Facial displays in red-capped mangabeys (Cercocebus torquatus): Repertoire, social context, and potential intentionality.
Primate communication relies strongly on the visual modality, notably through the production of a wide range of expressive facial signals. We investigated here the facial display repertoire of a relatively little-studied cercopithecid species, red-capped mangabeys (Cercocebus torquatus), and questioned whether their facial displays were dependent on social contexts and accompanied by indices of intentionality. Although the dual intentional and emotional use of apes' facial expressions has recently been suggested, the question of whether monkeys produce facial expressions intentionally to communicate remains open. We described 6 facial displays produced by captive red-capped mangabeys in social contexts. They are based on movements of the mouth, eyebrows, and ears, possibly graded in intensity and produced independently or in combination. We showed that most of the facial displays were produced preferentially in specific social contexts and that repertoires varied with subjects' characteristics, highlighting the communicative function of these displays. Moreover, behavioral markers of intentionality commonly used in gestural studies were found to accompany the production of some of the facial signals observed. Particularly, playful "open mouth" appeared strongly associated with intentionality indices, as previously noticed in ape species. All other facial displays, except yawns, did not exhibit all defined intentional indices but were, at least, directed toward a recipient. Interestingly, yawns presented different variants of intensity associated presumably with different social functions. Altogether, these results emphasize the communicative function of red-capped mangabeys' facial displays and provide a basis for further research on their intentional communication. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Proliferative processes in the epithelium of the autotransplant and surrounding skin of mice].
Proliferative processes were studied in epithelial cells of skin autografts and the surrounding skin in mice of CBA line. In the animals subjected to the operation but without cortisone injection (Fig. 1, a and Fig. 2, delta), a high proliferative activity in the skin epithelial cells surrounding the autograft was observed during the whole course of the experiment. In the cells of the autograft, the mitotic activity, after inhibition, restored quickly up to the original level, and in 10 days it sharply increased and did not differ from that in the epithelium of the surrounding skin. The amount of DNA-synthesising cells in the epithlium of the autograft at first remained at the original level, and then, after a short sharp rise, it decreased up to its level in the surrounding skin and then was changing nearly in the similar fashion with it. After repeated injection of cortisone both indices of proliferative activity (Fig 1, delta and Fig. 2, delta) in the epithlium of the autograft and of the surrounding skin gradually increased although slower than in the controls.


Modulation of cell growth and differentiation by ceramide.
Ceramide has been suggested as an intracellular modulator of cell growth and differentiation [Okazaki, T. et al. (1990) J. Biol. Chem. 265, 15823-15831]. In this study, parameters that modulate the effects of ceramide on HL-60 cell growth and differentiation were examined. A short-chain, cell-permeable analog of ceramide, C2-ceramide, induced differentiation of HL-60 human leukemia cells and inhibited HL-60 growth in a concentration-dependent manner. The potency of C2-ceramide was modulated by the starting cell density such that the concentration of C2-ceramide producing 50% inhibition of cell growth (IC50%) ranged from 2 microM (for cells suspended at 1 x 10(5) cells/ml) to 11 microM (for cells at 8 x 10(5) cells/ml). However, the IC50% showed little variation if the concentration of C2-ceramide was expressed as fmol of C2-ceramide per 10(5) cells. Therefore, the effectiveness of C2-ceramide appeared to be primarily determined by its cellular rather than molar concentration. Binding of C2-ceramide to serum proteins resulted in a 10-fold increase in the IC50%. These results demonstrate that the biologic activity of C2-ceramide is subject to surface dilution kinetics and is sensitive to the presence of lipid-binding proteins. In these properties, ceramide behaves as a prototypic lipid second messenger/intracellular mediator.


A framework for engaging stakeholders on the management of alien species.
Alien species can have major ecological and socioeconomic impacts in their novel ranges and so effective management actions are needed. However, management can be contentious and create conflicts, especially when stakeholders who benefit from alien species are different from those who incur costs. Such conflicts of interests mean that management strategies can often not be implemented. There is, therefore, increasing interest in engaging stakeholders affected by alien species or by their management. Through a facilitated workshop and consultation process including academics and managers working on a variety of organisms and in different areas (urban and rural) and ecosystems (terrestrial and aquatic), we developed a framework for engaging stakeholders in the management of alien species. The proposed framework for stakeholder engagement consists of 12 steps: (1) identify stakeholders; (2) select key stakeholders for engagement; (3) explore key stakeholders' perceptions and develop initial aims for management; (4) engage key stakeholders in the development of a draft management strategy; (5) re-explore key stakeholders' perceptions and revise the aims of the strategy; (6) co-design general aims, management objectives and time frames with key stakeholders; (7) co-design a management strategy; (8) facilitate stakeholders' ownership of the strategy and adapt as required; and (9) implement the strategy and monitor management actions to evaluate the need for additional or future actions. In case additional management is needed after these actions take place, some extra steps should be taken: (10) identify any new stakeholders, benefits, and costs; (11) monitor engagement; and (12) revise management strategy. Overall, we believe that our framework provides an effective approach to minimize the impact of conflicts created by alien species management.


Combination of extremum-seeking algorithms with effective hydraulic handling of equalization tanks to control anaerobic digesters.
The benefits of upgrading extremum-seeking controllers with an effective exploitation of the buffer capacity of equalization tanks have been investigated and applied to anaerobic digesters. In this respect, a Fuzzy-based supervisory module that monitors the state of the equalization tank has been designed and built on top of an extremum-seeking algorithm in charge of automatically regulating the wastewater fed into the anaerobic digester. The extremum-seeking controller guarantees good disturbance rejection and methane production around an upper limit set-point. The on-top Fuzzy module optimizes the long-term methane production by modifying this upper limit set-point as a function of the state of the equalization tank. A systematic simulation study has been carried out to evaluate the performance of the proposed control solution. Thus, on the basis of existing simulation benchmarks for assessment of control strategies in wastewater treatment plants, a dedicated simulation protocol for anaerobic digesters has been defined and implemented. Simulation results have shown that, compared with manual operation, effluent quality and methane production improvements of 10-15% are achieved using the proposed control approach.


