Dynamic leadership emergence: Differential impact of members' and peers' contributions in the idea generation and idea enactment phases of innovation project teams.
Integrating functional leadership theory with models of the team creativity and innovation, we present a dynamic model of leadership emergence where leadership emergence is shaped by (a) the type of contributions members express (constructive contributions proposing new ideas, or supportive contributions affirming ideas with merit), (b) when those contributions are expressed (i.e., in the idea generation or idea enactment phase), and (c) the extent fellow teammates themselves are contributing in constructive or supportive ways in those phases. We tested our theoretical model in two studies involving simulated teams engaged in an innovation design challenge. In both studies, we found that constructive contributions were more strongly related to leadership emergence in the idea generation phase than in the idea enactment phase. Moreover, the impact of constructive contributions on leadership emergence in the idea generation phase was stronger when there was a "void"-that is, fellow teammates' constructive contributions were low. Surprisingly, in both studies, we found consistent evidence that supportive contributions also enhanced leadership emergence in the idea generation phase, whereas the findings on supportive contributions and leadership emergence in the idea enactment phase were mixed. Overall, our model highlights the importance of integrating dynamic and contextualized aspects of teams into theories of leadership emergence and also sheds new light on the processes underlying emergent forms of leadership in the early phases of the innovation cycle. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The impact of postgraduate training on UK optometrists' clinical decision-making in glaucoma.
To investigate the impact of a postgraduate training module on optometrists' clinical decision-making in relation to the diagnosis and management of primary open-angle glaucoma. A group of United Kingdom community optometrists (n = 53) were assessed immediately before and again 3 months after completing a 3-day didactic postgraduate university module on the diagnosis and management of glaucoma. A smaller control cohort (n = 20), who did not receive the intervention, was recruited and completed the same assessments on two occasions, separated by approximately 3 months. The assessments comprised: knowledge of five key features of the optic disc in glaucoma, performance on a computer program (Discus) that assessed the ability to differentiate normal from glaucomatous discs and a clinical decision-making exercise using case-based scenarios. The scores for the knowledge of important disc features for the intervention cohort significantly increased from a median of 2/5 to 5/5 post-intervention (p < 0.001). For the control cohort, the difference in median scores between the two tests was not significant. Analysing the performance of the intervention cohort using the Discus program showed no significant improvement in ability to diagnose a glaucomatous disc following the intervention [mean area under the receiver operating characteristic curve pre-intervention = 0.85 (95% CI: 0.76-0.91), post-intervention = 0.84 (95% CI: 0.76-0.91)]. Similarly, there were no statistically significant differences in mean areas under the receiver operating characteristic curve between tests for the control cohort, although both cohorts compared favourably with a previously published Discus data set from a panel of experts in disc analysis (mean area = 0.87). For the clinical decision-making exercise the median test score for the intervention cohort was unchanged pre- and post-intervention. The results of the present study suggest that a traditional didactic approach, in isolation, is unlikely to be suited to training optometrists to achieve or develop the clinical competencies required for glaucoma detection and management. Consideration should be given to the development of specialist postgraduate training that is more practice-based, provides opportunities for active learning and includes strategies for feedback and reinforcement.


Phylogeography and conservation of impala and greater kudu.
The phylogeography of the bush habituated African bovid species impala (Aepyceros melampus) and greater kudu (Tragelaphus strepsiceros) is investigated using mitochondrial DNA (mtDNA) markers. Combined analysis of individual lineages, relationships and population genetics suggest a colonization process from Southern Africa toward Eastern regions in the greater kudu. Results are less clear for the impala, although remaining consistent with a similar pattern of historical dispersion. The study reveals a similar pattern, that is a marked divergence of lineages from South-western Africa relative to other regions. This pattern is opposed to previously published findings in other African bovid species. In the impala, the genetically isolated region is consistent with morphology because it is recognized as the subspecies A. m. petersi, the black-faced impala. In contrast, the similar split of South-western mitochondrial lineages was not expected in the greater kudu on the basis of morphology. Both species show a significant population genetic differentiation. Beyond their phylogeographical value, our results should raise conservation concerns about South-western populations of both species. The black-faced impala is categorized as vulnerable and our data show indications of hybridization with common impala A. m. melampus. The previously unrecognized genetic status of the South-western kudus could also imply conservation regulations.


Defining Dry Eye from a Clinical Perspective.
Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.


A sensitive and reliable assay for dopamine beta-hydroxylase in tissue.
A new assay procedure for dopamine beta-hydroxylase (DBH) in tissue extracts is described. Solubilized DBH was adsorbed from crude extracts on Concanavalin A-Sepharose (Con A-Sepharose), resulting in enrichment of the enzyme as well as removal of endogenous catecholamines and inhibitory substances. The enzymatic assay was carried out with DBH still adsorbed to Con A-Sepharose. The adsorption of the DBH to Con A-Sepharose offers three advantages over previous assay procedures. (1) Because of removal of the endogenous inhibitory substances, a single Cu2+ concentration can be used for the determination of DBH activity, regardless of the tissue dilution or inhibitor content of the analysed sample. Using this procedure, the optimal Cu2+ concentration for DBH of bovine adrenal gland extracts was 3 microM and for rat brain 10 microM. (2) Because of removal of endogenous catecholamines, dopamine, the main physiological substrate of DBH in noradrenergic neurons, can be used for the assay. The enzymatic reaction product, noradrenaline, was determined by high performance liquid chromatography and electrochemical detection (hplc-ec). This procedure resulted in an approx. 10-fold increase in sensitivity of the assay compared with other procedures, e.g., the radioenzymatic assay. (3) Direct determination of the immediate product of the enzymatic reaction (noradrenaline) permits kinetic analysis. It was found that the Michaelis constants for the substrate (dopamine) and co-factor (ascorbic acid) (2 mM and 0.65 mM, respectively) determined in bovine adrenal tissue extracts by the described procedure were identical with the values for the purified DBH preparation.


Cadmium induces reactive oxygen species-dependent pexophagy in Arabidopsis leaves.
Cadmium treatment induces transient peroxisome proliferation in Arabidopsis leaves. To determine whether this process is regulated by pexophagy and to identify the mechanisms involved, we analysed time course-dependent changes in ATG8, an autophagy marker, and the accumulation of peroxisomal marker PEX14a. After 3 hr of Cd exposure, the transcript levels of ATG8h, ATG8c, a, and i were slightly up-regulated and then returned to normal. ATG8 protein levels also increased after 3 hr of Cd treatment, although an opposite pattern was observed in PEX14. Arabidopsis lines expressing GFP-ATG8a and CFP-SKL enabled us to demonstrate the presence of pexophagic processes in leaves. The Cd-dependent induction of pexophagy was demonstrated by the accumulation of peroxisomes in autophagy gene (ATG)-related Arabidopsis knockout mutants atg5 and atg7. We show that ATG8a colocalizes with catalase and NBR1 in the electron-dense peroxisomal core, thus suggesting that NBR1 may be an autophagic receptor for peroxisomes, with catalase being possibly involved in targeting pexophagy. Protein carbonylation and peroxisomal redox state suggest that protein oxidation may trigger pexophagy. Cathepsine B, legumain, and caspase 6 may also be involved in the regulation of pexophagy. Our results suggest that pexophagy could be an important step in rapid cell responses to cadmium.


Cyclooxygenase-2-derived prostaglandin D(2) is an early anti-inflammatory signal in experimental colitis.
The ability of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors to exacerbate inflammatory bowel disease suggests that prostaglandins are important anti-inflammatory mediators in this context. Prostaglandin D(2) has been suggested to exert anti-inflammatory effects. We investigated the possibility that prostaglandin D(2) derived from cyclooxygenase-2 plays an important role in downregulating colonic inflammation in rats. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various times thereafter (from 1 h to 7 days), colonic prostaglandin synthesis and myeloperoxidase activity (index of granulocyte infiltration) were measured. Prostaglandin D(2) synthesis was elevated >4-fold above controls within 1-3 h of induction of colitis, preceding significant granulocyte infiltration. Treatment with a selective cyclooxygenase-2 inhibitor abolished the increase in prostaglandin D(2) synthesis and caused a doubling of granulocyte infiltration. Colonic granulocyte infiltration was significantly reduced by administration of prostaglandin D(2) or a DP receptor agonist (BW-245C). These results demonstrate that induction of colitis results in a rapid increase in prostaglandin D(2) synthesis via cyclooxygenase-2. Prostaglandin D(2) downregulates granulocyte infiltration into the colonic mucosa, probably through the DP receptor.


Spatial organization and mechanical properties of the pericellular matrix on chondrocytes.
A voluminous polymer coat adorns the surface of many eukaryotic cells. Although the pericellular matrix (PCM) often extends several microns from the cell surface, its macromolecular structure remains elusive. This massive cellular organelle negotiates the cell's interaction with surrounding tissue, influencing important processes such as cell adhesion, mitosis, locomotion, molecular sequestration, and mechanotransduction. Investigations of the PCM's architecture and function have been hampered by the difficulty of visualizing this invisible hydrated structure without disrupting its integrity. In this work, we establish several assays to noninvasively measure the ultrastructure of the PCM. Optical force probe assays show that the PCM of rat chondrocyte joint (RCJ-P) cells easily reconfigures around optically manipulated microparticles, allowing the probes to penetrate into rather than compress the matrix. We report distinct changes in forces measured from PCMs treated with exogenous aggrecan, illustrating the assay's potential to probe proteoglycan distribution. Measurements reveal an exponentially increasing osmotic force in the PCM arising from an inherent concentration gradient. With this result, we estimate the variation of the PCM's mesh size (correlation length) to range from ∼100 nm at the surface to 500 nm at its periphery. Quantitative particle exclusion assays confirm this prediction and show that the PCM acts like a sieve. These assays provide a much-needed tool to study PCM ultrastructure and its poorly defined but important role in fundamental cellular processes.


