Twelve tips to revitalise problem-based learning.
The role of the problem-based learning (PBL) facilitator has seen different interpretations ever since PBL first gained widespread use. What has remained unchanged is the challenge for facilitators to use their knowledge and expertise sparingly and to use their interpersonal skills to improve group dynamics. Medical undergraduates attending PBL sessions have also changed in their skill sets, expectations and the use of technology. Based on the published literature and a recent faculty workshop, we provide PBL facilitators and institutions with 12 tips on how to make PBL more vibrant and interesting. We discuss our tips with reference to published literature and International Academy of Medical Education (AMEE) guidance. Our tips help students to engage with PBL, avoid monotony and make this teaching format more vibrant and fun for all involved. Introducing greater variety to the PBL process may also help with group dynamics by catering for a broader audience with different learning styles.


Tail skin temperatures reflect coping styles in rats.
This study was carried out to elucidate the predictive value of tail skin temperatures (TSTs) assessed in naïve rats as a non-invasive pre-experimental method of classification of coping style. Male Lewis rats were classified according to tail skin temperatures (TST), and relative size within cage-groups. TSTs were monitored over two-hour periods following exposure to physical and emotional stressors. Bodyweight-shifts associated to the experiments were analysed. Six organs of neuroendocrine relevance to allostasis were weighed. Challenge-specific TST-profiles were size-related and consistent with proactive or reactive coping. Pro-active (A) rats showed a more pronounced TST-response to unknown conspecifics, but reactive (B) rats to environmental novelties. B-rats showed challenge-specific weight-losses while A-rats gained more after experiments. Second size males showed rapidly decreased TSTs (vasoconstriction) after nociceptive stimulation. Males that showed the highest basal TSTs and weight-loss in emotionality tests had lost a first rank position during a pre-experimental period, suggesting long-lasting effects of social defeat. Pre-experimental growth correlated positively to adiposisity post-experimentally, but negatively to testes relative weight in B-rats. Scaling effects explained heart-size in B-rats and pituitary-size in A-rats. The overall patterns that emerged, in factor analyses including organ sizes, were consistent with pro-active coping in A-rats and reactive in B-rats. Our results, controlling for rank-effects, suggest that non-invasively assessed TSTs may predict individual stress-coping phenotypes pre-experimentally in rats housed in groups.


[The development of stomatological care of adult population of the Northern territories].
The article presents the results of complex study of state of teeth and organs of oral cavity and also quality of life of adult population of the Northern territories. The relation ship is established between state of teeth and organs of oral cavity and quality of life ofpopulation, the most expressed in individuals of youth age. The results of analysis of opinion of population are presented related to issues of organization of stomatological care and also data of expertise, SWOT-analysis combined with expertise values used as basis for development of system of measures concerning its optimization. Five main blocks were singled out: methodology of evaluation of stomatological health of population and organization of stomatological care; normative legal support, including adapted standard of stomatological care rendering; provision of accessibility of stomatological care at the expense of functional alterations of actual system; development of healthy live-style through program of prevention of stomatological diseases in adult population considering regional characteristics; system of training and re-training of manpower.


Recommendations for pharmacological management of inpatient aggression in children and adolescents.
Objective. While there has been a great deal of speculation by clinical researchers over the last three decades on effective and safe methods for the pharmacological management of aggression in children and adolescents, it is only in the last decade that there have been well-designed studies available to address this issue. Medication is commonly used to control aggression in children and adolescents in inpatient units. Also, there exists a need for evidence-based guidelines for the use of these different pharmacological agents for managing pediatric aggression on inpatient units. The aims of this article are to provide a systemic review and to provide treatment guidelines based on these limited but currently available studies.Methods. The articles reviewed in this study were obtained through a PubMed search using the key words 'children,' 'adolescents,' 'aggression,' 'inpatient,' 'ziprasidone,' 'lithium,' and 'risperidone.' A total of 499 studies were generated. Only studies focusing on pharmacological management of inpatient pediatric aggression with mean duration less than six weeks and published during January 1980 to August 2009 were included. Only English articles were considered. A total of 13 studies met these criteria, which were included in the review without any further statistical analysis. Recommendations are made on this available evidenced-based literature.Results. There is some evidence for the standing use of oral lithium, haloperidol, olanzapine, and risperidone for aggression related to specific psychiatric diagnoses. Intramuscular ziprasidone and olanzapine administered as needed were found to be effective for the rapid management of moderate to severe aggression. Oral or intramuscular diphenhydramine administered as needed was found to be useful for managing mild aggression due to a placebo effect.Conclusions. Studies are available on managing aggression in children and adolescents in inpatient treatment settings but are limited. Further studies on the use of various psychotropic medications are needed in order to develop comprehensive guidelines for the safe and effective pharmacological management of child and adolescent inpatient aggression.


Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the Bench-Stable Solid Reagent (Me4N)SCF3.
A highly efficient, selective, and rapid transformation of primary amines and diamines to isothiocyanates and cyclic thioureas is disclosed. As opposed to established approaches that employ toxic or volatile electrophilic liquids and require reaction control (i.e., slow addition, cooling), this protocol utilizes the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is characterized by operational simplicity, high speed, efficiency, high functional group tolerance, and late-stage applicability. The byproducts are solids, allowing isolation of the target compounds by filtration.


Phylogeny and morphology of Ovipleistophora diplostomuri n. sp. (Microsporidia) with a unique dual-host tropism for bluegill sunfish and the digenean parasite Posthodiplostomum minimum (Strigeatida).
Microsporidia are diverse opportunistic parasites abundant in aquatic organisms with some species hyperparasitic in digenean parasites. In the current study, we describe a unique microsporidian parasite, Ovipleistophora diplostomuri n. sp. that has a tropism for both the bluegill sunfish Lepomis macrochirus, and its digenean parasite Posthodiplostomum minimum. Though the microsporidium first infects a fish, the subsequent infection causes hypertrophy of the metacercarial wall and degeneration of the P. minimum metacercariae within the fish tissue. Genetic analysis placed this species within Ovipleistophora and ultrastructural characteristics were consistent with the genus, including the presence of dimorphic spores within sporophorous vesicles. Meronts did not have a surface coat of dense material, which has been previously reported for the genus. This is the first Ovipleistophora species described that does not have a tropism for ovary. Genetics demonstrated that O. diplostomuri n. sp. groups closely within fish microsporidia and not other species known to be hyperparasitic in digeneans, suggesting that it evolved from fish-infecting microsporidians and developed a secondary tropism for a common and widespread digenean parasite. The high genetic identity to Ovipleistophora species demonstrates the close relationship of this unique microsporidian with other microsporidia that infect ovary.


Preclinical predictors that the orthosteric mGlu2/3 receptor antagonist LY3020371 will not engender ketamine-associated neurotoxic, motor, cognitive, subjective, or abuse-liability-related effects.
The novel mGlu2/3 receptor antagonist, LY3020371, has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted screen. Ketamine, but not LY3020371, increased dopamine efflux in the nucleus accumbens of rats. Ketamine also produced cognitively-impairing effects in rats in a T-maze and in a psychomotor vigilance task and altered theta synchrony between the hippocampus and mPFC, whereas LY3020371 had either no significant impact or lesser effects in these assays. In mice, ketamine, but not LY3020371, negatively affected spontaneous alternation in a Y-maze. Rats were trained to discriminate LY3020371 from vehicle where 30mg/kg produced 100% drug-appropriate responding and the ED50 for LY3020371 was 9.4mg/kg, i.p. In rats discriminating LY3020371, neither d-amphetamine nor phencyclidine fully substituted for LY3020371 (35-45%) and the mGlu2/3 receptor agonist LY354740 partially attenuated the discriminative stimulus effects of LY3020371. These are the first data to demonstrate the discriminative stimulus effects of an mGlu2/3 receptor antagonist. Some alterations were suggested to occur in the density of mGlu2/3 receptor binding sites in the drug discrimination rats relative to their age-matched non-drug-exposed controls. In preclinical toxicology studies of 14day dosing of doses up to 1000mg/kg, i.v. in rats and up to 500m/kg, i.v. in Cynomologous monkeys, LY3020371 produced uM plasma exposures without producing critical toxicological findings. It is concluded that LY3020371 does not recapitulate the motor, cognitive, subjective, neurochemical, electrophysiological, or toxicological findings reported with ketamine. Thus, LY3020371 possesses both the efficacy signatures of a rapidly-acting antidepressant and a safety profile enabling proof of concept studies in patients.


[A study on the immunologic effects in workers exposed to low levels of toluene-diisocyanate (TDI)].
Forty-three workers exposed to low levels of toluene diisocyanate (TDI) during the process of producing polyurethane forms were examined immunologically for IgG, A, M, and E and serum enzyme activities such as serum angiotensin converting enzyme (SACE), serum lysozyme (SLZM) and glycylproline dipeptidyl aminopeptidase (GP-DAP). Air concentration of TDI was annually measured in various places of work during the past five years from 1979 to 1983. The results obtained in the present study were as follows. 1. The air concentration of TDI at all places of work was below the permissible concentration level of 0.02 ppm throughout the study period. 2. Subjective symptoms and abnormal findings on chest X-ray considered directly related to TDI exposure were not observed. 3. No remarkable abnormal findings in blood cell counts and in serum biochemical studies could be seen in any of the workers. 4. The serum IgG levels in workers directly exposed to TDI were significantly higher (p less than 0.05) than those in workers indirectly exposed to TDI and in non-exposed workers. 5. In the study of serum enzymatic activity, SLZM activity in workers exposed directly to TDI was significantly higher (p less than 0.01) than those in workers indirectly exposed to TDI and in non-exposed workers.