Acetyl-11-Keto-β-Boswellic Acid Promotes Osteoblast Differentiation by Inhibiting Tumor Necrosis Factor-α and Nuclear Factor-κB Activity.
Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs. In the present study, we evaluated the NF-κB inhibitor Boswellic acid (BA) and its derivatives in the regulation of osteoblast differentiation and the molecular mechanism. Based on the cell model of TNF-α induced inhibition of osteoblast differentiation of MC3T3-E1, the regulatory role of BAs was studied. The result of MTT assay indicated that bone morphogenetic protein (BMP) -2, TNF-α, or acetyl-11-keto-β-BA (AKBA) impact no significant effect for cell viability of MC3T3-E1. The results of alkaline phosphatase (ALP activity assay and real-time polymerase chain reaction indicated that AKBA blocked TNF-α-induced inhibition of the expression of osteoblast markers, suggesting that AKBA rescued osteoblast differentiation from TNF-α-induced inhibition. Additionally, AKBA stimulated the BMP-2-induced expression of osteoblast markers, suggesting that AKBA promotes osteoblast differentiation directly. The results of western blotting and luciferase assay indicated that N-κB signaling was activated by TNF-α. The overexpression of NF-κB component p65 in MC3T3-E1 was found to attenuate the positive effect of AKBA in osteoblast differentiation, suggesting that AKBA potentiates osteoblast differentiation by inhibiting NF-κB signaling. Collectively, AKBA promotes osteoblast differentiation by inhibiting TNF-α and NF-κB. Our study revealed a new discovery of AKBA in regulating osteoblast differentiation, and demonstrated that AKBA may be a potential anabolic agent in the treatment of RA-derived bone loss disease.


Faculty diversity programs in U.S. medical schools and characteristics associated with higher faculty diversity.
To describe diversity programs for racial and ethnic minority faculty in U.S. medical schools and identify characteristics associated with higher faculty diversity. The authors conducted a cross-sectional survey study of leaders of diversity programs at 106 U.S. MD-granting medical schools in 2010. Main outcome measures included African American and Latino faculty representation, with correlations to diversity program characteristics, minority medical student representation, and state demographics. Responses were obtained from 82 of the 106 institutions (77.4%). The majority of the respondents were deans, associate and assistant deans (68.3%), members of minority ethnic/racial background (65.9% African American, 14.7% Latino), and women (63.4%). The average time in the current position was 6.7 years, with approximately 50% effort devoted to the diversity program. Most programs targeted medical trainees and faculty (63.4%). A majority of programs received monetary support from their institutions (82.9%). In bivariate analysis, none of the program characteristics measured were associated with higher than the mean minority faculty representation in 2008 (3% African American and 4.2% Latino faculty). However, minority state demographics in 2008, and proportion of minority medical students a decade earlier, were significantly associated with minority faculty representation. Medical student diversity 10 years earlier was the strongest modifiable factor associated with faculty diversity. Our results support intervening early to strengthen the minority medical student pipeline to improve faculty diversity. Schools located in states with low minority representation may need to commit additional effort to realize institutional diversity.


Pediatric cancer patients in clinical trials of sepsis: factors that predispose to sepsis and stratify outcome.
To delineate the factors that predispose pediatric oncology and hematopoietic stem cell transplant (HSCT) patients to sepsis and to identify factors that stratify their outcome. Peer-reviewed literature available via MEDLINE search. All types of study. Pediatric oncology patients account for a relatively high proportion of severe sepsis in children. Available data suggest that outcomes among the non-HSCT oncology population are not substantially different from that of the general population. Data suggest that children with cancer (non-HSCT) who survive their septic episode will have a high probability of 6-month survival. In light of these findings, pediatric oncology patients are an important source of potential candidates for clinical trials of sepsis. In addition, HSCT patients seem to have significantly worse outcomes from sepsis than the non-HSCT oncology population, and thus, their participation in clinical trials is needed. However, in view of these worse outcomes, it is important to stratify the randomization for this population and to ensure that studies are adequately powered to assess outcomes in this subgroup.


Principles of constructing efficient erythrocyte immunoglobulin diagnostics.
Selection of the method of loading erythrocytes with preparations of immunoglobulins (IG) should be determined by the properties of the sensitins to be used. For the production of efficient antibody diagnostics it is advisable to use amidol while in the case of highly active and concentrated sera, amidol, CrCl3 and glutaraldehyde should be employed. The application of IgG preparations considerably enhances the sensitivity of PHAR in the indication of antigens. Immunoglobulin diagnostics on the basis of IG preparations of normal sera should be produced by means of rivanol, tannin or previously heated erythrocytes. In the multiform group of erythrocyte immunoglobulin diagnostics it is necessary to distinguish antibody and non-antibody preparations. Such a classification is justified with respect to differences in the purpose and the optimum methods of production of immunoglobulin diagnostics.


Oxygen administration for patients with ARDS.
Acute respiratory distress syndrome (ARDS) is a fatal condition with insufficiently clarified etiology. Supportive care for severe hypoxemia remains the mainstay of essential interventions for ARDS. In recent years, adequate ventilation to prevent ventilator-induced lung injury (VILI) and patient self-inflicted lung injury (P-SILI) as well as lung-protective mechanical ventilation has an increasing attention in ARDS.Ventilation-perfusion mismatch may augment severe hypoxemia and inspiratory drive and consequently induce P-SILI. Respiratory drive and effort must also be carefully monitored to prevent P-SILI. Airway occlusion pressure (P0.1) and airway pressure deflection during an end-expiratory airway occlusion (Pocc) could be easy indicators to evaluate the respiratory drive and effort. Patient-ventilator dyssynchrony is a time mismatching between patient's effort and ventilator drive. Although it is frequently unrecognized, dyssynchrony can be associated with poor clinical outcomes. Dyssynchrony includes trigger asynchrony, cycling asynchrony, and flow delivery mismatch. Ventilator-induced diaphragm dysfunction (VIDD) is a form of iatrogenic injury from inadequate use of mechanical ventilation. Excessive spontaneous breathing can lead to P-SILI, while excessive rest can lead to VIDD. Optimal balance between these two manifestations is probably associated with the etiology and severity of the underlying pulmonary disease.High-flow nasal cannula (HFNC) and non-invasive positive pressure ventilation (NPPV) are non-invasive techniques for supporting hypoxemia. While they are beneficial as respiratory supports in mild ARDS, there can be a risk of delaying needed intubation. Mechanical ventilation and ECMO are applied for more severe ARDS. However, as with HFNC/NPPV, inappropriate assessment of breathing workload potentially has a risk of delaying the timing of shifting from ventilator to ECMO. Various methods of oxygen administration in ARDS are important. However, it is also important to evaluate whether they adequately reduce the breathing workload and help to improve ARDS.