Expression, purification, crystallization and preliminary X-ray diffraction analysis of dihydrodipicolinate synthase from Bacillus anthracis in the presence of pyruvate.
Dihydrodipicolinate synthase (DHDPS) catalyses the first committed step in the lysine-biosynthesis pathway in bacteria, plants and some fungi. In this study, the expression of DHDPS from Bacillus anthracis (Ba-DHDPS) and the purification of the recombinant enzyme in the absence and presence of the substrate pyruvate are described. It is shown that DHDPS from B. anthracis purified in the presence of pyruvate yields greater amounts of recombinant enzyme with more than 20-fold greater specific activity compared with the enzyme purified in the absence of substrate. It was therefore sought to crystallize Ba-DHDPS in the presence of the substrate. Pyruvate was soaked into crystals of Ba-DHDPS prepared in 0.2 M sodium fluoride, 20%(w/v) PEG 3350 and 0.1 M bis-tris propane pH 8.0. Preliminary X-ray diffraction data of the recombinant enzyme soaked with pyruvate at a resolution of 2.15 A are presented. The pending crystal structure of the pyruvate-bound form of Ba-DHDPS will provide insight into the function and stability of this essential bacterial enzyme.


Raloxifene hydrochloride for breast cancer risk reduction in postmenopausal women.
Raloxifene is an estrogen receptor modulator which competes with estrogens for binding to the estrogen receptor. Based on the results of the STAR (Study of Tamoxifen And Raloxifene) trial, raloxifene has been approved by the U.S. Food and Drug Administration for the reduction of breast cancer (BC) risk in postmenopausal women at increased risk. Areas covered: This analysis reviews the activity of raloxifene and the clinical trials for non-BC indications which led to investigate its use as BC preventive agent. We review the trial establishing its efficacy for BC prevention and the meta-analyses including different SERMs for BC prevention. Expert commentary: Compared with tamoxifen, raloxifene has shown a slightly lower efficacy in reducing BC risk and a better safety profile. Raloxifene also offers to postmenopausal women a benefit in terms of osteoporosis. Future research should investigate its use in premenopausal women and in association with other preventive agents.


Magnetic solid phase extraction coupled with in situ derivatization for the highly sensitive determination of acidic phytohormones in rice leaves by UPLC-MS/MS.
A simple, rapid and sensitive method based on magnetic solid phase extraction (MSPE) coupled with in situ derivatization (ISD) was developed for the determination of endogenous acidic phytohormones in rice leaves by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. With this method, acidic phytohormones were extracted onto the surface of a TiO2/magnetic hollow mesoporous silica sphere (MHMSS) through hydrophilic interaction, and then in situ derivatization was performed by the subsequent addition of 3-bromoactonyltrimethylammonium bromide (BTA). Thus, the process integrated extraction, purification, and derivatization into one step. Additionally, the permanent positively charged moiety from BTA significantly improved the ionization efficiencies of the acidic phytohormones. Several parameters affecting the efficiencies of the extraction, derivatization, and desorption were evaluated. The signal intensities of acidic phytohormones increased by 2 to 481 fold after treatment with MSPE-ISD. Under the optimized conditions, several endogenous acidic phytohormones, including GA4, GA9, GA20, JA, IAA, and ABA, were identified and quantified in rice leaves by the MSPE-ISD method. The limits of detection (LODs) were in the range of 1.03-91.21 pg mL(-1). The relative recoveries ranged from 71.6-112.8%, with the intra- and interday relative standard deviations (RSDs) being less than 14.9% and 16.2%, respectively. Taken together, the proposed method provides a novel approach of combining magnetic solid phase extraction and in situ derivatization for the highly sensitive determination of endogenous acidic phytohormones.


High Solar-to-Hydrogen Conversion Efficiency at pH 7 Based on a PV-EC Cell with an Oligomeric Molecular Anode.
In the urgent quest for green energy vectors, the generation of hydrogen by water splitting with sunlight occupies a preeminent standpoint. The highest solar-to-hydrogen (STH) efficiencies have been achieved with photovoltaic-electrochemical (PV-EC) systems. However, most PV-EC water-splitting devices are required to work at extreme conditions, such as in concentrated solutions of HClO4 or KOH or under highly concentrated solar illumination. In this work, a molecular catalyst-based anode is incorporated for the first time in a PV-EC configuration, achieving an impressive 21.2% STH efficiency at neutral pH. Moreover, as opposed to metal oxide-based anodes, the molecular catalyst-based anode allows us to work with extremely small catalyst loadings (<16 nmol/cm2) due to a well-defined metallic center, which is responsible for the fast catalysis of the reaction in the anodic compartment. This work paves the way for integrating molecular materials in efficient PV-EC water-splitting systems.


Laparoscopic radical prostatectomy with the Heilbronn technique: oncological results in the first 500 patients.
Laparoscopic radical prostatectomy has become an accepted alternative to open surgery. However, there is still a lack of data concerning the oncological outcome. From March 1999 to July 2004, 1,078 patients underwent laparoscopic radical prostatectomy at our institution. Oncological results in the first 500 patients with a minimal followup of 23 months were analyzed, focusing on positive margins, prostate specific antigen (PSA) failure, clinical progression and survival. Median followup was 40 months (range 23 to 65). Of the patients 417 underwent pelvic lymph node dissection, which revealed positive nodes in 6 (1.2%). Positive margins were documented in 22 of 296 pT2 tumors (7.4%), 27 of 107 pT3a tumors (25.2%) and 29 of 69 pT3b tumors (42.0%). PSA recurrence was diagnosed in 55 patients (11.0%) at a mean of 20.8 months (range 6 to 36) that is stages pT2a, pT2b, pT3a and pT3b/4 in 3.2%, 6.5%, 15.9% and 23.9%, respectively. PSA progression-free rates were 83.0% at 3 years and 73.1% at 5 years. Two patients died of disease and 6 died of other causes (99.2% overall survival). The clinical progression rate was to 4.1% at 3 years and 9.8% at 5 years. No port site metastasis was observed. At centers of expertise laparoscopic radical prostatectomy may provide an oncological outcome similar to that of the open procedure. However, it offers the advantages of minimally invasive surgery.


Does the timing of the first family planning visit still matter?
The timing of a first family planning visit relative to first intercourse can affect the likelihood of an early unintended pregnancy. Nationally representative data from the 1982, 1988 and 1995 cycles of the National Survey of Family Growth were used to examine changes in the timing of first family planning visits and to explore the degree to which young women are now more likely than in the past to practice contraception independently of making a visit to a provider. Cox proportional hazards models were used to estimate how background variables, visit status and the initiation of contraceptive use affected risks of unintended pregnancy in the four years preceding each survey. The proportion of women who waited a month or more after their first intercourse to see a provider grew slightly between 1978 and 1995, from 76% to 79%; women waited a median of 22 months after first intercourse in 1991-1995. Any contraceptive use at first intercourse increased among both women who delayed a first visit (from 51% to 75%) and among those whose first visit occurred before their first intercourse or within the same month (from 61% to 91%). Cox proportional hazards analysis suggests that the protective effect of a first family planning visit decreased over the period studied, due in part to the increase in early contraceptive use. The importance of the first family planning visit appears to be declining, as sexually active young women who delay their first visit increasingly do so because they are already using a provider-independent method (primarily the condom). Thus, a multifaceted approach to providing family planning may now be needed, in which independent method use and visits to providers both play a role.


Sampling and detection of airborne influenza virus towards point-of-care applications.
Airborne transmission of the influenza virus contributes significantly to the spread of this infectious pathogen, particularly over large distances when carried by aerosol droplets with long survival times. Efficient sampling of virus-loaded aerosol in combination with a low limit of detection of the collected virus could enable rapid and early detection of airborne influenza virus at the point-of-care setting. Here, we demonstrate a successful sampling and detection of airborne influenza virus using a system specifically developed for such applications. Our system consists of a custom-made electrostatic precipitation (ESP)-based bioaerosol sampler that is coupled with downstream quantitative polymerase chain reaction (qPCR) analysis. Aerosolized viruses are sampled directly into a miniaturized collector with liquid volume of 150 μL, which constitutes a simple and direct interface with subsequent biological assays. This approach reduces sample dilution by at least one order of magnitude when compared to other liquid-based aerosol bio-samplers. Performance of our ESP-based sampler was evaluated using influenza virus-loaded sub-micron aerosols generated from both cultured and clinical samples. Despite the miniaturized collection volume, we demonstrate a collection efficiency of at least 10% and sensitive detection of a minimum of 3721 RNA copies. Furthermore, we show that an improved extraction protocol can allow viral recovery of down to 303 RNA copies and a maximum sampler collection efficiency of 47%. A device with such a performance would reduce sampling times dramatically, from a few hours with current sampling methods down to a couple of minutes with our ESP-based bioaerosol sampler.