Real-time cytotoxicity assays in human whole blood.
A live cell-based whole blood cytotoxicity assay (WCA) that allows access to temporal information of the overall cell cytotoxicity is developed with high-throughput cell positioning technology. The targeted tumor cell populations are first preprogrammed to immobilization into an array format, and labeled with green fluorescent cytosolic dyes. Following the cell array formation, antibody drugs are added in combination with human whole blood. Propidium iodide (PI) is then added to assess cell death. The cell array is analyzed with an automatic imaging system. While cytosolic dye labels the targeted tumor cell populations, PI labels the dead tumor cell populations. Thus, the percentage of target cancer cell killing can be quantified by calculating the number of surviving targeted cells to the number of dead targeted cells. With this method, researchers are able to access time-dependent and dose-dependent cell cytotoxicity information. Remarkably, no hazardous radiochemicals are used. The WCA presented here has been tested with lymphoma, leukemia, and solid tumor cell lines. Therefore, WCA allows researchers to assess drug efficacy in a highly relevant ex vivo condition.


Disintegration mechanisms of charged aqueous nanodroplets studied by simulations and analytical models.
The mechanism of fragmentation processes in aqueous nanodroplets charged with ions is studied by molecular dynamics (MD) simulations. By using constant-temperature MD, the evaporation of the water is naturally taken into account and sequences of ion fragmentation events are observed. The size of the critical radius of the charged droplet just before the fragmentation and the distribution of the sizes of the fragments are estimated. Comparison of the Rayleigh critical radius for fragmentation and simulation data is within 0.23 nm. This seemingly small difference arises from a large difference in the number of water molecules that makes fragmentation an activated process as in the ion evaporation mechanism (IEM). This finding is in agreement with the predictions of Labowsky et al. [Anal. Chim. Acta 2000, 406, 105-118] for charged aqueous drops. The size of the daughter droplets is larger than the prediction of Born's theory by 0.1 to 0.15 nm. The nature and the dynamics of the intermediate states of the fragmentation process characterized by a bridge formed between the mother droplet and the evaporating ion or thorned structures where the ion sits on the tip are important for the outcome of the size-distribution of the fragments, while they are is missing in Born's theory.


Investigation of Water Absorption Behavior of Recycled Aggregates and its Effect on Concrete Strength.
The water-cement ratio (w/c) has a significant effect on the strength of recycled concrete. In this study, considering the effects of water/cement ratio, strength, and water content of recycled aggregates, two kinds of pulse sequences of low-field nuclear magnetic resonance (LF-NMR) were applied to investigate the water migration behavior between simulated recycled aggregates (SRA) and water or fresh mortar. Three sets of concrete strength tests were designed and the results were used to verify the findings of LF-NMR imaging tests. The results showed that the depth of water migration in the SRA increases with time: at first the change rate is rapid, then slows down, and eventually tends to remain stable. When the SRA is in contact with fresh mortar with low w/c, no water migration occurs because the hydration of the cement in the mixture consumes a large amount of water, resulting in the inability of water to migrate into the SRA through capillary pressure. For the recycled aggregate concrete with high strength, the addition of extra water will increase the effective w/c and reduce the compressive strength of the concrete.


Hospital workers: class conflicts in the making.
There is a real and conscious need for hospital workers to have meaningful work and to be adequately recognized for this work, both materially and in terms of respect and status within the institutions in which they are employed. These needs are frustrated by the conditions of work in the large modern hospital. Two main stabilizing forces, operating in part on different sets of workers, prevent hospital workers from collectively asserting their needs against the hospital's priorities. For the unskilled and semiskilled workers there are forces which lead to a typical industrial work ethic-alienation from the content of their work. For the skilled workers, there is the ideology of professionalism. The result is an increasing division of the nonmanagerial hospital work force into two groups with opposing class identifications: a proletarianized body of semiskilled and unskilled workers and a large group of skilled workers who are allowed to participate, through the ideology of professionalism, in the real status of the doctors.


Epidemiology and pathogenesis of diffuse obstructive coronary artery disease: the role of arterial stiffness, shear stress, monocyte subsets and circulating microparticles.
Despite falling age-adjusted mortality rates coronary artery disease (CAD) remains the leading cause of death worldwide. Advanced diffuse CAD is becoming an important entity of modern cardiology as more patients with historical revascularisation no longer have suitable anatomy for additional procedures. Advances in the treatment of diffuse obstructive CAD are hampered by a poor understanding of its development. Although the likelihood of developing clinically significant (obstructive) CAD is linked to traditional risk factors, the morphology of obstructive CAD among individuals is highly variable - some patients have diffuse stenotic disease, while others have a focal stenosis. This is challenging to explain in mechanistic terms as vascular endothelium is equally exposed to injury stimulants. Patients with diffuse disease are at high risk of adverse outcomes, particularly if unsuitable for revascularisation. We searched multiple electronic databases (MEDLINE, EMBASE and the Cochrane Database) and reviewed the epidemiology, pathogenesis and prognosis relating to advanced diffuse CAD with particular focus on the role of endothelial shear stress, large artery stiffness, monocyte subsets and circulating microparticles. Key messages Although traditional CAD risk factors correlate strongly with disease severity, significant individual variation in disease morphology exists. Advanced, diffuse CAD is difficult to treat effectively and can significantly impair quality of life and increases mortality. The pathophysiology associated with the progression of CAD is the result of complex maladaptive interaction between the endothelium, cells of the immune system and patterns of blood flow.


Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110.
Human B lymphocytes localize and differentiate within the microenvironment of lymphoid germinal centers. A frozen section binding assay was developed for the identification of those molecules involved in the adhesive interactions between B cells and lymphoid follicles. Activated human B cells and B cell lines were found to selectively adhere to germinal centers. The VLA-4 molecule on the lymphocyte and the adhesion molecule INCAM-110, expressed on follicular dendritic cells, supported this interaction. This cellular interaction model can be used for the study of how B cells differentiate.


Dual Activation of Nucleophiles and Electrophiles by N-Heterocyclic Carbene Organocatalysis: Chemoselective N-Imination of Indoles with Isocyanides.
The first chemoselective N-imination of indoles with isocyanides by using an N-heterocyclic carbene (NHC) as an organocatalyst was achieved. A concurrent activation of nucleophile (indole) and electrophile (isocyanide) took place facilitated by the novel NHC organocatalysis via initial activation of isocyanide. The in situ generated indole anion and imine-azolium species performed a coupling reaction, producing several new indole-based formamidines in high yields under mild conditions, which was not feasible via previously reported strategies.


Dithymine photodimers and photodecomposition products of thymidylyl-thymidine induced by ultraviolet radiation from 150 to 300 nm.
Solid thymidylyl-(3'-->5')-thymidine (dTpdT) was irradiated in a vacuum with monochromatic photons from 150 to 300 nm; the photoproducts were analyzed quantitatively by high-performance liquid chromatography. The results of the experiment were as follows: (1) above 210 nm the major photoproducts were three dithymine photodimers [the cis-syn and trans-syn cyclobutane thymine dimers and the thymine (6-4) photoproduct]; below 210 nm, they were three photodecomposition products (thymine, thymidine 5'-monophosphate and thymidine 3'-monophosphate). This shows that 210 nm is the wavelength at which the major photoproducts change from dithymine photodimers (far-UV type) to photodecomposition products (X-ray type). (2) The yields of the three dithymine photodimers had a similar wavelength dependence with each other: the yields had a peak at 260 nm and gradually decreased toward shorter wavelengths to 150 nm. (3) The yields of the three photodecomposition products also had a very similar wavelength dependence with each other: the yields increased exponentially with a decrease in the wavelength. (4) The average ratios of the yield of the (6-4) photoproduct to that of the cis-syn dimer were 0.30 between 170 and 220 nm, but 0.16 between 240 and 290 nm.


Survey nonresponse among ethnic minorities in a national health survey--a mixed-method study of participation, barriers, and potentials.
The participation rate in the Danish National Health Survey (DNHS) 2010 was significantly lower among ethnic minorities than ethnic Danes. The purpose was to characterize nonresponse among ethnic minorities in DNHS, analyze variations in item nonresponse, and investigate barriers and incentives to participation. This was a mixed-method study. Logistic regression was used to analyze nonresponse using data from DNHS (N = 177,639 and chi-square tests in item nonresponse analyses. We explored barriers and incentives regarding participation through focus groups and cognitive interviews. Informants included immigrants and their descendants of both sexes, with and without higher education. The highest nonresponse rate was for non-Western descendants (80.0%) and immigrants 25 (72.3%) with basic education. Immigrants and descendants had higher odds ratios (OR = 3.07 and OR = 3.35, respectively) for nonresponse than ethnic Danes when adjusted for sex, age, marital status, and education. Non-Western immigrants had higher item nonresponse in several question categories. Barriers to non-participation related to the content, language, format, and layout of both the questionnaire and the cover letter. The sender and setting in which to receive the questionnaire also influenced answering incentives. We observed differences in barriers and incentives between immigrants and descendants. Nonresponse appears related to linguistic and/or educational limitations, to alienation generated by the questions' focus on disease and cultural assumptions, or mistrust regarding anonymity. Ethnic minorities seem particularly affected by such barriers. To increase survey participation, questions could be sensitized to reflect multicultural traditions, and the impact of sender and setting considered.


Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.
Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P1 receptor (S1P1R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P1R on T cells, and that the requirement for S1P1R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.


Evaluation of the Health Situation among Recovered Cases of COVID-19 in West Bank, Palestine, and Their Onset/Recovery Time.
COVID-19 emerged at the end of 2019 and was classified as a global pandemic in March 2020. Infected cases of SARS-CoV-2 experience symptoms during initial infection 2-14 days after virus exposure, and some symptoms and complications may persist after recovery. This study evaluated the onset/recovery time, postrecovery symptoms, complications, and factors affecting the health situation of recovered cases of COVID-19 in West Bank, Palestine. This cross-sectional study was conducted using a questionnaire based on related scientific articles and expert recommendations. It was distributed to recovered COVID-19 patients either face-to-face or online. Chi-square and Fisher's exact tests were used to investigate the significant relationships. The data were analyzed using SPSS version 22. Findings. A total of 686 participants completed the questionnaire; the mean age was 28·1 ± 11·8. SARS-CoV-2 infection recovery time was 1-2 weeks in most participants. A total of 72·4% developed post-COVID-19 symptoms. Fatigue (260, 38.0%), loss of smell (224, 32.7%), headache (207, 30.7%), and joint pain (188, 27.4%) were the most reported postrecovery symptoms. In women, fatigue and headaches were the most common symptoms that persisted after recovery. Diabetic patients endured continuous muscle and joint pain. Interpretation. Patient health situation, recovery time, and symptoms post-COVID-19 infections are affected by many demographic factors and disease status.