Interannual variation and long-term trends in proportions of resident individuals in partially migratory birds.
Partial migration - a part of a population migrates and another part stays resident year-round on the breeding site - is probably the most common type of migration in the animal kingdom, yet it has only lately garnered more attention. Theoretical studies indicate that in partially migratory populations, the proportion of resident individuals (PoR) should increase in high latitudes in response to the warming climate, but empirical evidence exists for few species. We provide the first comprehensive overview of the environmental factors affecting PoR and the long-term trends in PoR by studying 27 common partially migratory bird species in Finland. The annual PoR values were calculated by dividing the winter bird abundance by the preceding breeding abundance. First, we analysed whether early-winter temperature, winter temperature year before or the abundance of tree seeds just before overwintering explains the interannual variation in PoR. Secondly, we analysed the trends in PoR between 1987 and 2011. Early-winter temperature explained the interannual variation in PoR in the waterbirds (waterfowl and gulls), most likely because the temperature affects the ice conditions and thereby the feeding opportunities for the waterbirds. In terrestrial species, the abundance of seeds was the best explanatory variable. Previous winter's temperature did not explain PoR in any species, and thus, we conclude that the variation in food availability caused the interannual variation in PoR. During the study period, PoR increased in waterbirds, but did not change in terrestrial birds. Partially migratory species living in physically contrasting habitats can differ in their annual and long-term population-level behavioural responses to warming climate, possibly because warm winter temperatures reduce ice cover and improve the feeding possibilities of waterbirds but do not directly regulate the food availability for terrestrial birds.


High throughput PRIME editing screens identify functional DNA variants in the human genome.
Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and base-pair resolution manner remains challenging. Here, we develop a novel pooled prime editing screen method, PRIME, which can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp MYC enhancer via PRIME-mediated saturation mutagenesis. Next, we applied PRIME to functionally characterize 1,304 non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate PRIME capable of characterizing genetic variants at base-pair resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.


Where Is the Drug? Quantitative 3D Distribution Analyses of Confined Drug-Loaded Polymer Matrices.
To enhance oral bioavailability of poorly soluble drugs, microfabricated devices can be utilized. One example of such devices is microcontainers. These are cylindrical in shape with an inner cavity for drug loading and with only the top side open for release. Supercritical CO2 (scCO2) impregnation is an interesting technique for loading drugs into polymeric matrices in, for example, microcontainers since it avoids the use of organic solvents and is cheap. One of the main drawbacks of this technique is the unknown three-dimensional drug distribution in the polymer matrix. The aim of this study was to investigate the loading of two poorly soluble drugs, naproxen and ketoprofen, by scCO2 impregnation into confined polymer matrices of different sizes. Three different sizes of microcontainers (small, medium, and large) and, thereby, different surface areas accessible for impregnation were compared. From in vitro studies, the amount of naproxen and ketoprofen loaded into the different microcontainers and their corresponding release profiles were seen to be similar. A custom-made Raman microscope facilitated volumetric Raman maps of an entire microcontainer filled with polyvinylpyrrolidone (PVP) and scCO2 impregnated with either naproxen or ketoprofen. In all microcontainer sizes, the drugs were only detected in the top layer of the polymer matrix, explaining the observed similar release profiles. Using X-ray powder diffraction and Raman spectroscopy, the solid state form of the drugs was evaluated, showing that ketoprofen was amorphous in all microcontainer sizes. Naproxen was found not to be crystalline nor amorphous but in a less ordered configuration than the crystalline state. In conclusion, volumetric Raman mapping is a powerful technology for imaging drug distribution and drug crystallinity in polymers and allowed us to conclude that (i) scCO2 impregnation depth does not depend on surface area and (ii) impregnated drugs are noncrystalline.


MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast.
The mating pathway in Saccharomyces cerevisiae has been the focus of considerable research effort, yet many quantitative aspects of its regulation still remain unknown. Using an integrated approach involving experiments in microfluidic chips and computational modelling, we studied gene expression and phenotypic changes associated with the mating response under well-defined pheromone gradients. Here we report a combination of switch-like and graded pathway responses leading to stochastic phenotype determination in a specific range of pheromone concentrations. Furthermore, we show that these responses are critically dependent on mitogen-activated protein kinase (MAPK)-mediated regulation of the activity of the pheromone-response-specific transcription factor, Ste12, as well as on the autoregulatory feedback of Ste12. In particular, both the switch-like characteristics and sensitivity of gene expression in shmooing cells to pheromone concentration were significantly diminished in cells lacking Kss1, one of the MAP kinases activated in the mating pathway. In addition, the dynamic range of gradient sensing of Kss1-deficient cells was reduced compared with wild type. We thus provide unsuspected functional significance for this kinase in regulation of the mating response.


Expression of bacterial genes and induction of INF-gamma in human myeloid dendritic cells during persistent infection with Chlamydophila pneumoniae.
The interactions between human monocyte-derived dendritic cells (DCs) and Chlamydophila pneumoniae (Cpn) infection were investigated. Cpn infection induced the maturation and functional activation of DCs, and Cpn antigens were present in all of the subpopulations during the maturation process. Chlamydial antigens were detected in DCs during an observation period of 28 days. The exponential production of infectious elementary bodies was not observed. Chlamydial transcripts of the 16S rRNA gene, groEL-1 and omcB genes were expressed, as determined by a quantitative real-time PCR, but the expression of the ftsK gene was limited. DC cultures produced IFN-gamma, but the presence of IFN-gamma in the culture medium was not the major factor that decreased the growth of Cpn, as was shown by neutralization of the IFN-gamma. A cell population identified as producing IFN-gamma had no markers for T, B, natural killer, monocyte cells or macrophages but displayed DC morphology and the expression of specific DC markers, such as CD11c and HLA-DR. These results reveal a persistent infection of DCs with the expression of some, but not cell division-related genes and the production of IFN-gamma that may contribute to the pathomechanism of chronic inflammatory diseases associated with persistent Cpn infection.