Evaluation of vehicular pollution levels using line source model for hot spots in Muscat, Oman.
A detailed investigation was carried out to assess the concentration of near-road traffic-related air pollution (TRAP) using a dispersion model in Muscat. Two ambient air quality monitoring (AQM) stations were utilized separately at six locations near major roadways (each location for 2 months) to monitor carbon monoxide (CO) and nitrogen oxides (NOx). The study aimed to measure the concentration of near-road TRAP in a city hot spots and develop a validated dispersion model via performance measures. The US Environmental Protection Agency (US EPA) Line Source Model was implemented in which the pollutant emission factors were obtained through Comprehensive Modal Emission Model (CMEM) and COmputer Programme to calculate Emissions from Road Transport (COPERT) model. Traffic data of all vehicle categories under normal driving conditions including average vehicle speed limits and local meteorological conditions were included in the modeling study. The analysis of monitoring data showed that hourly (00:00 to 23:00) concentrations of CO were within the US EPA limits, while NOx concentration was exceeded in most locations. Also, the measured pollutant levels were consistent with hourly peak and off-peak traffic volumes. The overall primary statistical performance measures showed that COPERT model was better than CMEM due to the high sensitivity of CMEM to the local meteorological factors. The best fractional bias (0.47 and 0.39), normalized mean square error (0.44 and 0.50), correlation coefficient (0.64 and 0.70), geometric mean bias (1.07 and 1.57), and geometric variance (2.00 and 2.32) were obtained for CO and NOx, respectively. However, the bootstrap 95% CI estimates over normalized mean square error, fractional bias, and correlation coefficient for COPERT and CMEM were found to be statistically significant from 0 in the case of combined model comparison across all the traffic locations for both CO and NOx. In overall, certain roads showed weak performance mainly due to the terrain features and the lack of reliable background concentrations, which need to be considered in the future study.


Camelization of a murine single-domain antibody against aflatoxin B1 and its antigen-binding analysis.
Aflatoxin B1 (AFB1), a highly toxic mycotoxin, always contaminated in a variety of agricultural products. Camelid variable domain of heavy chain antibody (VHH) is a noteworthy reagent in immunoassay, owing to its excellent characteristics. Immunization of camelid animals is a straightforward strategy to produce VHHs. In this study, to avoid the dependence on the large animals, the camelized, murine antibody (cVHs) against AFB1 was prepared in vitro based on the identities between murine VH and camelid VHH and then to develop an immunoassay for AFB1. A murine anti-AFB1 VH fragment (VH-2E6) was selected for camelization through replacement of conserved hydrophobic residues in framework region 2 (FR2) (cVH-FR2), point mutation at position 103 in the FR4 region (cVH-103), and CDR3-grafted with a high AFB1-affinity VHH (cVH-Nb26). The cVH-Nb26 had a yield of 5 mg/L as refolded protein expressed from Escherichia coli and 10 mg/L expressed from Pichia pastoris. Compared with anti-AFB1 single-chain fragment variable (scFv) 2E6, cVH-Nb26 performed more than 20-fold enhancement of AFB1-binding interactions. Although the AFB1-affinity of cVH-Nb26 cannot meet the application requirement in the present form, our study provides effective strategies for preparation of camelized antibody in vitro, which could be a promising immunoreagent for AFB1 detection.


Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease.
Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process. Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs). CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX. CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.


A reappraisal of the uncanny valley: categorical perception or frequency-based sensitization?
The uncanny valley (UCV) hypothesis describes a non-linear relationship between perceived human-likeness and affective response. The "uncanny valley" refers to an intermediate level of human-likeness that is associated with strong negative affect. Recent studies have suggested that the uncanny valley might result from the categorical perception of human-like stimuli during identification. When presented with stimuli sharing human-like traits, participants attempt to segment the continuum in "human" and "non-human" categories. Due to the ambiguity of stimuli located at a category boundary, categorization difficulty gives rise to a strong, negative affective response. Importantly, researchers who have studied the UCV in terms of categorical perception have focused on categorization responses rather than affective ratings. In the present study, we examined whether the negative affect associated with the UCV might be explained in terms of an individual's degree of exposure to stimuli. In two experiments, we tested a frequency-based model against a categorical perception model using a category-learning paradigm. We manipulated the frequency of exemplars that were presented to participants from two categories during a training phase. We then examined categorization and affective responses functions, as well as the relationship between categorization and affective responses. Supporting previous findings, categorization responses suggested that participants acquired novel category structures that reflected a category boundary. These category structures appeared to influence affective ratings of eeriness. Crucially, participants' ratings of eeriness were additionally affected by exemplar frequency. Taken together, these findings suggest that the UCV is determined by both categorical properties as well as the frequency of individual exemplars retained in memory.


Supplementation of micronutrient in community micronutrient deficiency prevention programmes.
Micronutrient deficiency affects about 2 billion people all over the world. The major micronutrient deficiencies which are of public health importance include vitamin A, iron and iodine deficiencies. The deficiencies of these micronutrients cause a variety of morbidities and increased mortality which are most severe in children, adolescent girls and pregnant women. Despite the magnitude of these deficiencies, research has shown that they are correctable using simple strategies. This review examines the strategies employed to reduce micronutrient deficiencies worldwide by reviewing bibliographic databases, monograms and journals up to the year 2007. These strategies include food based and micronutrient supplementation. Although micronutrient supplementation is widely embraced as a strategy to combat micronutrient deficiencies, they are most suitable when used as a measure to combat severe deficiencies. Food based strategies such as food fortification and dietary diversification are more effective than micronutrient supplementation which should only be used as a short term measure. Supplementation programmes should be evidence based, multi-nutrient in approach and backed up with other complementary public health interventions.


Stimulation mapping via implanted grid electrodes prior to surgery for gliomas in highly eloquent cortex.
To evaluate whether preoperative mapping of higher cortical functions with subdural grid electrodes can help to maximize resection in functional areas and avoid permanent injury. A consecutive series of 16 patients (female: n = 7, male: n = 9, mean age of 38 yr) with a history of seizures and without focal deficit was reviewed, harboring gliomas located in the dominant hemisphere adjacent to or in the F3 gyrus/Broca area (n = 11), parietal/perisylvian area (n = 5) and additionally the pre- or postcentral area (n = 15). All patients in this series were operated for cytoreductive purposes only and not for treatment of intractable seizures. To preoperatively define and intraoperatively tailor the extent of resection all patients had a presurgical grid implantation for functional brain mapping. No permanent morbidity/mortality was observed after grid implantation and resective surgery. On postoperative MRI the resection was complete (100%), nearly complete (>90%) in n = 9 and subtotal (60% to <90%) in n = 5 cases. Twice, only biopsies were taken according to the results of mapping. All patients with high-grade gliomas had adjuvant treatment with radiation and chemotherapy. After a mean follow up of 20.4 months, no tumor relapse or growth was seen in all cases of resection. Preoperative grid mapping is a safe and precise instrument to evaluate language and/or associated left perisylvian functions in patients with gliomas. It may be considered a valid alternative to awake craniotomy to maximize safe resection.


Neurotoxicity, behavioral changes and gene-expression profile of mice exposed to SnS2 nanoflowers.
Recently, interest in the potential applications of tin disulphide nanoflowers (SnS2 NFs) in the treatment of waste water and their antibacterial properties has increased. However, their effects on neurotoxicity, brain cognition and behavioural injury, as well as the underlying mechanisms of these effects have remained unknown. In the present study, we compared the neurotoxicity of SnS2 NFs (50 nm) administered intragastrically at different doses (5, 10, and 50 mg kg-1) in mice for 60 days. The results showed that the neurotoxicity of SnS2 NFs in mice is dose-dependent. Furthermore, expression levels of genes related to oxidative stress, metabolism and signal transduction were also modified in the brain tissues of mice exposed to SnS2 NFs, supporting the SnS2 NF-dependent neurotoxic phenotype. Additionally, SnS2 NF exposure resulted in an abnormal ultrastructure in the hippocampus of the treated mice. Nevertheless, their body weight, organ coefficient and behaviour assessed in an open-field test and learning and memory test results assessed using a Morris water maze test remained unaffected. This suggested that the increased risk of neurotoxicity in SnS2 NF-treated mice was dependent on the dosage of SnS2 NFs. The relative level of safety was <5 mg kg-1 for 50 nm SnS2 NFs. The present study provides an experimental basis for the safe application of SnS2 NFs; however, chronic behavioural effects of SnS2 NFs remain unknown.


Permeability of a growing biofilm in a porous media fluid flow analyzed by magnetic resonance displacement-relaxation correlations.
Biofilm growth in porous media is difficult to study non-invasively due to the opaqueness and heterogeneity of the systems. Magnetic resonance is utilized to non-invasively study water dynamics within porous media. Displacement-relaxation correlation experiments were performed on fluid flow during biofilm growth in a model porous media of mono-dispersed polystyrene beads. The spin-spin T2 magnetic relaxation distinguishes between the biofilm phase and bulk fluid phase due to water-biopolymer interactions present in the biofilm, and the flow dynamics are measured using PGSE NMR experiments. By correlating these two measurements, the effects of biofilm growth on the fluid dynamics can be separated into a detailed analysis of both the biofilm phase and the fluid phase simultaneously within the same experiment. Within the displacement resolution of these experiments, no convective flow was measured through the biomass. An increased amount of longitudinal hydrodynamic dispersion indicates increased hydrodynamic mixing due to fluid channeling caused by biofilm growth. The effect of different biofilm growth conditions was measured by varying the strength of the bacterial growth medium.


RNA vaccines in cancer treatment.
The Cancer Report from the World Health Organization states that in the year 2000 12% of all death cases worldwide were caused by cancer. In the western world, the cancer death rates are often devastating, being at about 25%. This fact stresses the urgency to find effective cures against malignant diseases. New approaches in the treatment of cancer focus on the development of immunotherapies to fight the disease. Besides other methods, the usage of tumor-specific RNA as part of vaccines is investigated lately. RNA, administered alone or used for transfection of dendritic cells, shows several advantages as a vaccine including feasibility, applicability, safeness, and effectiveness when it comes to the generation of immune responses. This review concentrates on results from in vitro experiments and recent trials using RNA vaccines to present an overview about this specific strategy.