Metabolomic-guided discovery of Alzheimer's disease biomarkers from body fluid.
The rapid increase in the older population has made age-related diseases like Alzheimer's disease (AD) a global concern. Given that there is still no cure for this neurodegenerative disease, the drastic growth in the number of susceptible individuals represents a major emerging threat to public health. The poor understanding of the mechanisms underlying AD is deemed the greatest stumbling block against progress in definitive diagnosis and management of this disease. There is a dire need for biomarkers that can facilitate early diagnosis, classification, prognosis, and treatment response. Efforts have been directed toward discovery of reliable and distinctive AD biomarkers but with very little success. With the recent emergence of high-throughput technology that is able to collect and catalogue vast datasets of small metabolites, metabolomics offers hope for a better understanding of AD and subsequent identification of biomarkers. This review article highlights the potential of using multiple metabolomics platforms as useful means in uncovering AD biomarkers from body fluids. © 2017 Wiley Periodicals, Inc.


Combination of Anti-VEGF and Laser Photocoagulation for Diabetic Macular Edema: A Review.
Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. Thirty years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid laser photocoagulation reduces moderate vision loss from DME by 50% or more; thus, macular photocoagulation became the gold standard treatment for DME. However, with the development of anti-VEGF drugs (bevacizumab, ranibizumab, and aflibercept), better outcomes were obtained in terms of visual acuity gain and decrease in macular thickness in some studies when antiangiogenic drugs were administered in monotherapy. Macular laser therapy may still play an important role as an adjuvant treatment because it is able to improve macular thickness outcomes and reduce the number of injections needed. Here, we review some of the clinical trials that have assessed the efficacy of macular laser treatment, either as part of the treatment protocol or as rescue therapy.


Trampolines: What's the Harm?
Trampolines hold the promise of fun and enjoyment for many children, but they are associated with a significant number of orthopedic and other injuries. Injuries vary from minor to severe, and the most common are extremity injuries. Although most injuries are associated with residential (ie, backyard) trampolines, a growing number of injuries now occur in trampoline parks. Adult supervision has not been effective for prevention. Emerging data on trampoline park-related injuries indicate that caution should be exercised in these settings as well. [Pediatr Ann. 2018;47(10):e385-e387.].


Trends in the treatment of hypertension from the perspective of traditional chinese medicine.
Hypertension is a major public-health issue. Much consensus has been reached in the treatment, and considerable progress has been made in the field of antihypertensive drugs. However, the standard-reaching rate of blood pressure is far from satisfaction. Considering these data and the seriousness of the effects of hypertension on the individual and society as a whole, both economically and socially, physicians must look for more effective and alternative ways to achieve the target blood pressure. Could treatment of hypertension be improved by insights from traditional Chinese medicine? As one of the most important parts in complementary and alternative therapies, TCM is regularly advocated for lowering elevated blood pressure. Due to the different understanding of the pathogenesis of hypertension between ancient and modern times, new understanding and treatment of hypertension need to be reexplored. Aiming to improve the efficacy of Chinese herbal medicine in treating hypertension, the basis of treatment is explored through systematically analyzing the literature available in both English and Chinese search engines. This paper systematically reviews the trends in emerging therapeutic strategies for hypertension from the perspective of traditional Chinese medicine.


Brown and beige adipose tissues: phenotype and metabolic potential in mice and men.
With the recent rediscovery of brown fat in adult humans, our outlook on adipose tissue biology has undergone a paradigm shift. While we attempt to identify, recruit, and activate classic brown fat stores in humans, identification of beige fat has also raised the possibility of browning our white fat stores. Whether such transformation of human white fat depots can be achieved to enhance the whole body oxidative potential remains to be seen. Evidence to date, however, largely points toward a major oxidative role only for classic brown fat depots, at least in rodents. White fat stores seem to provide the main fuel for sustaining thermogenesis via lipolysis. Interestingly, molecular markers consistent with both classic brown and beige fat identity can be observed in human supraclavicular depot, thereby complicating the discussion on beige fat in humans. Here, we review the recent advances made in our understanding of brown and beige fat in humans and mice. We further provide an overview of their plausible physiological relevance to whole body energy metabolism.


Proteomic tracking of serum protein isoforms as screening biomarkers of ovarian cancer.
Epithelial ovarian cancer is the fourth leading cause of cancer death among women. Due to the asymptomatic nature and poor survival characteristic of the disease, screening for specific biomarkers for ovarian cancer is a major health priority. Differentially expressed proteins in the serum of ovarian cancer patients have the potential to be used as cancer-specific biomarkers. In this study, proteomic methods were used to screen 24 serum samples from women with high-grade ovarian cancer and compared to a control group of 11 healthy women. Affigel-Blue treated serum samples were processed either by linear (pH 4-7) or narrow range (pH 5.5-6.7) IEF strips for the first dimension. Proteins separated in first dimension were resolved by 8-16% gradient SDS-PAGE. Protein spots were visualized by SYPRO Ruby staining, imaged by FX-imager and compared and analyzed by PDQuest software. Twenty-two protein spots were consistently differentially expressed between normal and ovarian cancer patients by resolving proteins in a linear pH strip of 4-7 for the first dimension. Six of the protein spots, significantly up-regulated in grade 3 ovarian cancer patients (p < 0.05), were identified by MALDI-TOF MS and Western blotting as the isoforms of haptoglobin precursor. When serum proteins were resolved on narrow pH range strips (5.5-6.7), 23 spots were consistently differentially expressed between normal and grade 3 ovarian cancer patients. Of these, 4 protein spots significantly down regulated in grade 3 ovarian cancer patients (p < 0.05) were identified by MALDI-TOF MS and Western blotting, as isoforms of transferrin precursor. Increased expression of serum haptoglobin and transferrin was also identified in peritoneal tumor fluid obtained from women diagnosed with grade 2/3 ovarian cancer (n = 7). Changes in the expression of haptoglobin and transferrin in the serum of women with different pathological grades of ovarian cancer was examined by one-dimensional Western blotting method. Serum samples collected from women suffering from benign, borderline, grade 1, grade 2 and grade 3 cancer (n = 4 for haptoglobin and n = 5 for transferrin in each group) were analyzed and compared to the serum of normal healthy women. The mean serum haptoglobin expression in grade 3 ovarian cancer patients was fourfold higher than in the control subjects (p < 0.05). On the other hand, transferrin expression in grade 3 ovarian cancer patients was decreased by twofold than in normal healthy women (p < 0.05). Haptoglobin expression in the serum of cancer patients (n = 7) decreased following chemotherapy (six cycles of taxol/carboplatin). Concomitant with the decrease of haptoglobin, transferrin expression remained constant in four patients, but increased in three out of seven patients included in the study. Changes in serum expression of haptoglobin correlated with the change of CA 125 levels before and after chemotherapy. In conclusion, proteomic profiling of differentially expressed proteins in the sera of normal women compared to women with ovarian cancer can greatly facilitate the discovery of a panel of biomarkers that may aid in the detection of ovarian cancer with greater specificity.


Primary adenocarcinoma of the anus treated with combined modality therapy.
The purpose of this study was to determine the local control and survival of patients with adenocarcinoma of the anus who received combined modality therapy as a component of their treatment. Thirteen patients with primary anal adenocarcinoma (T1: 1, T2: 4, T3: 3, T4: 5; and N0: 9, N1: 2, N2: 2) were treated between 1989 and 2001 in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center. Three general treatment approaches were used that were based on physician and patient preference as well as tumor stage. These included preoperative combined modality therapy followed by abdominoperineal resection (n = 5), with four of the five receiving postoperative chemotherapy; local excision followed by postoperative radiation alone or combined modality therapy (n = 5); and abdominoperineal resection followed by postoperative combined modality therapy (n = 3). Two patients received brachytherapy. With a median follow-up of 19 months, the median survival was 26 months, the local failure rate was 37 percent, and the two-year actuarial survival was 62 percent. In the subset of eight patients treated with abdominoperineal resection and preoperative or postoperative radiation or combined modality therapy, local control was 63 percent, and three of eight are without evidence of disease. Of the five patients who underwent a local excision followed by postoperative radiation or combined modality therapy, the local control rate was 60 percent, with one of the local failures salvaged by abdominoperineal resection and one of five patients without evidence of disease. Although the experience is limited, our data suggest that the combination of abdominoperineal resection and combined modality therapy is a reasonable approach for this rare tumor.


Reliable Entity Subtyping in Non-small Cell Lung Cancer by Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry on Formalin-fixed Paraffin-embedded Tissue Specimens.
Histopathological subtyping of non-small cell lung cancer (NSCLC) into adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) is of utmost relevance for treatment stratification. However, current immunohistochemistry (IHC) based typing approaches on biopsies are imperfect, therefore novel analytical methods for reliable subtyping are needed. We analyzed formalin-fixed paraffin-embedded tissue cores of NSCLC by Matrix-assisted laser desorption/ionization (MALDI) imaging on tissue microarrays to identify and validate discriminating MALDI imaging profiles for NSCLC subtyping. 110 ADC and 98 SqCC were used to train a Linear Discriminant Analysis (LDA) model. Results were validated on a separate set of 58 ADC and 60 SqCC. Selected differentially expressed proteins were identified by tandem mass spectrometry and validated by IHC. The LDA classification model incorporated 339 m/z values. In the validation cohort, in 117 cases (99.1%) MALDI classification on tissue cores was in accordance with the pathological diagnosis made on resection specimen. Overall, three cases in the combined cohorts were discordant, after reevaluation two were initially misclassified by pathology whereas one was classified incorrectly by MALDI. Identification of differentially expressed peptides detected well-known IHC discriminators (CK5, CK7), but also less well known differentially expressed proteins (CK15, HSP27). In conclusion, MALDI imaging on NSCLC tissue cores as small biopsy equivalents is capable to discriminate lung ADC and SqCC with a very high accuracy. In addition, replacing multislide IHC by an one-slide MALDI approach may also save tissue for subsequent predictive molecular testing. We therefore advocate to pursue routine diagnostic implementation strategies for MALDI imaging in solid tumor typing.