Developing and testing an algorithm for automatic segmentation of the fetal face from three-dimensional ultrasound images.
Fetal craniofacial abnormalities are challenging to detect and diagnose on prenatal ultrasound (US). Image segmentation and computer analysis of three-dimensional US volumes of the fetal face may provide an objective measure to quantify fetal facial features and identify abnormalities. We have developed and tested an atlas-based partially automated facial segmentation algorithm; however, the volumes require additional manual segmentation (MS), which is time and labour intensive and may preclude this method from clinical adoption. These manually refined segmentations can then be used as a reference (atlas) by the partially automated segmentation algorithm to improve algorithmic performance with the aim of eliminating the need for manual refinement and developing a fully automated system. This study assesses the inter- and intra-operator variability of MS and tests an optimized version of our automatic segmentation (AS) algorithm. The manual refinements of 15 fetal faces performed by three operators and repeated by one operator were assessed by Dice score, average symmetrical surface distance and volume difference. The performance of the partially automatic algorithm with difference size atlases was evaluated by Dice score and computational time. Assessment of the manual refinements showed low inter- and intra-operator variability demonstrating its suitability for optimizing the AS algorithm. The algorithm showed improved performance following an increase in the atlas size in turn reducing the need for manual refinement.


Evaluation of Different IOL Calculation Formulas of the ASCRS Calculator in Eyes After Corneal Refractive Laser Surgery for Myopia With Multifocal IOL Implantation.
To compare the accuracy of different intraocular lens (IOL) calculation formulas available on the American Society of Cataract and Refractive Surgery (ASCRS) post-refractive surgery IOL power calculator for the prediction of multifocal IOL power after previous corneal refractive laser surgery for myopia. An analysis and comparison were performed of the accuracy of three methods using surgically induced change in refraction (ie, Masket, Modified Masket, and Barrett True-K formulas) and three methods using no previous data (ie, Shammas, Haigis-L, and Barrett True-K No History formulas). The average of all formulas was also analyzed and compared. Thirty-six eyes of 36 patients were included. All formulas, except for the Masket, Modified Masket, and Barrett True-K formulas, had myopic mean numerical errors that were significantly different from zero (P ⩽ .01). The median absolute error of the Shammas formula (0.52 diopters [D]) was significantly higher compared to all of the other formulas (P < .05), except for the Haigis-L formula (P = .09). Comparing the formulas using no previous data, the Barrett True-K No History formula had the lowest median absolute error (0.33 D, P < .001). The Shammas formula showed the least accuracy in predicting IOL power in eyes with multifocal IOL implantation after previous corneal refractive laser surgery for myopia. In eyes with all available data, all formulas performed equally except for the Shammas formula, whereas in eyes lacking historical data, the Barrett True-K No History formula performed best. [J Refract Surg. 2019;35(1):54-59.].


[Cooperation protocol for imaging prescription by the emergency department IOA].
According to a study carried out at Caen University Hospital by Dr. Kevin Planchon between September 2021 and April 2022, waiting time in the emergency department was reduced by 33minutes thanks to the simplification of the patient pathway and the time given to teams to implement the cooperation protocol.


Stages of exercise behavior change at two time periods following coronary artery bypass graft surgery.
A sedentary lifestyle is the most prevalent coronary heart disease risk factor in the United States. It is a challenge for healthcare providers to promote the adoption and maintenance of regular exercise as a lifestyle change in sedentary individuals. For this effort to be effective, research on exercise behavior and the processes that promote the desired behavior is needed. Using the Transtheoretical Model of Change (TMC), this study was aimed at describing and comparing short- and long-term regular exercise behavior and the change processes used in the different stages, with subjects after coronary artery bypass graft (CABG) surgery. Questionnaires were sent to 253 patients aged 60 years and older at 4 to 6 months and 22 to 26 months after CABG surgery. The study findings indicate that 67% of the subjects had become long-term regular exercisers. However, there were more subjects who had begun exercise shortly after the surgery than at the 2-year point. The data suggest that health promotion efforts may be more cost-effective and efficient if focused on educating the smaller percentage of post-CABG surgery patients in the pre-regular-exercise stages. In addition, relapse prevention may be needed to maintain exercise adherence. This study also demonstrates that exercise behavior can be easily categorized into stages with the use of four questions. However, an instrument to evaluate the processes of exercise behavior change needs to be developed specifically for the older population.


Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies.
There is a longstanding association between substance-use disorders (SUDs) and the psychological construct of impulsivity. In the first section of this review, personality and neurocognitive data pertaining to impulsivity will be summarised in regular users of four classes of substance: stimulants, opiates, alcohol and 3,4-methylenedioxymethamphetamine (MDMA). Impulsivity in these groups may arise via two alternative mechanisms, which are not mutually exclusive. By one account, impulsivity may occur as a consequence of chronic exposure to substances causing harmful effects on the brain. By the alternative account, impulsivity pre-dates SUDs and is associated with the vulnerability to addiction. We will review the evidence that impulsivity is associated with addiction vulnerability by considering three lines of evidence: (i) studies of groups at high-risk for development of SUDs; (ii) studies of pathological gamblers, where the harmful consequences of the addiction on brain structure are minimised, and (iii) genetic association studies linking impulsivity to genetic risk factors for addiction. Within each of these three lines of enquiry, there is accumulating evidence that impulsivity is a pre-existing vulnerability marker for SUDs.


Exploring the concerns of persons with disabilities in Western Zambia.
Understandings of disability are rooted in contexts. Despite the world's significant contextual diversity, postcolonial power dynamics allow influential actors from the global North to imagine that most people across the global South understand disability in one generalised way. When it informs programmes and services for persons with disabilities in the global South, this imagining of a single generalised view could reduce effectiveness while further marginalising the people for whom the programmes and services were designed. In the interest of better understanding a contextually grounded meaning of disability, we explored the expressed concerns of two organisations of persons with disabilities and their members in Western Zambia. In this qualitative constructionist study, data collection focused upon life with a disability and services available to persons with disabilities. Data were collected through 39 individual interviews and eight focus group discussions with 81 members of organisations of persons with disabilities. Data were analysed thematically. The participants' main expressed concern was poverty. This concern was articulated in terms of a life of suffering and a need for material resources. Participants linked poverty to disability in two ways. Some participants identified how impairments limited resource acquisition, resulting in suffering. Others considered poverty to be an integral part of the experience of disability. This study contributes to literature on disability theory by providing a contextually grounded account of a particular understanding of disability and poverty. The study also contributes to disability practice and policymaking through the demonstration of poverty as the main concern of persons with disabilities in this context.