[Economics and ethics in public health?].
The topic suggests a conflict between ethics and economy in medical care. It is often argued that today's welfare state in affluent societies with their social insurance systems makes it easier for the doctor to translate ethical demands into reality without being hampered by economic restrictions. Both doctors and patients took advantage of this system of medical care by mingling social guarantees for health with the doctor's income. Hence, medical expenses expanded rapidly, additionally promoted by technical progress in medicine. This entailed a proportionate increase in medical expenses in relation to personal income, especially wage income. Budgets of state authorities were streamlined or deficits became larger. This state of affairs was promoted further by mechanisms of distribution of national income in accordance with the slogan "less state, more market". While national income continued to grow, although at a slower rate, the number of jobless persons grew continually and thus also the social expenses, this was not due, as is usually assumed and pretended, to an economic crisis. Society and economy are facing a crisis of distribution of national income under conditions of technical progress as a job killer, making economic production more productive and efficient. Not taking into account the new challenge of social market economy--the German innovation in market economy creating the economic miracle after World War II--reforms of the system of medical care took place and are still continuing along market principles, particularly the latest German reform law leading to individual contracts between patients and their doctors in respect of cost charging. However, marketing principles promote economy in medicine, but they do not promote medical ethics. Further German guidelines for medical care should take stock of past experiences. There will be more competition in the "growing market of medical care" (private and public) and this will need--as economic experience has shown and economists have affirmed--new organisational devices to ensure better outcomes for the individual patient as a consumer and the doctors as suppliers. More responsibility should be given to the different suppliers of collective security in medical care (private or social systems of insurance). No individual patient as a mere consumer has a genuine chance in handling contracts with doctors carefully who are considered to be "gods in white" according to a popular German saying. These consumers have only a slight chance when arguing in courts of justice for the performance of contracts. Diagnosis and therapy, the system of doctors who treat members of statutory social insurance schemes (National Health general practitioners in the U.K.) and doctors as "free entrepreneurs" in the growing market of medical care should be separated due to the different rules of charging costs and offering medical care. "Classless medical care" does not have a better chance by applying market principles. The same is true for ethics versus economy. Doctors as "free entrepreneurs" must learn that markets will not guarantee reimbursement of costs but react to supply and demand. Hence, regulation of medical care by economic instruments creates better chances even for ethics in medical care against economy.


Flucloxacillin (floxapen) in the treatment of skin and upper respiratory tract infections.
An appraisal of flucloxacillin (floxapen) for the treatment of infection of the skin and upper respiratiory tract was carried out in general practice by 34 doctors. The success rate in the treatment of skin infections was assessed as 92 percent and in upper respiratory tract infections as 84 percent. The incidence of side effects overall was 9.5 percent and their nature and severity are described. Also the results of the present study are compared with previous appraisals of flucloxacillin in general practic and the difference in dose regimes used in these studies is discussed.


Protective effect of N-acetylcysteine on MK-801-induced testicular oxidative stress in mice.
Experimental studies indicate that MK-801 causes organ injury in schizophrenic mice testes although it is molecular mechanism has not been clearly defined. In this study, we investigated the probable protective effect of N-Acetylcysteine (NAC) against MK-801- induced testicular toxicity in mice. In total, 24 Balb/C male mice were divided into 4 equal groups: the animals in the control group (vehicle treated) were intraperitoneally given 10 mL/kg/day saline solution, the animals in the experiment groups were intraperitoneally given 1 mg/kg/day MK-801 alone, 100 mg/kg/day NAC alone and MK-801 by 1 mg/kg/day for 14 days. The level of the testes' total oxidant status (TOS) in mice that were treated with MK-801 was significantly higher than those level in the other groups while the total antioxidant status (TAS) levels decreased. In comparison to the MK-801 group, the TOS levels were lower, and the TAS levels increased in the MK-801 + NAC group. In the morphometric analysis, the diameter and epithelial height of the seminiferous tubules of the testes showed no significant changes after MK-801 administration. Conversely, the weights of the testes decreased significantly. In the treatment with NAC, the weights of testes significantly increased in comparison to the MK-801 group. The histopathological examination revealed necrobiotic and degenerative changes in the epithelial cells, vacuole formation within the seminiferous tubules, a decrease in the number of the spermatozoid, and disorganization in the basement membrane of the seminiferous tubules in the MK-801 group in comparison to the control group. Administration of NAC alleviated several negative effects of MK-801 on the testicular damage in mice. In conclusion, our results showed that NAC protected the mice against the testicular toxicity of MK-801 when it was administrated intraperitoneally.


Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection.
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10-8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10-8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).


[MRI in testicular diagnosis: differentiation of seminoma, teratoma and inflammation using a statistical score].
To differentiate scrotal pathology via MRI by means of a statistical score. Between 1989 and 1995 MR images of 105 patients with scrotal pathology were rated retrospectively. In 69 cases linear discriminant analysis was used to differentiate seminoma, teratoma and inflammation. Six MRI attributes were found to be necessary and were weighted with a factor according to their importance. These factors were used to build a score. Criteria found to be important contained the distribution of the variate extensions of elements inside the pathological area and their maximal and minimal signal intensities. Furthermore, the contrast pattern of the pathological area and the visibility of healthy tissue in the pathological testicle was of importance. Seminoma was found to be homogeneous and well demarcated against healthy tissue. Teratoma was also well defined but characterised by inhomogeneous distribution of signal intensities. Inflammation showed diffuse signal increase of the pathological testicle, especially in T1-sequences. Using the score differentiation between tumors and inflammation succeeded in 94.2% between seminoma and teratoma in 89.7%. Compared to other studies using visual MR image analysis differentiation of scrotal diseases was improved by using a statistical score.


The effects of short term L-citrulline supplementation on wave reflection responses to cold exposure with concurrent isometric exercise.
Supplementation with L-citrulline (L-cit) has shown attenuating effects on blood pressure (BP) and pulse-wave-reflection responses (augmentation index (AIx)) to local exposure to cold, but the potential cardioprotective effects of L-cit during whole-body cold exposure with concurrent exercise are poorly understood. We hypothesized that L-cit would attenuate the BP and AIx responses to cold exposure and isometric handgrip (IHG) exercise. Sixteen healthy males with a mean age of 23±3 years volunteered for a study of the effect of L-cit on the BP and AIx responses to cold exposure and IHG exercise. Experiments were conducted inside an environmental chamber in cold conditions (4 ºC). Radial waveforms were obtained in duplicates and averaged through applanation tonometry. After 5 minutes of measurements made at rest in the supine position (RES), after the finalization of the exercise about the subjects were evaluated in non exercise condition that were basically the same as the RES. After initial measurements in cold conditions, subjects were randomized to receive either a placebo (Maltodextrin, PL) or L-cit (100mg/kg) for 14 days, followed by a 14-day washout period and then a 14-day regimen of the other agent. Subjects were re-evaluated after each treatment period. At RES, there was a significant treatment-by-time interaction for brachial systolic BP (BSBP; P < 0.01), aortic systolic BP (ASBP; P < 0.01), and AIx (P < 0.05), such that L-cit decreased BSBP (-11±2mm Hg; P < 0.01), ASBP (-10±2mm Hg; P < 0.05), and AIx (-2±2%; P < 0.05) as compared with their respective values before the intervention. During IHG, BSBP, ASBP, and AIx were increased (P < 0.05) as compared with their values at RES, but these responses were unaffected by either of the study treatments. L-citrulline may be a feasible adjuvant treatment for decrease the BP and AIx responses induced by cold. Further research is warranted to evaluate the impact of cold exposure and exercise on cardiovascular risk in clinical populations.


Home medicines reviews: a national survey of Australian accredited pharmacists' health service time investment.
In Australia, polypharmacy and medication-related problems are prevalent in the community. Therefore, medicines safety initiatives such as the Home Medicines Review (HMR) service are critical to health care provision. While the evidence continues to expand around HMR service, little is known of accredited pharmacists' experiences of HMR time investment. This study aimed to explore accredited pharmacists' experiences of HMR practice regarding time investment in the study's defined HMR Stages: 1 (initial paper-based assessment and review), 2 (in-home patient-accredited pharmacist consultation), and 3 (HMR report collation, generation, completion, and provision to the patient's General Practitioner, including any liaison time). An electronic survey was developed and piloted by a panel of reviewers. Convenience sampling was used to distribute the final anonymous survey nationally via professional pharmacy organisations. Data were analyzed for frequency distributions and a chi-square test of independence was performed to evaluate any association between demographic variables relating to HMR time investment. There was a total of 255 survey respondents, representing approximately 10% of national accredited pharmacist membership. The majority were experienced accredited pharmacists who had completed >100 HMRs (73%), were female (71%), and aged >40 years (60%). Regarding time investment for a typical instance of HMR, most spent: <30 minutes performing Stage 1 (46.7%), and 30-60 minutes performing Stage 2 (70.2%). In Stage 3, 40.0% invested 1-2 hours, and 27.1% invested 2-3 hours in HMR report collation and completion. Quantitative analysis revealed statistically significant (p=0.03) gender findings where females performed longer patient consultations than males (Stage 2). More HMR career experience resulted in statistically significant (p=0.01) less time performing Stage 1 (initial paper-based assessment and review); with a trend to less time performing Stage 3 (HMR report writing). Accredited pharmacists invest significant time in performing comprehensive HMRs, especially during in-home patient consultations and during HMR report collation and completion. Their significant HMR time investment as medicines experts provides insight for program and workforce considerations and warrants further research to better understand their work processes for optimizing medicines use and improving health.