Human ventromedial prefrontal cortex and the positive affective processing of safety signals.
Human functional magnetic resonance imaging (fMRI) studies suggest that the ventromedial prefrontal cortex (vmPFC) contributes to the learned discrimination of threat and safety signals, although its precise contribution to these processes remains unclear. One hypothesis is that the vmPFC supports the positive affective processing of safety signals linked to their implicit stress-relieving properties. We set out to test this hypothesis and to examine the specificity of vmPFC responses to safety signal processing versus its high level of 'default mode' activity. Sixty participants completed an fMRI conditioning task that involved the generation of a conditioned threat (CS+) and safety (CS-) signal following the completion of a pre-conditioning baseline. Confirming past findings, activation of the vmPFC and other midline cortical and parietal areas - broadly resembling the default mode network - robustly discriminated between the CS- and CS+. However, when adjusting for this network's characteristic 'baseline' activity, only a subset of regions, including the vmPFC, was activated by the CS-. Regional selectivity for safety signal processing was confirmed by demonstrating a significant correlation between the magnitude of vmPFC responses and self-rated positive affect evoked by the CS-. Taken together, our current findings confirm a link between human vmPFC activity and the positive affective processing of safety signals. We discuss these findings with regards a broader model of human vmPFC function and its suggested higher-order contribution to emotionally adaptive behavior.


Facile Way of Making Hydrothermally Synthesized Crystalline SrSnO3 Perovskite Nanorods Suitable for Blue LEDs and Spintronic Applications.
Mn doping in SrSnO3 perovskite material via hydrothermal process under subcritical conditions is reported for the very first time. The present article aims to carry this perovskite suitable for blue light-emitting diodes (LEDs) and spintronic applications. The influence of various Mn doping percentages on structural, morphological, compositional, optical, photoluminescent, and magnetic properties of SrSnO3 is demonstrated. The perovskite material is grown in an orthorhombic crystal structure having a space symmetry of Pnma along with point group of mmm as determined from the Rietveld refinement. Doping is an excellent way to modify the properties of wide-band-gap perovskite nanostructures. Incorporation of Mn is the result of exact substitution. Morphological studies indicate formation of rodlike structures with thickness in nanoscale dimensions (180-280 nm), and the thickness is a function of doping concentration. The higher doping concentration resulted in enhanced growth of the nanorods. Selected area electron diffraction (SAED) results showed the single-crystal nature of the nanorods. Thermogravimetric analysis (TGA) confirmed the high stability of the material at elevated temperatures. Also, the doped perovskite material is transparent in the visible light, active in the ultraviolet region having a band gap of ∼2.78 eV, and is tuned up to 2.25 eV as the Mn doping concentration reaches 10%. The transfer of excitonic energy from the host material to the dopant Mn2+ ion leads to the formation of spin-forbidden [4T1-6A1] emission. Later on, photoluminescence study indicates an enhancement in luminescence behavior of Mn doped perovskite nanostructures. The Commission Internationale de l'éclairage (CIE) diagram drawn to find the color coordinates of the nanorods determines their suitability for blue LEDs. In addition, Mn doping results the conversion of diamagnetic SrSnO3 into a ferromagnetic material, making the nanorods suitable for spintronic applications.


Ion distributions around left- and right-handed DNA and RNA duplexes: a comparative study.
The ion atmosphere around nucleic acids is an integral part of their solvated structure. However, detailed aspects of the ionic distribution are difficult to probe experimentally, and comparative studies for different structures of the same sequence are almost non-existent. Here, we have used large-scale molecular dynamics simulations to perform a comparative study of the ion distribution around (5'-CGCGCGCGCGCG-3')2 dodecamers in solution in B-DNA, A-RNA, Z-DNA and Z-RNA forms. The CG sequence is very sensitive to ionic strength and it allows the comparison with the rare but important left-handed forms. The ions investigated include Na(+), K(+) and Mg(2 +), with various concentrations of their chloride salts. Our results quantitatively describe the characteristics of the ionic distributions for different structures at varying ionic strengths, tracing these differences to nucleic acid structure and ion type. Several binding pockets with rather long ion residence times are described, both for the monovalent ions and for the hexahydrated Mg[(H2O)6](2+) ion. The conformations of these binding pockets include direct binding through desolvated ion bridges in the GpC steps in B-DNA and A-RNA; direct binding to backbone oxygens; binding of Mg[(H2O)6](2+) to distant phosphates, resulting in acute bending of A-RNA; tight 'ion traps' in Z-RNA between C-O2 and the C-O2' atoms in GpC steps; and others.


Pericentromeric genes for non-specific X-linked mental retardation (MRX).
Extensive linkage analyses in three families with non-specific X-linked mental retardation (MRX) have localized the gene in each family to the pericentromeric region of the chromosome. The MRX17 gene is localized with a peak lod of 2.41 (theta = 0.0) with the trinucleotide repeat polymorphism at the androgen receptor (AR) gene locus. This gene lies in the interval between the markers DXS255 and DXS990, as defined by recombinants. The MRX18 gene maps to the interval between the markers DXS538 and DXS1126, with a peak lod score of 2.01 (theta = 0.0) at the PFC gene locus. In the third family (Family E) with insufficient informative meioses for assignment of an MRX acronym, the maximum lod score is 1.8 at a recombination fraction of zero for several marker loci between DXS207 and DXS426. Exclusions from the regions of marker loci spanning Xq support the localization of the MRX gene in Family E to the pericentromeric region. Localizations of these and other MRX genes have determined that MRX2 and MRX19 map to distal Xp, MRX3, and MRX6 map to distal Xq, whilst the majority cluster in the pericentromeric region. In addition, we confirm that there are at least two distinct MRX genes near the centromere as delineated by the non-overlapping regional localizations of MRX17 and MRX18. Determination of these non-overlapping localizations is currently the only means of classifying non-syndromal forms of mental retardation and determining the minimum number of MRX loci.


Atmospheric pressure plasma treatment of skin: penetration into hair follicles.
Sterilization of skin prior to surgery is challenged by the reservoir of bacteria that resides in hair follicles. Atmospheric pressure plasma jets (APPJs) have been proposed as a method to treat and deactivate these bacteria as atmospheric plasmas are able to penetrate into structures and crevices with dimensions similar to those found in hair follicles. In this paper, we discuss results from a computational investigation of an APPJ sustained in helium flowing into ambient air, and incident onto a layered dielectric similar to human skin in which there are idealized hair follicles. We found that, depending on the location of the follicle, the bulk ionization wave (IW) incident onto the skin, or the surface IW on the skin, are able to launch IWs into the follicle. The uniformity of treatment of the follicle depends on the location of the first entry of the plasma into the follicle on the top of the skin. Typically, only one side of the follicle is treated on for a given plasma pulse, with uniform treatment resulting from rastering the plasma jet across the follicle over many pulses. Plasma treatment of the follicle is sensitive to the angle of the follicle with respect to the skin, width of the follicle pocket, conductivity of the dermis and thickness of the underlying subcutaneous fat layer, the latter due to the change in capacitance of the tissue.


Synthetic biology-instructed transdermal microneedle patch for traceable photodynamic therapy.
5-Aminolevulinic acid-based photodynamic therapy heavily depends on the biological transformation efficiency of 5-aminolevulinic acid to protoporphyrin IX, while the lack of an effective delivery system and imaging navigation are major hurdles in improving the accumulation of protoporphyrin IX and optimizing therapeutic parameters. Herein, we leverage a synthetic biology approach to construct a transdermal theranostic microneedle patch integrated with 5-aminolevulinic acid and catalase co-loaded tumor acidity-responsive copper-doped calcium phosphate nanoparticles for efficient 5-aminolevulinic acid-based photodynamic therapy by maximizing the enrichment of intratumoral protoporphyrin IX. We show that continuous oxygen generation by catalase in vivo reverses tumor hypoxia, enhances protoporphyrin IX accumulation by blocking protoporphyrin IX efflux (downregulating hypoxia-inducible factor-1α and ferrochelatase) and upregulates protoporphyrin IX biosynthesis (providing exogenous 5-aminolevulinic acid and upregulating ALA-synthetase). In vivo fluorescence/photoacoustic duplex imaging can monitor intratumoral oxygen saturation and protoporphyrin IX metabolic kinetics simultaneously. This approach thus facilitates the optimization of therapeutic parameters for different cancers to realize Ca2+/Cu2+-interferences-enhanced repeatable photodynamic therapy, making this theranostic patch promising for clinical practice.


Studies on immunoassays of peptide factors. III. Gastrin/iso-1-cytochrome C as immunogen for raising anti-gastrin antisera.
Iso-1-cytochrome c contains in penultimate position of its sequence a cysteine residue which in analogy to the known tertiary structures of cytochromes c should be exposed on the surface of the protein. Its selective reaction with N alpha-maleoyl-beta-alanyl-human-little-gastrin-I-[2-17] led to a well characterized and homogeneous gastrin conjugate to be used as immunogen in rabbits. The antisera raised by this procedure exhibited a degree of specificity for the hormone gastrin parallel to that of the gastrin receptor. This is clearly documented by comparison of the immune crossreactivities of gastrin-peptides of increasing chain length and of fragments corresponding to various regions of the hormone molecule with their biological activity. The immune response provoked in the animals by the use of an homogeneous immunogen was found to be highly reproducible in terms of specificity of the antigastrin antibodies.