Dermatologic manifestations of fibromyalgia.
The aim of this study was to determine the common dermatologic diagnoses and skin-related symptoms in a cohort of patients with fibromyalgia seen in a tertiary referral center. A retrospective chart review was performed of all patients with a fibromyalgia diagnosis from January 1 to December 31, 2008, whose diagnosis was confirmed in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota. Charts were reviewed for dermatologic conditions and cutaneous symptoms. Demographic and clinical data were collected to assess the frequency of skin-related issues in patients with fibromyalgia. Of 2,233 patients screened, 845 patients met the inclusion criteria of having a confirmed diagnosis of fibromyalgia. Among these fibromyalgia patients, various dermatologic conditions and cutaneous problems were identified, including hyperhidrosis in 270 (32.0 %), burning sensation of the skin or mucous membranes in 29 (3.4 %), and various unusual cutaneous sensations in 14 (1.7 %). Pruritus without identified cause was noted by 28 patients (3.3 %), with another 16 patients (1.9 %) reporting neurotic excoriations, prurigo nodules, or lichen simplex chronicus. Some form of dermatitis other than neurodermatitis was found in 77 patients (9.1 %). Patients with fibromyalgia may have skin-related symptoms associated with their fibromyalgia. No single dermatologic diagnosis appears to be overrepresented in this population, with the exception of a subjective increase in sweating.


LMNA Co-Regulated Gene Expression as a Suitable Readout after Precise Gene Correction.
LMNA-related muscular dystrophy is an autosomal-dominant progressive disorder caused by mutations in LMNA. LMNA missense mutations are becoming correctable with CRISPR/Cas9-derived tools. Evaluating the functional recovery of LMNA after gene editing bears challenges as there is no reported direct loss of function of lamin A/C proteins in patient-derived cells. The proteins encoded by LMNA are lamins A/C, important ubiquitous nuclear envelope proteins but absent in pluripotent stem cells. We induced lamin A/C expression in induced pluripotent stem cells (iPSCs) of two patients with LMNA-related muscular dystrophy, NM_170707.4 (LMNA): c.1366A > G, p.(Asn456Asp) and c.1494G > T, p.(Trp498Cys), using a short three-day, serum-induced differentiation protocol and analyzed expression profiles of co-regulated genes, examples being COL1A2 and S100A6. We then performed precise gene editing of LMNA c.1366A > G using the near-PAMless (PAM: protospacer-adjacent motif) cytosine base editor. We show that the mutation can be repaired to 100% efficiency in individual iPSC clones. The fast differentiation protocol provided a functional readout and demonstrated increased lamin A/C expression as well as normalized expression of co-regulated genes. Collectively, our findings demonstrate the power of CRISPR/Cas9-mediated gene correction and effective outcome measures in a disease with, so far, little perspective on therapies.


Tracking the formation of eumelanin from L-Dopa using coupled measurements.
Melanin plays a crucial role as a pigment all through the animal kingdom. Being a macromolecule just on the divide between an ordered crystalline or a purely amorphous form melanin has proven a challenge to structure-function analysis. Melanin assembles from small molecules much like a jigsaw and much like in a jigsaw the fine detail quickly vanishes in the overall picture. With melanin being first and foremost a photo-active molecule we focus on spectral properties for the characterisation of its structure. We use absorption measurements to illustrate the complex nature of the formation process. To gain a better hold on the formation pathway we use coupled measurements of excitation and emission to identify 'areas of interest' in the excitation-emission matrix (EEM). We then probe one area for characteristic fluorescence lifetimes to track one melanin building block through the formation process. Comparison of the EEMs of L-Dopa derived melanin with natural Sepia melanin shows characteristic differences. We show how the presence of copper ions creates a melanin closer to its natural form.


Cryosurgery in the treatment of giant cell tumor. A long-term followup study.
Between 1983 and 1993, 102 patients with giant cell tumor of bone were treated at three institutions. Sixteen patients (15.9%) presented with already having had local recurrence. All patients were treated with thorough curettage of the tumor, burr drilling of the tumor inner walls, and cryotherapy by direct pour technique using liquid nitrogen. The average followup was 6.5 years (range, 4-15 years). The rate of local recurrence in the 86 patients treated primarily with cryosurgery was 2.3% (two patients), and the overall recurrence rate was 7.9% (eight patients). Six of these patients were cured by cryosurgery and two underwent resection. Overall, 100 of 102 patients were cured with cryosurgery. Complications associated with cryosurgery included six (5.9%) pathologic fractures, three (2.9%) cases of partial skin necrosis, and two (1.9%) significant degenerative changes. Overall function was good to excellent in 94 patients (92.2%), moderate in seven patients (6.9%), and poor in one patient (0.9%). Cryosurgery has the advantages of joint preservation, excellent functional outcome, and low recurrence rate when compared with other joint preservation procedures. For these reasons, it is recommended as an adjuvant to curettage for most giant cell tumors of bone.


No differences in hippocampal volume between carriers and non-carriers of the ApoE ε4 and ε2 alleles in young healthy adolescents.
Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life.


[The adaptation methodology of a guideline for the management of adults with community-acquired pneumonia].
Clinical practice guidelines (CPG) are widely used as tools for improving quality of health care. Guidelines developed elsewhere, can be adapted using a valid and systematic process. To describe the methodology used in the process of adaptation of a guideline for the management of adults with community-acquired pneumonia (CAP) in a private health care organization. We used the ADAPTE framework involving three main phases. At the set-up phase a guideline adaptation group integrated by medical specialists from different disciplines, a methodologist and a nurse coordinator was formed. At the adaptation phase, the specific clinical questions to be addressed by the guidelines were identified. Twenty five guidelines were initially retrieved. After their assessment, the number was reduced to only three. Recommendations from these guidelines were 'mapped' and focused searches were carried out where 'evidence gaps' were identified. An initial draft was written and revised by the adaptation group. At the finalization phase, the external review of the guideline was carried out and a process for the regular review and update of the adapted guideline was defined. We developed a guideline for the management of adults with CAP, adapted to the local context of our health care system, using guidelines developed elsewhere. This guideline creation method can be an efficient means of saving professional resources.