Morning resistance exercise and cricket-specific repeated sprinting each improve indices of afternoon physical and cognitive performance in professional male cricketers.
To compare two modes (general and cricket-specific) of morning priming exercise on afternoon physical and cognitive performance, and subjective readiness to perform in professional male cricketers. Randomised, crossover, counterbalanced. On three occasions, 16 professional men's cricketers completed afternoon tests of countermovement jump height, cricket-specific sprint performance (running between the wickets, two runs), cognitive function (Stroop test, time taken), and subjective readiness to perform. Control (CON; passive rest), lower-body resistance exercise priming (LIFT; trap bar deadlifts, 6 × 4 repetitions up to 85% of one repetition maximum), or cricket-specific running priming (RUN; 6 × 35.36 m sprints including a 180° change of direction) interventions were implemented 5.5 h before testing. Afternoon sprint times were faster in RUN (-0.04 s, p = 0.013) and LIFT (-0.07 s, p < 0.001) versus CON, and faster in LIFT than RUN (-0.03 s, p = 0.032). Jump height (+1.1 cm, p = 0.021) and cognitive function (-3.83 s, p = 0.003) were greater in LIFT than CON, whilst RUN outperformed CON for cognition (-2.52 s, p = 0.023). Although perceived readiness was not influenced by trial (p > 0.05), players reported favourable responses on the "aggression" subscale in LIFT relative to CON (+1 arbitrary unit, p = 0.022). Both general (lower-body resistance exercise) and cricket-specific (simulated running between wickets) morning priming are effective match-day strategies to improve afternoon markers of physical and cognitive performance in professional men's cricketers. Practitioners may thus be afforded flexibility in situations where resistance exercise is not feasible on the morning of a match.


Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation.
Inducing cancer differentiation is a promising approach to treat cancer. Here, we identified chlorogenic acid (CA), a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells. Cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CA was evaluated both in vitro and in vivo. Results: Cancer cells treated with CA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CA resulted in elevated SUMO1 expression through acting on its 3'UTR and stabilizing the mRNA. The increased SUMO1 caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G0/G1 arrest and maturation phenotype. CA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naïve mice. In glioma cells, CA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CA in glioma cells was comparable to that of temozolomide. CA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CA was safe even at very high doses. CA might be a safe and effective differentiation-inducer for cancer therapy. "Educating" cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.


The combination of insulin and GLP-1 analogues in the treatment of type 2 diabetes.
GLP-1 analogues have been proven to be effective in the treatment of type 2 diabetes mellitus. They stimulate insulin production and secretion, and suppress glucagon secretion, depending on the blood glucose level. They also have an effect on the brain, enhancing satiety, and on the gut, where they delay gastric emptying. Theoretically, in type 2 diabetes mellitus patients, the combination of a GLP-1 analogue with insulin seems attractive, because of the weight loss perceived in users of GLP-1 analogues in contrast to the weight gain seen in most patients starting insulin therapy, leading to even more insulin resistance. There are only a few randomised controlled trials which have studied this combination and several uncontrolled studies, which will be reviewed here.


Paradoxical embolism: a rare complication of thrombolysis.
Paradoxical embolus is a rare complication of thrombolysis. With a high prevalence of clinically silent septal defects and widespread use of thrombolysis, recognition of the risks, clinical signs and symptoms is important. A case is reported of paradoxical embolus following thrombolysis in a woman with a previously undiagnosed patent foramen ovale.


Effect of Bacterial Biofilm on the Osteogenic Differentiation of Stem Cells of Apical Papilla.
Although clinical success in regenerative endodontics is substantially high, histological success is limited to finding bone/cementum-like tissue instead of dentin within the canal space. The aims of this study were to investigate (1) the effect of bacterial biofilm on osteogenic gene expression in stem cells of the apical papilla (SCAP) and (2) the effect of bacterial antigens on the functional differentiation of SCAP into a mineralizing phenotype. Using an ex vivo organotypic root canal model and an American Association of Endontists-recommended regenerative endodontic procedures, we evaluated SCAP differentiation in the presence and absence of an Enterococcus faecalis biofilm. Gene expression analysis for dentinogenic and osteoblastic markers was performed with real-time polymerase chain reaction. The effect of E. faecalis antigens on SCAP differentiation into mineralizing cells in vitro was evaluated with 2 functional assays: Alizarin Red and alkaline phosphatase activity assays. After regenerative endodontic procedures, residual bacteria continued to sustain within the root canal system. SCAP in the presence of E. faecalis biofilm significantly downregulated dentinogenic genes such as dentin sialophosphoprotein and upregulated osteoblastic genes such as bone sialoprotein, osteocalcin, distal-less homeobox 5, and runt-related transcription factor 2. E. faecalis antigens significantly inhibited SCAP differentiation into a mineralizing phenotype when alizarin red staining and alkaline phosphatase assays were used in vitro. Current disinfection protocols were ineffective in eliminating bacteria from root tips and the levels of the residual bacterial biofilm, and its byproducts, were able to significantly alter osteogenic-differentiation of SCAP.


A new modified live porcine reproductive and respiratory syndrome vaccine improves growth performance in pigs under field conditions.
The change in growth performance resulting from a new modified live porcine reproductive and respiratory syndrome (PRRS) vaccine was evaluated under field conditions for registration with the government as guided by the Republic of Korea's Animal and Plant Quarantine Agency. Three farms were selected based on their history of PRRS-associated respiratory diseases. On each farm, a total of 45 3-week-old pigs were randomly allocated to one of two treatment groups, (i) vaccinated (n = 25) or (ii) control (n = 20) animals. A new modified live PRRSV vaccine increased market weight by 1.26 kg/pig (104.71 kg versus 103.45 kg; P < 0.05) and decreased mortality by 17% (1.33% versus 18.33%; P < 0.05). Pathological examination indicated that vaccination effectively reduced microscopic lung lesions compared with control animals on the 3 farms. Thus, the new modified live PRRS vaccine improved growth performance and decreased mortality and lung lesions when evaluated under field conditions.


Clear Cell Renal Cell Carcinoma with Prominent Micropapillary Pattern: A Case Report of a Previously Undescribed Morphology.
The classic morphology of clear cell renal cell carcinoma consists of nests of cells with clear cytoplasm. Nevertheless, other histologic patterns may be seen including cells with eosinophilic cytoplasm, bizarre multinucleated giant tumor cells and pseudopapillary structures. In this article, we present the first case of clear cell renal cell carcinoma with a prominent micropapillary pattern.


Synthesis and metabolic studies of 1α,2α,25-, 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3.
Three different A-ring perhydroxylated trihydroxyvitamin D3 metabolites were synthesized from their appropriate A-ring precursors and CD-ring for their potential therapeutic applications. We first chemically synthesized 1α,2α,25-trihydroxyvitamin D3 [1α,2α,25(OH)3D3] to study its VDR binding affinity because this metabolite is a product of recombinant human CYP3A4 catalysis when 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (O2C3), a more potent vitamin D receptor (VDR) binder than 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], is used as the substrate. We found that this metabolite retained 27.3% of the VDR binding affinity compared to 1α,25(OH)2D3. The kcat/Km value of CYP24A1 for 1α,2α,25(OH)3D3 is 60% of that for 1α,25(OH)2D3. Since the biological activity and the metabolic fate of a naturally occurring C4-hydroxylated vitamin D2 metabolite found in the serum of rats treated with pharmacological doses of vitamin D2 have never been described, we next synthesized 1α,4α,25-trihydroxyvitamin D3 and its diastereoisomer, 1α,4β,25-trihydroxyvitamin D3, to study their metabolism and biological activities. Both 4-hydroxylated isomers showed weaker VDR binding affinity than 1α,25(OH)2D3. Although either 4-hydroxylated isomer can be metabolized by CYP24A1 almost at the same level as 1α,25(OH)2D3, their metabolic patterns catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) are different; only the 4α-hydroxylated analog can be metabolized by UGT to produce a glucuronate conjugate. The results provide important information for the synthesis of new novel chemotherapeutic vitamin D analogs which would be less subjective to degradation and therefore more bioavailable than 1α,25(OH)2D3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.


Molecular cloning and characterization of STAMP1, a highly prostate-specific six transmembrane protein that is overexpressed in prostate cancer.
We have identified a novel gene, six transmembrane protein of prostate 1 (STAMP1), which is largely specific to prostate for expression and is predicted to code for a 490-amino acid six transmembrane protein. Using a form of STAMP1 labeled with green fluorescent protein in quantitative time-lapse and immunofluorescence confocal microscopy, we show that STAMP1 is localized to the Golgi complex, predominantly to the trans-Golgi network, and to the plasma membrane. STAMP1 also localizes to vesicular tubular structures in the cytosol and colocalizes with the early endosome antigen 1 (EEA1), suggesting that it may be involved in the secretory/endocytic pathways. STAMP1 is highly expressed in the androgen-sensitive, androgen receptor-positive prostate cancer cell line LNCaP, but not in androgen receptor-negative prostate cancer cell lines PC-3 and DU145. Furthermore, STAMP1 expression is significantly lower in the androgen-dependent human prostate xenograft CWR22 compared with the relapsed derivative CWR22R, suggesting that its expression may be deregulated during prostate cancer progression. Consistent with this notion, in situ analysis of human prostate cancer specimens indicated that STAMP1 is expressed exclusively in the epithelial cells of the prostate and its expression is significantly increased in prostate tumors compared with normal glands. Taken together, these data suggest that STAMP1 may have an important role in the normal prostate cell as well as in prostate cancer progression.


