organelles showed a biphasic type of disappearance curve consistent with the two-phase theory of phagocytosis: attachment and engulfment. The estimated half-life for mitochondria of the liver was in the range of 3 to 4 hours, whereas that of the microsomes was considerably longer, or 8 hours. There was an increase of trichloroacetic acid-soluble material in the crude lysosomal fraction up to 2 hours after injection of glycerol-labeled microsomes, whereas the peak was reached at 60 minutes after 14C-leucine labeling. In vitro hydrolysis rate of hydrolysis. Experiments with Kupffer cells previously labeled with Thorotrast and biochemical assay of hydrolysis indicated that there was a lag phase of approximately 10 to 20 minutes before the phagosomes gained acid hydrolases, presumably by fusion with lysosomes. It is concluded at somewhat different rates. The remnants from lipid degradation, in comparison with protein degradation, seem to remain for a longer period within the lysosomal apparatus. These results are compatible with the concept that lysosomes represent an important, and at the present the only well defined locus for organelle turnover.


Health activism in Cape Town: a case study of the Health Workers Society.
The Health Workers Society (HWS), founded in 1980, was one of several progressive health organisations that fought for a democratic health system in South Africa. We document the sociopolitical context within which it operated and some of its achievements. HWS, many of whose members were staff and students of the University of Cape Town (UCT), provided a forum for debate on health-related issues, politics and society, and worked closely with other organisations to oppose the apartheid state's health policies and practices. They assisted with the formation of the first dedicated trade union for all healthcare workers and were one of the first to pioneer the primary healthcare approach in an informal settlement in Cape Town.