The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis.
The alpha(2)beta(1) integrin is a collagen/laminin receptor expressed on platelets, endothelial cells, fibroblasts, and epithelial cells. To define the role of the alpha(2)beta(1) integrin in vivo, we created a genetically engineered mouse in which expression of the alpha(2)beta(1) integrin was completely eliminated. Mice deficient in the alpha(2)beta(1) integrin are viable, fertile, and develop normally with no excess lethality of homozygotes. Both alpha(2)beta(1)-integrin protein and alpha(2) mRNA were undetectable in the alpha(2)-null mice. Gross and histological evaluation of the heart, lungs, kidneys, gastrointestinal tract, pancreas, skin, and reproductive tracts revealed no abnormalities. However, quantitative analysis of mammary gland branching morphogenesis demonstrated that branching complexity is markedly diminished in the alpha(2)-deficient animals. Studies in the alpha(2)-deficient animals do not support the proposed roles for the alpha(2)beta(1) integrin on fibroblasts and keratinocytes in wound healing. When compared to platelets from wild-type littermates, platelets from alpha(2)-null mice failed to adhere to type I collagen under either static or shear-stress conditions. Although platelets from alpha(2)-deficient animals aggregated in response to collagen, they did so with prolonged lag time and lessened intensity. The alpha(2)beta(1) integrin-null mouse thus exhibits diverse, sometimes subtle, phenotypes consistent with the widespread pattern of alpha(2)beta(1) integrin expression.


Heritability of LDL peak particle diameter in the Quebec Family Study.
LDL size has been associated with the risk of coronary heart disease. The objective of the present study was to verify whether familial factors influence LDL peak particle diameter (LDL-PPD), a quantitative trait reflecting the size of the major LDL subclass. LDL-PPD was measured by 2-16% polyacrylamide gradient gel electrophoresis in 681 members of 236 nuclear families participating in the Quebec Family Study. LDL-PPD was adjusted for age (LDL-PPD1), age and body mass index (LDL-PPD2), or age, body mass index, and plasma triglyceride levels (LDL-PPD3) separately in men and women. The residual scores were used to test for familial aggregation, using an ANOVA and to compute maximum likelihood estimates of familial correlations. The ANOVA test revealed that family lines accounted for 47.4%, 46.7%, and 48.9% of the variance in the LDL-PPD1, LDL-PPD2, and LDL-PPD3 phenotypes, respectively. The pattern of familial correlations revealed no significant spouse correlations but significant parent-offspring and sibling correlations for the three LDL-PPD phenotypes, with maximal heritability estimates of 59%, 58%, and 52% for LDL-PPD1, LDL-PPD2, and LDL-PPD3, respectively. These results suggest that LDL-PPD strongly aggregates in families, and that the familial resemblance appears to be primarily attributable to genetic factors. Genes responsible for this genetic contribution remain to be identified.


Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.
Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the cerebrospinal fluid (CSF) has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism, and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signaling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.


Anemia evaluation and management in nursing home residents.
Anemia is often an unrecognized and/or undertreated diagnosis in older adults. Failure to diagnose anemia leads to delayed treatment and thus delayed relief of symptoms. Given the potentially significant impact of anemia on cardiovascular disease and physical performance among older nursing home (NH) residents, it is important to evaluate current clinical practice related to anemia.The purpose of this secondary data analysis was to evaluate the frequency of laboratory evaluation and medication treatment for anemia among older NH residents. Results indicated that more than half of NH residents were anemic at baseline, and of those, less than 20% had additional testing done to further evaluate for an underlying cause of their anemia and only 45.3% received any pharmacologic treatment. Future research is needed to clarify the potential benefits of timely diagnosis and appropriate treatment for anemic older adults in long-term-care settings and establish evidence-based guidelines to direct care in this area.


Motor recovery and anatomical evidence of axonal regrowth in spinal cord-repaired adult rats.
Behavioral assessments of hindlimb motor recovery and anatomical assessments of extended axons of long spinal tracts were conducted in adult rats following complete spinal cord transection. Rats were randomly divided into 3 groups: 1) sham control group (laminectomy only; n = 12); 2) transection-only group, spinal cord transection at T8 (n = 20); and 3) experimental treatment group, spinal cord transection at T8, with peripheral nerve grafts (PNG) and application of acidic fibroblast growth factor (aFGF) (n = 14). The locomotor behavior and stepping of all rats were analyzed over a 6-month survival time using the Basso, Beattie, Bresnahan (BBB) open field locomotor test and the contact placing test. Immunohistochemistry for serotonin (5-HT), anterograde tracing with biotinylated dextran amine (BDA), and retrograde tracing with fluoro-gold were used to evaluate the presence of axons below the damage site following treatment. When compared with the transection-only group, the nerve graft with the aFGF group showed 1) significant improvement in hindlimb locomotion and stepping, 2) the presence of 5-HT-labeled axons below the lesion site at lumbar cord level (these were interpreted as regenerated axons from the raphe nuclei), 3) the presence of anterograde BDA labeling of corticospinal tract axons at the graft site and below, and 4) fluoro-gold retrograde labeling of neuron populations in motor cortex and in red nucleus, reticulospinal nuclei, raphe nuclei, and vestibular nuclei. We conclude that peripheral nerve grafts and aFGF treatments facilitate the regrowth of the spinal axons and improve hindlimb function in a T-8 spinal cord-transected rat model.