Characterization of bile acid absorption across the unstirred water layer and brush border of the rat jejunum.
We have examined the rate-limiting steps involved in bile acid absorption across the unstirred water layer and lipid cell membrane of the jejunal mucosa. Uptake of the polar bile acid taurocholate is limited solely by the cell membrane since this compound permeates the unstirred water layer more rapidly than the lipid cell membrane and stirring does not enhance uptake. With less polar bile acids which permeate the cell membrane relatively more rapidly, however, the unstirred water layer does exert resistance to mucosal uptake of these compounds. That the unstirred water layer is even more rate limiting to uptake from micellar solutions is indicated by the facts that the rate of bile acid absorption from such solutions is lower than from corresponding monomer solutions, stirring markedly enhances uptake from micellar solutions while increases in viscosity of the incubation media depress uptake and expansion of the micelle size further depresses absorption rates. We also have examined the important question of whether the micelle crosses the brush border intact once it reaches the aqueous-lipid interface. The observations that the calculated permeation rate of the micelle should be extremely low, the rate of mucosal cell uptake plateaus at a constant value when the critical micelle concentration is reached at the aqueous-lipid interface, and the different components of a mixed micelle are taken up at different rates indicate that uptake of the intact micelle does not occur; rather, bile acid absorption must be explained in terms of monomers in equilibrium with the micelle. Finally, after correction of the permeability coefficients of the various bile acids for the unstirred layer resistance the incremental partial molar free energy of solution of the hydroxyl group in the brush border membrane was calculated to equal -6126 cal.mole(-1) indicating that passive diffusion of these compounds occurs through a very polar region of the cell membrane.


Prediction of human protein function from post-translational modifications and localization features.
We have developed an entirely sequence-based method that identifies and integrates relevant features that can be used to assign proteins of unknown function to functional classes, and enzyme categories for enzymes. We show that strategies for the elucidation of protein function may benefit from a number of functional attributes that are more directly related to the linear sequence of amino acids, and hence easier to predict, than protein structure. These attributes include features associated with post-translational modifications and protein sorting, but also much simpler aspects such as the length, isoelectric point and composition of the polypeptide chain.


Identification and analysis of MKK and MPK gene families in canola (Brassica napus L.).
Eukaryotic mitogen-activated protein kinase (MAPK/MPK) signaling cascades transduce and amplify environmental signals via three types of reversibly phosphorylated kinases to activate defense gene expression. Canola (oilseed rape, Brassica napus) is a major crop in temperate regions. Identification and characterization of MAPK and MAPK kinases (MAPKK/MKK) of canola will help to elucidate their role in responses to abiotic and biotic stresses. We describe the identification and analysis of seven MKK (BnaMKK) and 12 MPK (BnaMPK) members from canola. Sequence alignments and phylogenetic analyses of the predicted amino acid sequences of BnaMKKs and BnaMPKs classified them into four different groups. We also examined the subcellular localization of four and two members of BnaMKK and BnaMPK gene families, respectively, using green fluorescent protein (GFP) and, found GFP signals in both nuclei and cytoplasm. Furthermore, we identified several interesting interaction pairs through yeast two-hybrid (Y2H) analysis of interactions between BnaMKKs and BnaMPKs, as well as BnaMPK and BnaWRKYs. We defined contiguous signaling modules including BnaMKK9-BnaMPK1/2-BnaWRKY53, BnaMKK2/4/5-BnaMPK3/6-BnaWRKY20/26 and BnaMKK9-BnaMPK5/9/19/20. Of these, several interactions had not been previously described in any species. Selected interactions were validated in vivo by a bimolecular fluorescence complementation (BiFC) assay. Transcriptional responses of a subset of canola MKK and MPK genes to stimuli including fungal pathogens, hormones and abiotic stress treatments were analyzed through real-time RT-PCR and we identified a few of BnaMKKs and BnaMPKs responding to salicylic acid (SA), oxalic acid (OA), Sclerotinia sclerotiorum or other stress conditions. Comparisons of expression patterns of putative orthologs in canola and Arabidopsis showed that transcript expression patterns were generally conserved, with some differences suggestive of sub-functionalization. We identified seven MKK and 12 MPK genes from canola and examined their phylogenetic relationships, transcript expression patterns, subcellular localization, and protein-protein interactions. Not all expression patterns and interactions were conserved between canola and Arabidopsis, highlighting the limitations of drawing inferences about crops from model species. The data presented here provide the first systematic description of MKK-MPK-WRKY signaling modules in canola and will further improve our understanding of defense responses in general and provide a basis for future crop improvement.


US adults with diabetes mellitus: Variability in oral healthcare utilization.
Diabetic patients are advised to have at least one dental examination per year. It is unclear to what extent different subgroups of US diabetic adults closely follow this recommendation. Thus, we assessed dental care utilization and related factors in a representative sample of US diabetic adults from rural and urban counties. Cross-sectional data were from the 2018 Behavioral Risk Factor Surveillance System (BRFSS). Survey logistic regression was used to account for the complex sampling design. Among 40,585 eligible participants, 24,887 (60% of the population) had at least one dental visit for any reason within the past year. The lowest compliance was observed among edentulous participants (27%, adjusted OR = 0.26, 95% CI = 0.22-0.31 vs. fully dentate). Dental compliance was also negatively associated with having a lower income or education, ever being a smoker, or having barriers to access to care. Rural residents had lower dental compliance compared to urban residents, particularly those without healthcare coverage. Dental compliance among US adult diabetic individuals was low, particularly among rural residents, and as compared to other recommended diabetic care practices. Future public health interventions may target rural individuals without healthcare coverage, smokers and edentulous individuals. There is a need to integrate dental and medical care to facilitate cross-talks among different health professionals, so that educational preventive messages are reinforced at every healthcare visit.


Genomic diversity within the Enterobacter cloacae complex.
Isolates of the Enterobacter cloacae complex have been increasingly isolated as nosocomial pathogens, but phenotypic identification of the E. cloacae complex is unreliable and irreproducible. Identification of species based on currently available genotyping tools is already superior to phenotypic identification, but the taxonomy of isolates belonging to this complex is cumbersome. This study shows that multilocus sequence analysis and comparative genomic hybridization based on a mixed genome array is a powerful method for studying species assignment within the E. cloacae complex. The E. cloacae complex is shown to be evolutionarily divided into two clades that are genetically distinct from each other. The younger first clade is genetically more homogenous, contains the Enterobacter hormaechei species and is the most frequently cultured Enterobacter species in hospitals. The second and older clade consists of several (sub)species that are genetically more heterogeneous. Genetic markers were identified that could discriminate between the two clades and cluster 1. Based on genomic differences it is concluded that some previously defined (clonal and heterogenic) (sub)species of the E. cloacae complex have to be redefined because of disagreements with known or proposed nomenclature. However, further improved identification of the redefined species will be possible based on novel markers presented here.


Schistosoma mansoni schistosomula antigens induce Th1/Pro-inflammatory cytokine responses.
Larvae of Schistosoma (schistosomula) are highly susceptible to host immune responses and are attractive prophylactic vaccine targets, although cellular immune responses against schistosomula antigens in endemic human populations are not well characterized. We collected blood and stool from 54 Schistosoma mansoni-infected Ugandans, isolated peripheral blood mononuclear cells and stimulated them for 24 hours with schistosome adult worm and soluble egg antigens (AWA and SEA), along with schistosomula recombinant proteins rSmKK7, Lymphocyte Antigen 6 isoforms (rSmLy6A and rSmLy6B), tetraspanin isoforms (rSmTSP6 and rSmTSP7). Cytokines, chemokines and growth factors were measured in the culture supernatants using a multiplex luminex assay, and infection intensity was determined before and at 1 year after praziquantel (PZQ) treatment using the Kato-Katz method. Cellular responses were grouped and the relationship between groups of correlated cellular responses and infection intensity before and after PZQ treatment was investigated. AWA and SEA induced mainly Th2 responses. In contrast, rSmLy6B, rSmTSP6 and rSmTSP7 induced Th1/pro-inflammatory responses. While recombinant antigens rSmKK7 and rSmLy6A did not induce a Th1/pro-inflammatory response, they had an association with pre-treatment infection intensity after adjusting for age and sex. Testing more schistosomula antigens using this approach could provide immune-epidemiology identifiers necessary for prioritizing next generation schistosomiasis vaccine candidates.


p53 regulates the minimal promoter of the human topoisomerase IIalpha gene.
DNA topoisomerase IIalpha is an essential enzyme for chromosome segregation during mitosis. Consistent with a cell division-specific role, the expression of the topoisomerase IIalpha gene is strongly influenced by the proliferation status of cells. The p53 protein is one of the most important regulators of cell cycle progression in mammals, with an apparent dual role in the induction of cell cycle arrest following cytotoxic insults and in the regulation of the apoptotic cell death pathway. We have analysed whether p53 plays a role in regulating expression of the human topoisomerase IIalpha gene. We show that wild-type, but not mutant, p53 is able to decrease substantially the activity of the full length topoisomerase IIalpha gene promoter. Using a series of constructs comprising various deleted or mutated versions of the promoter lacking critical cis-acting elements, we show that this p53-specific regulation of the topoisomerase IIalpha promoter is independent of all characterised transcription factor binding sites and is directed at the minimal gene promoter. We conclude that expression of wild-type p53 induces downregulation of the human topoisomerase IIalpha promoter by acting on the basal transcription machinery. These findings implicate topoisomerase II as one of the downstream targets for p53-dependent regulation of cell cycle progression in human cells.