Analysis of Methods for Long Vehicles Speed Estimation Using Anisotropic Magneto-Resistive (AMR) Sensors and Reference Piezoelectric Sensor.
With rapidly increasing traffic occupancy, intelligent transportation systems (ITSs) are a vital feature for urban areas. This paper analyses methods for estimating long (L > 10 m) vehicle speed and length using a self-developed system, equipped with two anisotropic magneto-resistive (AMR) sensors, and introduces a method for verifying the results. A well-known cross-correlation method of magnetic signatures is not appropriate for calculating the vehicle speed of long vehicles owing to limited resources and a long calculation time. Therefore, the adaptive signature cropping algorithm was developed and used with a difference quotient of a magnetic signature. An additional piezoelectric polyvinylidene fluoride (PVDF) sensor and video camera provide ground truth to evaluate the performances. The prototype system was installed on the urban road and tested under various traffic and weather conditions. The accuracy of results was evaluated by calculating the mean absolute percentage error (MAPE) for different methods and vehicle speed groups. The experimental result with a self-obtained data set of 600 unique entities shows that the average speed MAPE error of our proposed method is lower than 3% for vehicle speed in a range between 40 and 100 km/h.


Phonon and electron transport in Janus monolayers based on InSe.
We systematically investigated the phonon and electron transport properties of monolayer InSe and its Janus derivatives including monolayer In2SSe and In2SeTe by first-principles calculations. The breaking of mirror symmetry produces a distinguishable A 1 peak in the Raman spectra of monolayer In2SSe and In2SeTe. The long-range harmonic and anharmonic interactions play an important role in the heat transport of the group-III chalcogenides. The room-temperature thermal conductivity ([Formula: see text]) of monolayer InSe, In2SSe and In2SeTe are 44.6, 46.9, and 29.9 W (mK)-1, respectively. There is a competition effect between atomic mass, phonon group velocity and phonon lifetime. The [Formula: see text] can be further effectively modulated by sample size for the purpose of thermoelectric applications. Meanwhile, monolayer In2SeTe exhibits a direct band gap of 1.8 eV and a higher electron mobility than that of monolayer InSe, due to the smaller electron effective mass caused by tensile strain on the Se side and smaller deformation potential. These results indicate that 2D Janus group-III chalcogenides can provide a platform to design the new electronic, optoelectronic and thermoelectric devices.


Rats given dopamine-depleting brain lesions as neonates do not respond to acute homeostatic imbalances as adults.
Rats given near-total dopamine-depleting brain lesions as neonates exhibit none of the severe sensorimotor or ingestive dysfunctions that result when adult rats are given comparable lesions. These experiments showed that the apparent sparing of function is incomplete; when tested as adults, the brain-damaged animals did not eat in response to acute glucoprivation, nor did they drink water and saline in response to hypovolemia. Indeed, after receiving these homeostatic challenges, the animals became much less able to simply move about. In contrast to these marked effects, the dopamine-depleted rats ate normally after glucoprivation when they were handled hourly instead of being left alone. Similarly, administration of caffeine permitted them to drink while hypovolemic. These and other observations suggest that some central neurons other than those containing dopamine are responsible for maintaining behavioral activation in rats after neonatal destruction of dopaminergic fiber systems in the brain and that the homeostatic challenges compromise their function and thereby disrupt behavior.


Evaluation of the usefulness of nitroblue tetrazolium reduction test (NBT test) for detection of bacterial infection in cancer patients.
False positivity of the NBT test in neoplastic diseases described by some authose may be a limitation in the use of the test for infection screening in cancer patients. For explaining this problem studies were performed in a group of 30 patients with various untreated malignancies without infection and in 20 of these with bacteriologically confirmed infections. The obtained results were compared with those in groups of normal persons without and with infection. Slightly modified Park method for spontaneous and stimulated NBT test was used. No significant differences between patients of both groups without infection were found. The increase in positivity of the test in presence of infection was lower in cancer patients than in normal subjects, however, it was non-significant. We did not observe any false-positive results in our patients, though one case of false negativity in myeloma is described separately. It is concluded that neoplastic disease does not cause, as such positivity of the NBT test. Because of similar response of NBT test to presence of infection, the NBT test is recognized as very useful for infection screening in cancer patients similarly as in normal persons.


Bayesian action&perception: representing the world in the brain.
Theories of perception seek to explain how sensory data are processed to identify previously experienced objects, but they usually do not consider the decisions and effort that goes into acquiring the sensory data. Identification of objects according to their tactile properties requires active exploratory movements. The sensory data thereby obtained depend on the details of those movements, which human subjects change rapidly and seemingly capriciously. Bayesian Exploration is an algorithm that uses prior experience to decide which next exploratory movement should provide the most useful data to disambiguate the most likely possibilities. In previous studies, a simple robot equipped with a biomimetic tactile sensor and operated according to Bayesian Exploration performed in a manner similar to and actually better than humans on a texture identification task. Expanding on this, "Bayesian Action&Perception" refers to the construction and querying of an associative memory of previously experienced entities containing both sensory data and the motor programs that elicited them. We hypothesize that this memory can be queried (i) to identify useful next exploratory movements during identification of an unknown entity ("action for perception") or (ii) to characterize whether an unknown entity is fit for purpose ("perception for action") or (iii) to recall what actions might be feasible for a known entity (Gibsonian affordance). The biomimetic design of this mechatronic system may provide insights into the neuronal basis of biological action and perception.


A comparative in vitro efficacy of conventional rotatory and chemomechanical caries removal: Influence on cariogenic flora, microhardness, and residual composition.
Chemomechanical caries removal system is part of the minimal invasive dentistry; the aim of the study was to compare the amount of bacteria after caries removal with chemomechanical system and conventional rotatory instruments and to test the Vickers microhardness and micro-RAMAN analysis of residual dentin after excavation. Molars were induced for demineralization, confirmed with DIAGNOdent; Streptococcus mutans were inoculated into the cavities and filled. Caries removal was performed with rotatory instruments and chemomechanical system; surviving bacteria were cultured for 24 and 48 hours at 37°C. Vickers microhardness and micro-RAMAN analysis were tested after excavation. Data were analyzed with Wilcoxon, continuity correction, odds ratio, ANOVA post hoc Tukey test, and Spearman correlation. Demineralization was significantly detectable at 240 hours of incubation; conventional rotatory instruments and chemomechanical caries removal were effective in 19.4%-22.6% and 25.8%-32.3%, respectively. Vickers microhardness of chemomechanical system was higher (P < 0.0001) than conventional rotatory instruments and comparable to healthy dentin. Micro-RAMAN analysis showed that healthy dentin is correlated to chemomechanical system (R (2) = 0.683, P < 0.00001) and drilling with burs (R (2) = 0.139, P < 0.00001). The chemomechanical system is effective for caries elimination, comparable to conventional rotatory instruments; the remaining Vickers microhardness and composition surface tissue are similar to healthy dentin.


Etiological Classification of Cerebral Ischemic Stroke by the TOAST, SSS-TOAST, and ASCOD Systems: The Impact of Observer's Experience on Reliability.
To assess the impact of observer's experience on reliability of etiological classification systems in patients with ischemic stroke. We retrospectively reviewed medical records of 80 patients with ischemic stroke in hospitals from August 2016 to March 2017 consecutively. Patients were classified by 4 observers with different clinical experiences and backgrounds (A, B, C, and D) according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST), Stop Stroke Study TOAST (SSS-TOAST), and ASCOD (A-atherosclerosis, S-small vessel disease, C-cardiac pathology, O-other cause, and D-dissection). The intraobserver reliability was assessed based on the initial and a second delayed assessment after 3 months, and the interobserver reliability of different pairs (A-B and C-D) and overall (A, B, C, and D) were compared based on the initial classification. The reliability values of the 3 classification systems were improved with observer's experience increasing, particularly in the TOAST system, in which the intraobserver reliability values of observers A, B, C, and D were 0.62, 0.73, 0.80, and 0.88, respectively, and slight differences were observed between the SSS-TOAST and ASCOD systems. The A-B pair had lower interobserver reliability value than the C-D pair, particularly in TOAST system with reliability values of 0.36 and 0.74, respectively, and a slight variation of interobserver reliability values were noted in the SSS-TOAST and ASCOD system. Observer's experience may affect the reliability of etiological classification systems in patients with ischemic stroke.


Micro-computed tomography analysis of the lumbar pedicle wall.
Although the pedicle is routinely used as a surgical fixation site, the pedicle wall bone area fraction (bone area per unit area) and its distribution at the isthmus of the pedicle remain unknown. The bone area fraction at the pedicle isthmus is an important factor contributing to the strength of pedicle screw constructs. This study investigates the lumbar pedicle wall microstructure based on micro-computed tomography. Six fresh-frozen cadaveric lumbar spines were analyzed. Left and right pedicles of each vertebra from L1 to L5 were resected for micro-computed tomography scanning. Data was analyzed with custom-written software to determine regional variation in pedicle wall bone area fraction. The pedicular cross-section was divided into four regions: lateral, medial, cranial, and caudal. The mean bone area fraction values for each region were calculated for all lumbar spine levels. The lateral region showed lower bone area fraction than the medial region at all spinal levels. Bone area fraction in the medial region was the highest at all levels except for L4, and the median values were 99.8% (95.9-100%). There were significant differences between the lateral region and the caudal region at L1, L2 and L3, but none at L4 and L5. The bone area fraction in the lateral region was less than 64% at all spinal levels and that in the caudal region was less than 67% at the L4 and L5 levels. This study provides initial detailed data on the lumbar pedicle wall microstructure based on micro-computed tomography. These findings may explain why there is a higher incidence of pedicle screw breach in the pedicle lateral and caudal walls.


Antimicrobial and antioxidant phytochemicals in leaf extracts of Bergenia ligulata: a Himalayan herb of medicinal value.
Phenolic and flavonoid contents in leaf extracts of Bergenia ligulata have been analysed for their contribution in antimicrobial and antioxidant activities. The extracts were prepared in three solvents (separately) following maceration and soxhelt methods. The antimicrobial activity was tested using disc diffusion assay against a range of microorganisms along with the determination of minimum inhibitory concentration (MIC), while the antioxidant activity was tested following DPPH assay. Leaf extracts exhibited antimicrobial activity against all the three groups of microorganisms; results coincided with respective MIC. In general, the methanol extracts prepared through maceration favoured the determination of antimicrobial and antioxidant activities. Maximum values for phenolic and flavonoid contents were obtained in macerated methanol and ethyl acetate extracts, respectively. The statistical correlations exhibited the extent of the contribution of phenolic and flavonoid contents in antimicrobial and antioxidant activities and also indicated the involvement of other plant metabolites.