Detection of hazardous pollutants in chrome-tanned leather using locally developed laser-induced breakdown spectrometer.
Highly toxic contaminants like Cr, As, and Pb were detected in chrome-tanning process of animal skin to produce leather by applying locally developed laser-induced breakdown spectrometer. An Nd-YAG laser with 1,064 nm wavelength was focused on the surface of leather samples (natural and manufactured) to generate a plasma spark and spectrally resolved spectra were used for identification and quantification of contaminants. The leather samples were collected from a tannery located in industrial cities of Riyadh and Jeddah, Saudi Arabia. The study was carried out on fully, half manufactured (wet blue leather), and natural hide (skin). To the best of our knowledge, this is the first attempt where laser-induced breakdown spectroscopy (LIBS) technique has been applied for the analysis of leather before and after tanning process. The maximum concentration of different elements of environmental significance like chromium, lead, arsenic, sulfur, magnesium were 199, 289, 31, 38, and 39 ppm, respectively, in one of the manufactured leather samples. The limit of detection (LOD) of our LIBS system for chromium, lead, arsenic, sulfur, and magnesium were 2, 3, 1.5,7, and 3 ppm, respectively. The safe permissible limit for tanned leather for highly toxic elements like chromium, lead, and arsenic are 1, 0.5, 0.01 ppm, respectively, as prescribed in Environmental Regulation Standards for Saudi Industries set by Royal Commission Jubail, Saudi Arabia. The LIBS technique is superior to other conventional techniques like ICP or atomic absorption that a little or no sample preparation is required, no chemicals are needed, multi-elemental analysis is possible for all kinds of samples (natural and anthropogenic materials), microgram of sample is essential, and LIBS could be applied for remote analysis. It is highly selective and sensitivity higher than ICP, and as no sample and chemicals are required, it is cost effective for multi-sample analysis per unit time as compared with other conventional techniques. The concentration of some toxic elements (Cr, Pb, As) is much higher than the safe permissible limits set by Occupational Safety and Health Administration in USA or Saudi environmental regulatory agencies. Results obtained with our LIBS systems were in close agreement with the results obtained using other standard analytical technique such as the inductively coupled plasma atomic emission spectroscopy.


Characterization of a proteinaceous adhesin of Staphylococcus epidermidis which mediates attachment to polystyrene.
Coagulase-negative staphylococci (CoNS) have evolved into important agents of foreign body-related infections. Adhesion of causative bacteria to biomaterials is considered to be an essential step in these infections. We and others have shown that adhesion of CoNS to biomaterials may be mediated by protease-sensitive surface constituents. In the present study we expanded on these investigations by characterizing a biomaterial adhesin of Staphylococcus epidermidis 354 by using a strain-specific monoclonal antibody (MAb 36.4). MAb 36.4 was strongly and exclusively reactive with strain 354 in an enzyme-linked immunosorbent assay in which whole bacteria were used as antigens. Immunoblotting of cell wall polypeptides of strain 354 revealed strong reactivity with a 200- to 220-kDa band and a weaker reaction in the 100- to 110-kDa range. Preincubation of strain 354 with MAb 36.4 resulted in a 54 to 91% (mean +/- standard deviation, 74% +/- 14%; n = 10) inhibition of adhesion to polystyrene spheres. Fab fragments prepared from MAb 36.4 also inhibited adhesion effectively, indicating specific blocking of an adhesion antigen rather than aspecific inhibition. Immunogold electron microscopy with MAb 36.4 revealed deposition of gold particles on the cell surface and possibly also on fimbrialike surface projections. It is concluded that a surface-located protein antigen of S. epidermidis 354 recognized by MAb 36.4 acts as an adhesin mediating attachment to uncoated foreign material. It is speculated that this type of adhesion to biomaterials may play an important role in the pathogenesis of foreign body-related infections caused by CoNS.


Dual Roles of Glutathione in Ecdysone Biosynthesis and Antioxidant Function During Larval Development in Drosophila.
Ecdysteroids, including the biologically active hormone 20-hydroxyecdysone (20E), play essential roles in controlling many developmental and physiological events in insects. Ecdysteroid biosynthesis is achieved by a series of specialized enzymes encoded by the Halloween genes. Recently, a new class of Halloween gene, noppera-bo (nobo), encoding a glutathione S-transferase (GST) in dipteran and lepidopteran species, has been identified and characterized. GSTs are well known to conjugate substrates with the reduced form of glutathione (GSH), a bioactive tripeptide composed of glutamate, cysteine, and glycine. We hypothesized that GSH itself is required for ecdysteroid biosynthesis. However, the role of GSH in steroid hormone biosynthesis has not been examined in any organisms. Here, we report phenotypic analysis of a complete loss-of-function mutant in the γ-glutamylcysteine synthetase catalytic subunit (Gclc) gene in the fruit fly Drosophila melanogasterGclc encodes the evolutionarily conserved catalytic component of the enzyme that conjugates glutamate and cysteine in the GSH biosynthesis pathway. Complete Gclc loss-of-function leads to drastic GSH deficiency in the larval body fluid. Gclc mutant animals show a larval-arrest phenotype. Ecdysteroid titer in Gclc mutant larvae decreases, and the larval-arrest phenotype is rescued by oral administration of 20E or cholesterol. Moreover, Gclc mutant animals exhibit abnormal lipid deposition in the prothoracic gland, a steroidogenic organ during larval development. All of these phenotypes are reminiscent to nobo loss-of-function animals. On the other hand, Gclc mutant larvae also exhibit a significant reduction in antioxidant capacity. Consistent with this phenotype, Gclc mutant larvae are more sensitive to oxidative stress response as compared to wild-type. Nevertheless, the ecdysteroid biosynthesis defect in Gclc mutant animals is not associated with loss of antioxidant function. Our data raise the unexpected hypothesis that a primary role of GSH in early D. melanogaster larval development is ecdysteroid biosynthesis, independent from the antioxidant role of GSH.


[Effect of partial ileoshunting on hyperlipoproteinemia in patients with atherosclerosis].
In 57 atherosclerotic patients with concomitant hyperlipoproteinemia operations of partial ileoshunts were performed consisting in shunting the distal third of the small intestine. The follow-up observation was up to 6 years. A persistent decrease of the elevated level of lipids and cholesterol of atherogenic LDL and VLDL was noted as well as a considerable and stable increase of the level of cholesterol of antiatherogenic very high density lipoproteins and a lower atherogeneity coefficient. It facilitates stabilization and regression of atherosclerosis.