Quantifying anthropogenic emission of iron in marine aerosol in the Northwest Pacific with shipborne online measurements.
Anthropogenic emissions are recognized as significant contributors to atmospheric soluble iron (Fe) in recent years, which may affect marine primary productivity, especially in Fe-limited areas. However, the contribution of different emission sources to Fe in marine aerosol has been primarily estimated by modeling approaches. Quantifying anthropogenic Fe based on field measurements remains a great challenge. In this study, online multi-element measurements and Positive Matrix Factorization (PMF) were combined for the first time to quantify sources of atmospheric Fe and soluble Fe in the Northwest Pacific during a cruise in spring 2015. Fe concentration in 624 atmospheric PM2.5 samples measured online was 74.58 ± 90.87 ng/m3. The PMF results showed anthropogenic activities, including industrial coal combustion, biomass burning, and maritime transport, were important in this region, contributing 31.4 % of atmospheric Fe on average. In addition, anthropogenic Fe concentration resolved by PMF was comparable to the simulation results of the CMAQ (Community Multiscale Air Quality) and GEOS-Chem (Goddard Earth Observing System-Chemical transport) models, with better correlation to CMAQ (r = 0.76) than GEOS-Chem (r = 0.26). This study developed a new method to estimate atmospheric soluble Fe, which integrates Fe source apportionment results and Fe solubility from different sources. Soluble Fe concentration was estimated as 3.93 ± 5.14 ng/m3, of which 87.0 % was attributed to anthropogenic emissions. Notably, ship emission alone contributed 27.5 % of soluble Fe, though its contribution to total Fe was only 2.2 %. Finally, the total deposition fluxes of atmospheric Fe (37.11 ± 38.43 μg/m2/day) and soluble Fe (1.85 ± 2.13 μg/m2/day) were estimated. This study developed a new methodology for quantifying contribution of anthropogenic emissions to Fe in marine aerosol, which could greatly help the assessment of impacts of human activities on marine environment.


Serum detection of thymidine kinase 1 as a means of early detection of lung cancer.
Thymidine kinase 1 (TK1) is a biomarker elevated in several malignancies, including lung cancer. Up-regulation of TK1 is an early event in carcinogenesis and therefore a target for early cancer detection. We have developed a novel Enzyme Linked Immunosorbent Assay (ELISA) to detect TK1 in serum. Forty patients with pulmonary nodules and 18 healthy individuals had their serum collected prior to surgery. All samples were analyzed using a radioassay and ELISA. TK1 was significantly elevated in all lung cancer samples. Patients with stage I (n=16) and stage II (n=17) disease had significantly higher TK1 levels than controls. The area under the curve was 0.792, using 4.9 nM TK1 as cut-off, for early-stage lung cancer. The sensitivity and specificity were 75.0 and 83.3, respectively. TK1 concentration was a more sensitive and accurate indicator of lung cancer than TK1 activity. TK1 is significantly elevated in serum from patients with stage I and stage II lung cancer as measured using the established ELISA. This novel TK1 ELISA is both sensitive and specific for the detection of early-stage and advanced lung cancer, and therefore may be an important tool in the management of this disease.


Shrinking lung syndrome in systemic lupus erythematosus: a single-centre experience.
Introduction Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE), characterized by decreased lung volumes and extra-pulmonary restriction. The aim of this study was to describe the characteristics of SLS in our lupus cohort with emphasis on prevalence, presentation, treatment and outcomes. Patients and methods Patients attending the Toronto Lupus Clinic since 1980 ( n = 1439) and who had pulmonary function tests (PFTs) performed during follow-up were enrolled ( n = 278). PFT records were reviewed to characterize the pattern of pulmonary disease. SLS definition was based on a restrictive ventilatory defect with normal or slightly reduced corrected diffusing lung capacity for carbon monoxide (DLCO) in the presence of suggestive clinical (dyspnea, chest pain) and radiological (elevated diaphragm) manifestations. Data on clinical symptoms, functional abnormalities, imaging, treatment and outcomes were extracted in a dedicated data retrieval form. Results Twenty-two patients (20 females) were identified with SLS for a prevalence of 1.53%. Their mean age was 29.5 ± 13.3 years at SLE and 35.7 ± 14.6 years at SLS diagnosis. Main clinical manifestations included dyspnea (21/22, 95.5%) and pleuritic chest pain (20/22, 90.9%). PFTs were available in 20 patients; 16 (80%) had decreased maximal inspiratory (MIP) and/or expiratory pressure (MEP). Elevated hemidiaphragm was demonstrated in 12 patients (60%). Treatment with prednisone and/or immunosuppressives led to clinical improvement in 19/20 cases (95%), while spirometrical improvement was observed in 14/16 patients and was mostly partial. Conclusions SLS prevalence in SLE was 1.53%. Treatment with glucocorticosteroids and immunosuppressives was generally effective. However, a chronic restrictive ventilatory defect usually persisted.


Assessment of antibacterial and anti-biofilm effects of zinc ferrite nanoparticles against Klebsiella pneumoniae.
In response to the emergence of drug resistance and limited therapeutic options, researchers are in action to look for more effective and sustainable antimicrobial practices. Over few years, novel nanoparticles are proving to be potent and promising for effectively dealing with ever- evolving microbial pathogens and diseases. In the present investigation, antibacterial and anti-biofilm efficiencies of zinc ferrite nanoparticles (ZnFe2O4 NPs) are explored against opportunistic pathogens Klebsiella pneumoniae (K. pneumoniae). Results of the present study demonstrate that the ZnFe2O4 NPs endow an excellent antibacterial efficiency with a maximum zone of inhibition i.e.16 mm. The reactive oxygen species (ROS)-induced bacterial damage is caused by the ZnFe2O4 NPs. Subsequently, intracellular cytoplasmic leakage of sugar and protein confirms their ability to disturb the membrane integrity of bacteria. This study also demonstrates the prominent efficiency of ZnFe2O4 NPs in an anti-biofilm study by inhibiting biofilm formation up to 81.76% and reducing mature biofilm up to 56.22% at 75 μg/mL the minimum inhibitory concentration value. Therapeutic possibilities of the ZnFe2O4 NPs in antimicrobial applications are discussed which are helpful to overcome the challenges associated with biofilm infectivity.


In situ sulfur isotopes (δ(34)S and δ(33)S) analyses in sulfides and elemental sulfur using high sensitivity cones combined with the addition of nitrogen by laser ablation MC-ICP-MS.
The sulfur isotope is an important geochemical tracer in diverse fields of geosciences. In this study, the effects of three different cone combinations with the addition of N2 on the performance of in situ S isotope analyses were investigated in detail. The signal intensities of S isotopes were improved by a factor of 2.3 and 3.6 using the X skimmer cone combined with the standard sample cone or the Jet sample cone, respectively, compared with the standard arrangement (H skimmer cone combined with the standard sample cone). This signal enhancement is important for the improvement of the precision and accuracy of in situ S isotope analysis at high spatial resolution. Different cone combinations have a significant effect on the mass bias and mass bias stability for S isotopes. Poor precisions of S isotope ratios were obtained using the Jet and X cones combination at their corresponding optimum makeup gas flow when using Ar plasma only. The addition of 4-8 ml min(-1) nitrogen to the central gas flow in laser ablation MC-ICP-MS was found to significantly enlarge the mass bias stability zone at their corresponding optimum makeup gas flow in these three different cone combinations. The polyatomic interferences of OO, SH, OOH were also significantly reduced, and the interference free plateaus of sulfur isotopes became broader and flatter in the nitrogen mode (N2 = 4 ml min(-1)). However, the signal intensity of S was not increased by the addition of nitrogen in this study. The laser fluence and ablation mode had significant effects on sulfur isotope fractionation during the analysis of sulfides and elemental sulfur by laser ablation MC-ICP-MS. The matrix effect among different sulfides and elemental sulfur was observed, but could be significantly reduced by line scan ablation in preference to single spot ablation under the optimized fluence. It is recommended that the d90 values of the particles in pressed powder pellets for accurate and precise S isotope analysis should be less than 10 μm. Under the selected optimized analytical conditions, excellent agreements between the determined values and the reference values were achieved for the IAEA-S series standard reference materials and a set of six well-characterized, isotopic homogeneous sulfide standards (PPP-1, MoS2, MASS-1, P-GBW07267, P-GBW07268, P-GBW07270), validating the capability of the developed method for providing high-quality in situ S isotope data in sulfides and elemental sulfur.


Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity.
IFNγ is a cytokine that plays a pivotal role in antitumor host immunity. IFNγ elicits potent antitumor immunity by inducing Th1 polarization, CTL activation, and dendritic cell tumoricidal activity. However, there are significant discrepancies in our understanding of the role of IFNγ as an antitumor cytokine. In certain circumstances, IFNγ obviously acts to induce tumor progression. IFNγ treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFNγ insensitivity and the downregulation of the MHC complex, have been regarded as the reasons for this discrepancy, but they do not fully explain it. We propose IFNγ-induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFNγ impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of IFNγ secreted from CTLs, which induces PD-L1 expression in preparation for an immune attack. Thus, tumor cells acquire the capability to counterattack immune cells. These findings indicate that although IFNγ is thought to be a representative antitumor cytokine, it actually has dual roles: one as a hallmark of antitumor immunity and the other as an inducer of the immune escape phenomenon through various mechanisms, such as PD-L1 expression. In this context, the optimization of immunotherapy according to the local immune environment is important. Anti-PD-1/PD-L1 treatment may be particularly promising when efficient tumor immunity is present, but it is disturbed by PD-L1 expression. Clin Cancer Res; 22(10); 2329-34. ©2016 AACR.