A cysteine residue in the third membrane-spanning segment of the human D2 dopamine receptor is exposed in the binding-site crevice.
The binding site in G-protein-linked neurotransmitter receptors is formed among their membrane-spanning segments. Because the binding site is in the plane of the bilayer and is accessible to charged, water-soluble agonists, it must lie in a crevice open to the extracellular, aqueous medium. Information about the structure of these receptors can be obtained by identifying the residues in the membrane-spanning segments which face this water-filled crevice. Human D2 dopamine receptor was expressed in human embryonic kidney 293 cells. Small, charged, sulfhydryl-specific methanethiosulfonate (MTS) derivatives irreversibly inhibited the binding of the D2-specific antagonist [3H]YM-09151-2 to these cells. The highly polar MTS derivatives should react with cysteine sulfhydryl groups only at the water-accessible surface of the receptor, which includes the surface of the binding-site crevice. In contrast, these reagents will have little access to sulfhydryls facing the lipid bilayer or buried in the protein interior. Positively charged MTS reagents irreversibly inhibited binding several hundredfold faster than a negatively charged MTS reagent, consistent with the affinity of the binding site for positively charged dopamine agonists and antagonists. Furthermore, both agonists and antagonists of the D2 receptor protected against irreversible inhibition by the MTS reagents. To identify the susceptible cysteine, we mutated, one at a time, five transmembrane and two extracellular cysteine residues to serine. Only the mutation of Cys118 to serine decreased the susceptibility of antagonist binding to irreversible inhibition by the MTS reagents. Thus, Cys118, a residue in the middle of the third membrane-spanning segment, is exposed in the D2 receptor binding-site crevice.


RC3/Neurogranin and Ca2+/calmodulin-dependent protein kinase II produce opposing effects on the affinity of calmodulin for calcium.
The interaction of calmodulin with its target proteins is known to affect the kinetics and affinity of Ca(2+) binding to calmodulin. Based on thermodynamic principles, proteins that bind to Ca(2+)-calmodulin should increase the affinity of calmodulin for Ca(2+), while proteins that bind to apo-calmodulin should decrease its affinity for Ca(2+). We quantified the effects on Ca(2+)-calmodulin interaction of two neuronal calmodulin targets: RC3, which binds both Ca(2+)- and apo-calmodulin, and alphaCaM kinase II, which binds selectively to Ca(2+)-calmodulin. RC3 was found to decrease the affinity of calmodulin for Ca(2+), whereas CaM kinase II increases the calmodulin affinity for Ca(2+). Specifically, RC3 increases the rate of Ca(2+) dissociation from the C-terminal sites of calmodulin up to 60-fold while having little effect on the rate of Ca(2+) association. Conversely, CaM kinase II decreases the rates of dissociation of Ca(2+) from both lobes of calmodulin and autophosphorylation of CaM kinase II at Thr(286) induces a further decrease in the rates of Ca(2+) dissociation. RC3 dampens the effects of CaM kinase II on Ca(2+) dissociation by increasing the rate of dissociation from the C-terminal lobe of calmodulin when in the presence of CaM kinase II. This effect is not seen with phosphorylated CaM kinase II. The results are interpreted according to a kinetic scheme in which there are competing pathways for dissociation of the Ca(2+)-calmodulin target complex. This work indicates that the Ca(2+) binding properties of calmodulin are highly regulated and reveals a role for RC3 in accelerating the dissociation of Ca(2+)-calmodulin target complexes at the end of a Ca(2+) signal.


In vitro selection for K562 cells with higher retrovirally mediated copy number of aldehyde dehydrogenase class-1 and higher resistance to 4-hydroperoxycyclophosphamide.
Previously, we have reported the successful expression of human aldehyde dehydrogenase class-1 (ALDH-1) in K562 leukemia cells using a retroviral vector and demonstrated low expression that resulted in up to three-fold increase in resistance to 4-hydroperoxycyclophosphamide (4-HC), an active derivative to cyclophosphamide. The purpose of this study was to investigate whether in vitro treatment with 4-HC will allow selection of K562 cells expressing higher levels of ALDH-1, and whether these selected cells are more resistant to 4-HC. Stably transfected or transduced K562 cells with retroviral pLXSN vector containing ALDH-1 cDNA (ALDH-1 cells) were treated repeatedly with 4-HC and then allowed to grow to confluence in liquid culture. Subsequently, the resistance to 4-HC of ALDH-1 cells treated once (ALDH-1+) or twice (ALDH-1++) with 4-HC was compared to ALDH-1 cells or wild-type K562 cells (WT cells). The results show significant increase in 4-HC resistance of ALDH-1+ (2- to 16-fold, p < 0.005) over ALDH-1 or WT cells. No difference was detected between ALDH-1+ and ALDH-1++. In addition, higher ALDH-1 mRNA and enzyme activity were found in ALDH-1+ compared to ALDH-1 cells. Southern analysis of DNA extracted from the different experimental groups demonstrated an eight-fold increase in ALDH-1 cDNA in ALDH-1+ versus the ALDH-1 cells. This was confirmed by sequential FISH analysis using biotin labeled pLXSN/ALDH-1 vector. Positive signals consistently localized to the centromeric region of chromosome 9 and the long arm of chromosome 17 were demonstrated only in the ALDH-1+ cells and represented a fusion product of multiple copies of the pLXSN/ALDH-1 vector. In summary, we have demonstrated that in vitro treatment with 4-HC results in the selection of K562 cells with multiple copies of ALDH-1 gene that are clustered in two main integration sites. These cells demonstrate significantly higher resistance to 4-HC when compared to previously untreated cells. Such successful in vitro selection could have significant implications for future cancer gene therapy protocols.


Interaction of polar molecules with resonant radio frequency electric fields: imaging of the NO molecular beam splitting.
The interaction between a NO supersonic beam and a resonant radio frequency (RF) field is investigated using laser ionization coupled to imaging techniques. It is shown how the resonant interaction leads to a beam splitting of +/-0.2 degrees toward both positive and negative direction perpendicular to the beam propagation axis. This phenomenon is rationalized using a model based on molecular interferences produced by the action of the resonant RF electric field.


Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study.
This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and -6 degrees head-down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0- infinity, AUC0-t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 microg/mL [day 1] to 14.74 microg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.


[Double-blind comparison of cefadroxil and cephalexin granules in the treatment of impetigo].
A double-blind clinical comparison of cefadroxil granules (CDX) and a long-acting preparation of cephalexin granules (L-CEX) was conducted in the treatment of impetigo in children. The long-acting cephalexin preparation was composed of 3 parts of granules soluble in the stomach and 7 parts of those soluble in the intestine. Drugs were administered at 3 different doses depending on the body weight of patients (Group I: less than 10 kg, Group II: between 10 kg and 20 kg, Group III: over 20 kg). Overall clinical evaluation by attending doctors: CDX group scored slightly better but not statistically significant results. Evaluation of usefulness: CDX group scored slightly better but not statistically significant results. Partially standardized evaluation: CDX scored statistically significantly higher points in the evaluation of total cases and Group II on Day 5, and Group II on Day 7. Cumulative points through Day 5 and Day 7 were not statistically significant. Follow-up evaluation by attending doctors: CDX group got a better result in total cases and Group II on day 3, and in total cases on days 5 and 7. Otherwise there was no statistically significant difference. Incidence of side effects was not significantly different between the 2 drug groups. As shown in Fig. 1, CDX was administered on rising in the morning, after lunch, and at bed time whereas L-CEX was given on rising and at bed time when the patients were relatively in fasting condition. This may have reduced the expected merit of L-CEX and some reserve is required in the interpretations of the results shown herein.


The Prevalence of Video Game Addiction and Its Relation to Anxiety, Depression, and Attention Deficit Hyperactivity Disorder (ADHD) in Children and Adolescents in Saudi Arabia: A Cross-Sectional Study.
Background and objective Video games have become a popular source of entertainment among children and adolescents, not only targeting the young generation but also increasingly popular among older demographics as well. This study aimed to assess the association between video game addiction and depression, anxiety, and attention deficit hyperactivity disorder (ADHD) among children and adolescents in Saudi Arabia. Materials and methods This was a cross-sectional study involving Saudi adolescents aged 12-16 years. A self-administered online survey was distributed on social media (Twitter, WhatsApp, and Snapchat). The survey addressed sociodemographic characteristics (i.e., age, gender, area of residence city, etc.). Arabic versions of the Patient Health Questionnaire-9 (PHQ-9), the seven-item Generalized Anxiety Disorder Scale (PHQ-GAD7), the ADHD Rating Scale-IV (ADHD-RS), and the seven-item Game Addiction Scale (GAS-7) questionnaires were distributed as well, including Arabic terms for depression, anxiety, and ADHD. Results A total of 393 surveys were completed (males: 58.3% vs. females: 41.7%). Of note, 63.1% of the respondents reported playing video games every day with an average of more than five hours of gaming time per day (25.2%). The prevalence of video game addiction was 62.1%. Independent risk factors of video game addiction included being young in age, playing video games every day, playing more than three hours per day, and playing multiplayer games. Furthermore, our findings suggest that a higher video game addiction score is correlated with higher scores in inattention, anxiety, and depression. Conclusion This study found a high prevalence of video game addiction among Saudi children and adolescents. Excessive video game playing negatively influences mental health and leads to issues including anxiety, depression, and ADHD. Also, younger males with an increased rate of regular playtime were more likely to exhibit video game addiction in comparison to the rest of the population. Further research is required to more comprehensively assess the prevalence rate of video game addiction and its effect on the mental health of the younger generation within the region.


Novel Ultra Localized and Dense Nitrogen Delta-Doping in Diamond for Advanced Quantum Sensing.
We introduce and demonstrate a new approach for nitrogen-vacancy (NV) patterning in diamond, achieving a deterministic, nanometer-thin, and dense delta-doped layer of negatively charged NV centers in diamond. We employed a pure nitridation stage using microwave plasma and a subsequent in situ diamond overgrowth. We present the highest reported nitrogen concentration in a delta-doped layer (1.8 × 1020 cm-3) while maintaining the pristine diamond crystal quality. This result combined with the large optically detected magnetic resonance contrast can pave the way toward highly sensitive NV-based magnetometers. We further employed this delta-doping technique on high-quality fabricated diamond nanostructures for realizing a topographic NV patterning in order to enhance the sensing and hyperpolarization capabilities of NV-based devices.