Ready, Set, Go: How Patients and Caregivers Are Prepared for Self-Management of an Implantable Ventricular Assist Device.
Since the first use of an implantable ventricular assist device (VAD) nearly 3 decades ago, many VAD Centers in the United States expect patients and caregivers to manage the device and related care following hospital discharge. Despite this customary practice and the rapid advancements in VAD technology, no research data about the patient and caregiver preparations exist for self-management of VAD. This study explored the process of preparing patients and caregivers for VAD care before hospital discharge along with their perceived experiences of the discharge process. Using an exploratory research design, we collected the data with self-administered demographics and VAD Hospital Discharge Survey questionnaires. We analyzed the data provided by 102 patients and 116 caregivers from different regions in the United States. Patients' mean age was 51.4 ± 13.8 years; they were predominantly White (78%); male (66%); and duration of device between 2 and 74 months. Caregivers were predominantly White (80%); female (81%); and had a mean of age 48.9 ± 12.7 years. Participants reported that their VAD care preparations, a crucial component of hospital discharge, were extensive and intensive processes comprising education, training, competency validation, and provision of resources for VAD self-management in home settings. Participants were satisfied with the process and felt prepared for discharge. Further research is needed to rectify the study limitations, advance the science of VAD self-management, and develop evidenced-based VAD self-management guidelines that are aimed at optimizing longevity of the VAD, patients' health, and quality of life.


Unstable angina pectoris: the first half century: natural history, pathophysiology, and treatment.
Unstable angina pectoris as a distinct syndrome intermediate between chronic stable angina and acute myocardial infarction was first described about a half century ago. The incidence of death or myocardial infarction rises in the first few months after destabilization of angina. Hemodynamic, scintigraphic, and arteriographic studies in the last 15 years have shown that unstable angina is chiefly due to "dynamic" coronary stenoses, transient reversible limitations in coronary blood flow caused by a complex interaction between coronary vasoconstriction, transient platelet plugging, and transient thrombosis. The trigger for the onset of dynamic coronary stenoses is probably acute changes in coronary arterial morphology in or near atherosclerotic plaques making those areas more thrombogenic. A large fraction of patients with unstable angina restabilize initially with medical management. The role of beta blockers is unclear, but they may protect against development of coronary events for patients with unstable angina similar to that reported for patients with myocardial infarction. Nitrates and calcium blockers are probably superior to beta blockers in restabilization of angina, but protection against coronary events has not yet been demonstrated clearly. Further investigation is needed to distinguish the relative benefits of a two-drug (heart rate-limiting calcium blocker plus nitrates) regimen vs. a three-drug regimen including beta blocker. There is no basis for emergency coronary bypass surgery to prevent myocardial infarction or death. Urgent surgery should be limited to patients who do not stabilize readily with medical therapy. One third or more of the patients who initially restabilize with medical therapy will require coronary revascularization in the year after unstable angina because of severe angina. An antithrombotic regimen of aspirin (or possibly heparin) reduces the incidence of progression to death or myocardial infarction. Two important future directions for research should be promising: development of better antithrombotic regimens other than aspirin alone for protection against coronary events; and improved ability to distinguish the patients who initially respond to medical therapy who are at low risk for later severe angina from those at higher risk.


CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype.
CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.


Adrenergic vasoconstriction lessens transmural steal during coronary hypoperfusion.
The hypothesis that alpha-receptor-mediated coronary vasoconstriction can lessen transmural steal during hypoperfusion was tested in 14 open-chest, chloralose-anesthetized dogs. Coronary flow to two regions of the left ventricle was controlled by separately cannulating and pump perfusing the anterior descending and circumflex coronary arteries. An intracoronary infusion of the alpha-receptor blocking agent phenoxybenzamine (0.25 mg/kg) was administered to one region while coronary sinus blood flow was trapped to minimize recirculation. All animals received atropine (0.5 mg/kg) and propranolol (2 mg/kg) intravenously. alpha-Receptor activation in both regions of the left ventricle was achieved with an intracoronary infusion of norepinephrine. Radioactive microspheres were used to measure the transmural distribution of myocardial blood flow as coronary flow in the paired regions was reduced from 100 to 80, 70, 60, and 50% of normal. When total coronary flow was reduced sufficiently to cause ischemia and maldistribution of flow across the myocardial wall, the subendocardial blood flow was greater in the alpha-receptor-intact region than in the alpha-blocked region. This indicates that alpha-receptor-mediated coronary vasoconstriction has an unexpected beneficial effect that lessens transmural steal during hypoperfusion.


What Historians of Medicine Can Learn from Historians of Capitalism.
After briefly surveying the New History of Capitalism and its objectives, this article explores ways that the history of medicine and the history of capitalism can productively interact. The article argues that historians of medicine should adopt a broad definition of "capitalism" to accommodate the distinctive nature of medical and health care markets. Across millennia and diverse cultures, medical markets have demonstrated extensive commodification, with spiritual or religious goods and services composing a significant portion of commercial trade. Moreover, health care markets, at least since the ancient era, have been susceptible to third-party interventions by both the state and voluntary organizations. Accordingly, historians of medicine should look for pockets of capitalist exchange in otherwise noncapitalist economies and also assess how the logic of capitalism has influenced government programming and other types of third-party involvement in the health care market. To illustrate that insights from the history of capitalism can be applied to many topics within the history of medicine, this article presents three case studies. It examines medical markets in ancient Egypt; in Medieval Europe as managed by the Catholic Church; and in Germany, England, and the United States at the end of the nineteenth century and into the twentieth.


On the improved correlative prediction scheme for aliased electrocardiogram (ECG) data compression.
An improved scheme for aliased electrocardiogram (ECG) data compression has been constructed, where the predictor exploits the correlative characteristics of adjacent QRS waveforms. The twin-R correlation prediction and lifting wavelet transform (LWT) for periodical ECG waves exhibits feasibility and high efficiency to achieve lower distortion rates with realizable compression ratio (CR); grey predictions via GM(1, 1) model have been adopted to evaluate the parametric performance for ECG data compression. Simulation results illuminate the validity of our approach.


A phase I study of combination of intravenous gemcitabine, oxaliplatin, and 5-FU with daily oral thalidomide (GOFT) in metastatic/locally advanced pancreatic carcinoma patients.
The phase I study was to determine the maximum tolerance dose and dose-limiting toxicity of gemcitabine/oxaliplatin/5-FU/thalidomide (GOFT) in patients with advanced pancreatic cancer. Chemotherapy-naive patients with histologically proven locally advanced or metastatic pancreatic cancer were enrolled. Gemcitabine was given in a 1-hour infusion followed by oxaliplatin in a 2-hour infusion on day 1, and 5-FU in a 24-hour infusion on day 2, and oral thalidomide 100mg was given daily after intravenous chemotherapy. This regimen was given every 2 weeks. Dose levels of regimen were: level I: gemcitabine 1000mg/m2 + oxaliplatin 60mg/ m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day, level II: gemcitabine 1000mg/m2 + oxaliplatin 70mg/m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day, level III: gemcitabine 1250mg/m2 + oxaliplatin 60mg/m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day. The NCI-CTC grade 3/4 toxicity was used for dose-limiting toxicity. Maximum tolerance dose was determined after the first two cycles in each patient. There were 6 patients in level I, 6 patients in level II, and 1 patient in level III. One of the 6 patients had DLT in level I (grade 3 infection and vomiting), 2 of 6 patients had DLT in level II (grade 3 leukopenia) and 1 patient in level III had DLT (grade 3 leukopenia and stomatitis). Other toxicities at level I/II were grade 1/2 leukopenia (7 episodes), grade 1/2 anemia (5), grade 1/2 nausea (5), grade 1 diarrhea (2), grade 1 alopecia (2), grade 1 skin (2), grade 1 allergy (1). The GOFT regimen was well tolerated and showed good treatment effect on the pancreatic cancer. We recommended the dose of level II GOFT regimen for further phase II trial.


[Status of 3D Printing Technology for Preparing Bioceramic Materials].
3D printing technology has great advantages in small batch and personalized customization, so it has attracted much attention in the biomedical field. The consumables available for 3D printing include polymer, metal, ceramic and derived materials. Biomedical ceramics, with high melting point and poor toughness, are the most difficult materials to be used in 3D printing. The progress of 3D printing ceramic preparation process using ceramic powder, ceramic slurry, ceramic wire, ceramic film and other different raw materials as consumables are reviewed, and the surface roughness, size, density and other parameters of ceramics prepared by SLS, 3DP, DIW, IJP, SL, DLP, FDM, LOM and other different processes are compared. The study also summarizes the clinical application status of 3D printed bioceramics in the field of hard tissue repair such as bone tissue engineering scaffolds and dental prostheses. The SL ceramic additive manufacturing technology based on the principle of UV polymerization has better manufacturing precision, forming quality and the ability to prepare large-size parts, and can also endow bioceramics with better biological properties, mechanical properties, antibacterial, tumor treatment and other functions by doping trace nutrients and surface functional modification. Compared with the traditional subtractive manufacturing process, the bioceramics prepared by 3D printing not only have good mechanical properties, but also often have better biocompatibility and osteoconductivity.