Examining Engagement With Public Health in the Implementation of School-Based Health Initiatives: Findings From the COMPASS Study.
Adolescence coincides with the adoption of health behaviors that schools are not necessarily equipped to properly address. Collaboration between schools and external health services such as public health could fill gaps in addressing student health. The current study uses student- and school-level survey data from 59 nonprivate secondary schools in Ontario, Canada in year 6 (2017-2018) of the COMPASS study to examine barriers to improving student health, and analyze the effect of public health engagement on student health behaviors. The majority of schools have received resources from their local public health unit, however, less than one third of schools were developing/implementing programs jointly, and 12% of schools reported no engagement. Students had higher odds of better overall mental health, of meeting screen time guidelines, and were less likely to bully others if public health units solved issues together with schools regarding these health behaviors. There is a notable lack of consistent public health engagement in schools participating in the COMPASS study despite a need for such services. Creating mechanisms to develop and strengthen effective partnerships between schools and external service providers such as public health might alleviate some barriers to implementing health interventions in Ontario secondary schools.


Antimicrobial susceptibility of bacteraemic isolates of Salmonella enterica serovar typhi and paratyphi infection in Pakistan from 2017-2020.
To determine the antibacterial susceptibility pattern of bacteraemia isolates of Salmonella enterica serovar typhi and paratyphi. The retrospective descriptive observational study was conducted at the Microbiology section of Dow Diagnostic Research and Reference Laboratory, and comprised blood culture reports from January 1, 2017, to Dec 30, 2020, which were screened for the presence of Salmonella typhi and paratyphi growth The frequency of the isolates and their antibiotic resistance patterns were analysed. Data was analysed using SPSS 20. Of the 174,190 blood culture samples, 62,709(36%) were positive for bacterial growth. Salmonella were isolated in 8,689(13.8%) samples of which 8,041(92.5%) were Salmonella typhi, 529(6%) were Salmonella paratyphi A and 119(1.3%) were Salmonella paratyphi B. There was a drastic increase in resistance to third-generation cephalosporin in Salmonella typhi from 71(12.8%) in 2017 to 1,420(71%) in 2018, 2,850(74.6%) in 2019 and 1,251(77%) in 2020. All isolates were sensitive to meropenem and azithromycin. A high number of extensively drug-resistant typhoid cases due to Salmonella typhi were found. All isolates were sensitive to meropenem and azithromycin.


Cellular assessment of muscle in COPD: case studies of two males.
The objective of this paper is to provide an overview of the recent developments in muscle physiology and biochemistry in general, and with respect to chronic obstructive pulmonary disease (COPD) specifically. As a way of illustration, we have presented data on the remodeling that occurs in vastus lateralis in two patients with COPD (COPD #1, forced expiratory volume in one second/forced vital capacity [FEV(1)/FVC] = 63%; COPD #2, FEV(1)/FVC = 41%) exhibiting differences in muscle wasting as compared to healthy controls (CON; FEV(1)/FVC = 111 +/- 2.2%, n = 4). Type I fibers percentages were lower in both COPD #1 (16.7) and COPD #2 (24.9) compared to CON (57.3 +/- 5.2). Cross sectional area of the type I fibers of the patients ranged between 65%-68% of CON and for the type II subtypes (IIA, IIAX, IIX) between 74% and 89% (COPD #1) and 17%-32% (COPD #2). A lower number of capillary contacts were observed for all fiber types in COPD #1 but not COPD #2. Lower concentrations of adenosine triphosphate (ATP) (24%-26%) and phosphocreatine (18%-20%), but not lactate occurred in COPD. In contrast to COPD #1, who displayed normal glucose transporter content, GLUT1 and GLUT4 were only 71% and 54%, respectively of CON in COPD #2. Lower monocarboxylate contents were found for MCT1 in both COPD #1 (63%) and COPD #2 (41%) and for MCT4 (78%) in COPD #1. Maximal oxidative enzyme activities (V(max)) for COPD #2 ranged between 37% (succinic dehydrogenase) and 70% (cytochrome C oxidase) of CON. For the cytosolic enzymes, V(max) ranged between 89% (hexokinase) to 31% (pyruvate kinase) of CON. Depressions were also observed in V(max) of the Na(+)-K(+)-ATPase for COPD #1 (66% of CON) but not COPD #2 (92% of CON) while V(max) of the Ca(2+)-ATPase was near normal in COPD #1 (84% CON). It is concluded that disturbances can occur in muscle to a wide range of excitation, contraction and metabolic processes in COPD.


Exosomes miR-22-3p Derived from Mesenchymal Stem Cells Suppress Colorectal Cancer Cell Proliferation and Invasion by Regulating RAP2B and PI3K/AKT Pathway.
Exosomes (exo) which contain proteins, microRNAs (miRNAs), and other bioactive substances can participate in intercellular signal transduction and material transport. Bone marrow mesenchymal stem cells (BMSCs) have a strong ability to produce exosomes. The purpose of this study was to observe the effect of hBMSCs-derived-exo miR-22-3p on proliferation and invasion of colorectal cancer (CRC) cells and to explore its mechanism. miR-22-3p and RAS oncogene family (RAP2B) expression was detected using qRT-PCR or Western blotting. Their interaction was confirmed by dual luciferase activity assay. Effects of miR-22-3p on cell proliferation and invasion were evaluated by CCK-8 and Transwell assay, respectively. Exosomes were extracted by the ultracentrifugation and identified through electron microscopy and Western blotting. In CRC tissues and cells, downregulation of miR-22-3p and upregulation of RAP2B were observed. According to the analysis of dual luciferase activity, RAP2B was a target gene of miR-22-3p. In addition, miR-22-3p obviously repressed the cells proliferation and invasion via mediating RAP2B/PI3K/AKT pathway. Coculture experiments indicated that miR-22-3p derived from hBMSCs-exo had inhibition effects on SW480 cell proliferation and invasion. Collectively, miR-22-3p from hBMSCs-exo might impede CRC progression, which emphasized the potential of hBMSCs-exo-miR-22-3p as CRC treatment in the future.


Polymerization-Induced Proteinosome Formation Initiated by Artificial Cells.
Cellular communication is essential for living cells to coordinate the individual cellular responses and make collective behaviors. In the past decade, the communications between artificial cells have aroused great interest due to the potential applications of the structures in bioscience and biotechnology. To mimic the cellular communication, artificial cell assisted synthesis of proteinosomes was studied in this research. Multienzyme proteinosomes with glucose oxidase (GOx) and horseradish peroxidase (HRP) decorated on the membranes were synthesized by the thermally triggered self-assembly approach. Free radicals produced in a cascade reaction taking place on the surfaces of the multienzyme proteinosomes initiated reversible addition-fragmentation chain transfer (RAFT) polymerization of NIPAM at a temperature above LCST of PNIPAM in the presence of bovine serum albumin (BSA) or alcohol dehydrogenase (ADH)/acetaldehyde dehydrogenase (ALDH), and daughter proteinosomes with BSA or ADH/ALDH on the surfaces were fabricated. The structures of the GOx/HRP initiator proteinosomes, and the synthesized daughter proteinosomes were characterized with transmission electron microscopy, atomic force microscopy, fluorescence microscopy, dynamic light scattering, and micro-DSC. Enzyme activity assays demonstrate the high bioactivities of the enzymes on the surfaces of the initiator and the synthesized daughter proteinosomes.


Risk Factors for Post-stroke Depression: A Meta-analysis.
Background: Stroke not only impacts patients physically but also economically. Post-stroke depression (PSD), as a common complication of stroke, always obstructs the process of stroke rehabilitation. Accordingly, defining the risk factors associated with PSD has extraordinary importance. Although there have been many studies investigating the risk factors for PSD, the results are inconsistent. Objectives: The objectives of this study were to identify the risk factors for PSD by evidence-based medicine. Data sources: A systematic and comprehensive database search was performed of PubMed, Medline, CENTRAL, EMBASE.com, the Cochrane library and Web of Science for Literature, covering publications from January 1, 1998 to November 19, 2016. Study Selection: Studies on risk factors for PSD were identified, according to inclusion and exclusion criteria. The risk of bias tool, described in the Cochrane Handbook version 5.1.0, was used to assess the quality of each study. Meta-analysis was performed using RevMan 5.3 software. Results: Thirty-six studies were included for review. A history of mental illness was the highest ranking modifiable risk factor; other risk factors for PSD were female gender, age (<70 years), neuroticism, family history, severity of stroke, and level of handicap. Social support was a protective factor for PSD. Conclusion: There are many factors that have effects on PSD. The severity of stroke is an important factor in the occurrence of PSD. Mental history is a possible predictor of PSD. Prevention of PSD requires social and family participation.


Analysis of Feature Extraction Methods for Prediction of 30-Day Hospital Readmissions.
This article aims to determine possible improvements made by feature extraction methods to the machine learning prediction methods for predicting 30-day hospital readmissions. The study evaluates five feature extraction methods including principal component analysis (PCA), kernel principal component analysis (KPCA), isomap, Laplacian eigenmaps, and locality preserving projections (LPPs) for improving the accuracy of nine machine learning prediction methods in predicting 30-day hospital readmissions. The specific prediction methods considered include logistic regression, Cox regression, linear discriminant analysis, k-nearest neighbor (KNN), support vector machines (SVMs), bagged trees, boosted trees, random forest, and artificial neural networks. All models are developed in MATLAB and validated using area under the curve based on two population-based data sets from partner hospitals. Laplacian eigenmaps and isomap feature extraction provide the most improvement to the readmission predictive accuracy of KNN, SVM, bagged trees, boosted trees, and linear discriminant analysis methods. The results for artificial neural networks, random forest, Cox regression, and logistic regression show improvement for only one of the data sets. Also, PCA and LPP provided the best computation efficiency followed by KPCA, Laplacian eigenmaps, and isomap. Feature extraction methods can improve the predictive performance of machine learning methods for predicting readmissions. However, the improvement depended on the specific choice of the prediction method, feature extraction method, and the complexity of the data set features.


Angioneurotic edema associated with haloperidol.
Background. Angioneurotic edema is a life-threatening medical emergency that requires urgent diagnosis and treatment. Haloperidol is in the butyrophenone class of antipsychotic medications. Acute anaphylaxis to Haloperidol is very rare and no cases have been reported in literature. Objective. To report the association of life-threatening angioneurotic edema with intramuscular Haloperidol. Case Report. We present a case of an adult with no known allergies in whom angioneurotic edema with tongue swelling and protrusion developed after the administration of a single IM dose of Haloperidol. Conclusion. We propose angioneurotic edema in a rare side effect of Haloperidol. The onset of the symptoms is abrupt, but it may take 12-36 hours to resolve completely. Therefore patient should be monitored for 12-36 hrs.


[Intensity of protein synthesis in different sections of the brain of rats after arrest of systemic circulation].
Protein synthesis intensity in the tissue of various portions of the brain of rats pre-exposed to 10 min systemic circulation arrest was studied with the use of 3H-leucin, a protein synthesis labeled precursor, and compared with that in intact animals. Protein synthesis intensity in the brain of resuscitated animals was found to correlate with the degree of their neurologic status recovery. In rapidly recovering animals a significant intensification of protein synthesis is observed on day 4 after resuscitation in the sensorimotor cortex, hippocampus, and cerebellum. In the animals whose resuscitation was not so smooth this process develops only in the hippocampus and the intermedial and lateral portions of the cerebellum. In patients with disturbed neurologic status protein synthesis intensity was unchanged in all the examined portions of the brain. The authors suggest that protein synthesis activation phase is an obligatory stage in full-value neurologic recovery of resuscitated animals.


Jan Evangelista Purkinje: A Passion for Discovery.
December 2017 was the 230th anniversary of Jan Evangelista Purkinje's birth, which prompted us to review the life of this remarkable man who established the world's first department of physiology in Wroclaw and whose name is immortalized in the cardiologic eponym, Purkinje fibers. This paper offers an overview of Purkinje's life, legacy, and numerous scientific discoveries.


Tight glycemic control reduces infection and improves neurological outcome in critically ill neurosurgical and neurological patients.
Tight glycemic control (TGC) may improve outcomes in hyperglycemic neurosurgical patients. The adoption of TGC has been limited by a lack of adequate data on optimal insulin delivery protocols and serum glucose concentration and by concerns about the risks of hypoglycemia. This study was designed as a meta-analysis of outcomes to compare intensive insulin therapy and TGC with conventional insulin therapy and conventional glucose control. The secondary objective was to determine retrospectively whether a particular glucose range correlates with better outcomes. Using electronic databases, we retrieved all English language studies published between January 1997 and December 2010 reporting outcomes in neurological and neurosurgical patients as a function of glucose levels and insulin protocols. We conducted a meta-analysis around 4 outcome measures: infection, neurological outcome, hypoglycemia, and mortality. Effect sizes in each study were individually correlated with target intensive insulin therapy glucose levels. Individual studies were assessed for quality by use of the Jadad scale. Nine studies reporting on 1459 patients met the inclusion criteria. Five were restricted to neurosurgical patients. Four included neurological patients. Compared with conventional glucose control, TGC lowered infection rates (odds ratio, 0.59; 95% confidence interval, 0.47-0.76; P < .001) and yielded better neurological outcomes (odds ratio, 1.72; 95% confidence interval, 1.36-2.16; P < .001). Beneficial effects increased as glucose limits tightened and study quality improved (R > 0.9 for both). TGC resulted in a higher rate of hypoglycemic events (odds ratio, 8.04; 95% confidence interval, 4.85-13.31; P < .001). Mortality was not affected. TGC reduced infection risk and improved neurological outcome despite increased rates of hypoglycemic events. An optimal target for serum glucose concentrations could not be determined.


The p38 mitogen-activated protein kinase is activated by ligation of the T or B lymphocyte antigen receptors, Fas or CD40, but suppression of kinase activity does not inhibit apoptosis induced by antigen receptors.
We have investigated the activation of the p38 mitogen-activated protein kinase (MAPK) in normal mouse T and B cells and its role in apoptosis. Cross-linking of the CD3 chains of the TCR complex on proliferating T cells resulted in activation of p38 MAPK and MAPKAP kinase-2. Cross-linking of CD28 failed to activate p38 MAPK or MAPKAP kinase-2, but synergized strongly with low doses of anti-CD3. Cross-linking of Fas on T cells also induced rapid activation of p38 MAPK and MAPKAP kinase-2. The in vivo activation of MAPKAP kinase-2 in response to cross-linking of CD3, Fas, or CD3 and CD28 was shown to be dependent on p38 MAPK activity using a specific inhibitor, SB 203580. SB 203580 did not inhibit activation-induced cell death in T cells when used at concentrations that suppressed activation of MAPKAP kinase-2 in vivo. Cross-linking of the B cell Ag receptor (BCR) or CD40 on freshly isolated or LPS-activated splenic B cells or the immature B lymphoma, WEHI 231, resulted in activation of p38 MAPK and MAPKAP kinase-2. In vivo inhibition of p38 MAPK activity in WEHI 231 cells by SB 203580 had no effect on either BCR-induced apoptosis or anti-CD40-mediated suppression of apoptosis. We conclude that the activation of p38 MAPK and MAPKAP kinase-2 by cross-linking of the TCR, BCR, Fas, or CD40 was not correlated with their roles in regulating lymphocyte survival, and that suppression of kinase activity did not inhibit the induction of apoptosis.


Forest corridors between the central Andes and the southern Atlantic Forest enabled dispersal and peripatric diversification without niche divergence in a passerine.
The central Andean rainforests and the Atlantic Forest are separated by the Chaco and the Cerrado domains. Despite this isolation, diverse evidence suggests that these rainforests have been connected in the past. However, little is known about the timing and geographic positions of these connections, as well as their effects on diversification of species. In this study, we used the Black-goggled Tanager (Trichothraupis melanops, Thraupidae) as a model to study whether the Andean and the Atlantic forests have acted as a refugia system, and to evaluate biogeographic hypotheses of diversification and connection between these rainforests. We compared alternative biogeographic scenarios by using Approximate Bayesian Computation (ABC), modeled range shifts across time, and assessed niche divergence between regions. The results indicated that the major phylogeographic gap within T. melanops is located between these rainforests. The ABC analysis supported peripatric diversification, with initial dispersal from the Atlantic Forest to the Andes during the Mid-Pleistocene. Also, the results supported an Andean-Atlantic forests connection through the current Cerrado-Chaco transition, linking the southern Atlantic Forest with the central Andes. Our findings, taken together with other studies, support that the connection between these biomes has been recurrent, and that has occurred mostly through the Cerrado and/or the Cerrado-Chaco transition. The data also support that the connection dynamic has played an important role in the biological diversification, by promoting peripatric divergence in some forest taxa restricted to both biomes.


Positive changes after breast cancer: A qualitative study.
Traumatic events such as breast cancer along with negative effects on patients also have positive effects. These cases have been studied less in Iran. Therefore, this study was conducted with the aim of explanation of positive changes after breast cancer by using a qualitative approach. This qualitative study was conducted in 2012 in one of the specialized centers for cancer affiliated to Isfahan University of Medical Sciences. In this study, it was interviewed with 19 women with breast cancer about positive changes after cancer by using individual, open and deep methods. The interviews were analyzed with conventional content analysis method. The titles of the three major categories were included as behavioral changes to maintain and promote health (acquisition of health information and adopting promoting health behaviors), spiritual development (attention to the God and sense of meaning in life, revising the values and priorities, strengthening moral and behavioral traits) and personal growth and flourish (feeling empowerment, confidence and efforts to achieve the goals and desires). These three categories have led to emerge themes in this study as the "Awakening after cancer." The results of this study indicated positive changes after breast cancer. Considering such changes while providing care and consulting to patients with breast cancer in addition to facilitate and accelerate positive changes will be prompted to provide care and proper and influential consulting to promote patient health.


Enhancement of the luteinising hormone surge by male olfactory signals is associated with anteroventral periventricular Kiss1 cell activation in female rats.
Olfactory stimuli play an important role in regulating reproductive functions in mammals. The present study investigated the effect of olfactory signals derived from male rats on kisspeptin neuronal activity and luteinising hormone (LH) secretion in female rats. Wistar-Imamichi strain female rats were ovariectomised (OVX) and implanted with preovulatory levels of 17β-oestradiol (E2 ). OVX+E2 rats were killed 1 hour after exposure to either: clean bedding, female-soiled bedding or male-soiled bedding. Dual staining for Kiss1 mRNA in situ hybridisation and c-Fos immunohistochemistry revealed that the numbers of Kiss1-expressing cells and c-Fos-immunopositive Kiss1-expressing cells in the anteroventral periventricular nucleus (AVPV) were significantly higher in OVX+E2 rats exposed to male-soiled bedding than those of the other groups. No significant difference was found with respect to the number of c-Fos-immunopositive Kiss1-expressing cells in the arcuate nucleus and c-Fos-immunopositive Gnrh1-expressing cells between the groups. The number of c-Fos-immunopositive cells was also significantly higher in the limbic system consisting of several nuclei, such as the bed nucleus of the stria terminalis, the cortical amygdala and the medial amygdala, in OVX+E2 rats exposed to male-soiled bedding than the other groups. OVX+E2 rats exposed to male-soiled bedding showed apparent LH surges, and the peak of the LH surge and area under the curve of LH concentrations in the OVX+E2 group were significantly higher than those of the other two groups. These results suggest that olfactory signals derived from male rats activate AVPV kisspeptin neurones, likely via the limbic system, resulting in enhancement of the peak of the LH surge in female rats. Taken together, the results of the present study suggests that AVPV kisspeptin neurones are a target of olfactory signals to modulate LH release in female rats.