Advances and applications of molecular biology techniques in hepatitis B and C.
Recent advances in molecular biology have led to the development of techniques that have the potential to allow rapid quantitative detection of viral particles. Research kits using some of these techniques are available for the detection of HBV and HCV. The principles of these tests and their potential clinical utility and limitations are presented.


p53 expression and p21 expression are mutually exclusive in esophageal squamous cell carcinoma.
The accumulation of p53 protein, which is considered to be caused by a p53 gene mutation, is closely associated with poor prognosis in patients with certain types of carcinomas. The progression of esophageal squamous cell carcinoma (ESCC) is also suspected to depend on p53 gene status. We analyzed the relationship between p53 and p21 protein accumulation in ESCC, and simultaneously analyzed the frequency of apoptosis. Formalin-fixed paraffin-embedded sections were taken from 46 patients who underwent esophagectomy for ESCC. These sections were examined by immunostaining with monoclonal antibodies PAb1801 and EA10 to determine p53 and p21 protein accumulation, respectively. We also analyzed the frequency of apoptosis by TdT-mediated dUTP-biotin nick end-labeling (TUNEL). For estimation of the proportion of stained cells, we used computer analysis with NIH image analysis software. p21 protein accumulation showed an almost inverse distribution to that of p53 protein. In areas where both p53 and p21 proteins were accumulated, few apoptotic cells were observed. Particularly in cases of mucosal tumors, p53 protein was prominently accumulated in the lower layer of the tumor, whereas p21 protein accumulation was confined to the upper layer. Our results suggest that progression of esophageal squamous cell carcinoma is controlled by a p53-dependent pathway.


Expression of serum inflammatory cytokines and oxidative stress markers and their correlation with coronary artery calcium score in patients with coronary heart disease.
The present study was conducted to explore the expression of serum inflammatory cytokines and oxidative stress markers in patients with coronary heart disease (CHD), with an attempt to analyze their relationship with the coronary artery calcium score (CACS) by coronary computed tomography angiography (CCTA). It total 81 patients with coronary heart disease and 81 healthy adults were included as the observation group and the control group, respectively. The levels of serum interleukin (IL)-6 and IL-12 of the two groups were detected by ELISA, and serum superoxide dismutase (SOD) was detected by the hydroxylamine oxidation method. Micro-RNA-497-5p (miR-497-5p) was screened out as a possible new CHD biomarker and its serum level was measured by real-time fluorescence quantitative PCR. The CACS of patients in the observation group was calculated by the Agatston method to analyze the correlation between the abovementioned indexes and CACS. With increase in the number of CHD lesions, the levels of IL-6, IL-12 and miR-497-5p rose gradually while the level of SOD decreased gradually. In the observation group, IL-6, IL-12 and miR-497-5p were positively correlated with CACS while SOD was negatively correlated with CACS. Abnormal expression levels of serum IL-6, IL-12, SOD and miR-497-5p may be able to reveal the severity of the disease, and the combination with CACS is of potential value in terms of evaluating the condition of patients harboring coronary heart disease.


Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours.
Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU x ml(-1), or a alpha-foetoprotein level higher than 2000 mIU ml(-1). Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.


Tripartite Motif Containing 52 (TRIM52) Promotes Cell Proliferation in Hepatitis B Virus-Associated Hepatocellular Carcinoma.
BACKGROUND Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). HBV X protein (HBx) plays a crucial role in the development of HCC. Moreover, many tripartite motif (TRIM) family proteins exert diverse biological functions in hepatocarcinogenesis. However, as a novel member of this family, the specific effect of TRIM52 is still largely obscure. In the present study, we investigated the expression and function of TRIM52 in HBV-associated HCC. MATERIAL AND METHODS Fluorescence quantitative polymerase chain reaction (FQ-PCR) was performed to detect the HBV DNA levels in the peripheral blood of HCC patients. Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the expression of TRIM52, HBx, and NF-κB p65. HBx-pcDNA3.1 and TRIM52-shRNA were used to induce HBx ectopic expression and TRIM52 silencing, respectively. Pyrrolidine dithiocarbamate (PDTC) was used to block the activation of NF-κB. Cell proliferation was detected using the Cell Counting Kit-8 (CCK-8) assay. RESULTS TRIM52 expression was up-regulated together with HBx in HBV-associated HCC tissues. Ectopic expression of HBx elevated TRIM52 expression in HepG2 cells. TRIM52 silencing repressed the proliferation of HepG2.2.15 cells. Moreover, NF-κB p65 expression was increased in HCC cell lines. Blocking NF-κB activation with PDTC suppressed TRIM52 expression and attenuated the viability of HepG2.2.15 cells. CONCLUSIONS These findings indicate that TRIM52 can promote cell proliferation and HBx may regulate TRIM52 expression via the NF-κB signaling pathway in HBV-associated HCC.


Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome.
We have identified six children in three families with subtelomeric deletions of 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy-Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There is considerable clinical overlap between these children and individuals with the Ritscher-Schinzel (or cranio-cerebello-cardiac (3C)) syndrome (OMIM #220210). Clinical features of 3C syndrome include craniofacial anomalies (macrocephaly, prominent forehead and occiput, foramina parietalia, hypertelorism, down-slanting palpebral fissures, ocular colobomas, depressed nasal bridge, narrow or cleft palate, and low-set ears), cerebellar malformations (variable manifestations of a Dandy-Walker malformation with moderate mental retardation), and cardiac defects (primarily septal defects). Since the original report, over 25 patients with 3C syndrome have been reported. Recessive inheritance has been postulated based on recurrence in siblings born to unaffected parents and parental consanguinity in two familial cases. Molecular and cytogenetic mapping of the 6p deletions in these three families with subtelomeric deletions of chromosome 6p have defined a 1.3 Mb minimally deleted critical region. To determine if 6p deletions are common in 3C syndrome, we analyzed seven unrelated individuals with 3C syndrome for deletions of this region. Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder. No deletions or disease-causing mutations were identified.


Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice.
Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class II(low) macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood.


Procainamide and survival in ventricular fibrillation out-of-hospital cardiac arrest.
Procainamide is an antiarrhythmic drug of unproven efficacy in cardiac arrest. The association between procainamide and survival from out-of-hospital cardiac arrest was investigated to better determine the drug's potential role in resuscitation. The authors conducted a 10-year study of all witnessed, out-of-hospital, ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) cardiac arrests treated by emergency medical services (EMS) in King County, Washington. Patients were considered eligible for procainamide if they received more than three defibrillation shocks and intravenous (IV) bolus lidocaine. Four logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI) describing the relationship between procainamide and survival. Of the 665 eligible patients, 176 received procainamide, and 489 did not. On average, procainamide recipients received more shocks and pharmacologic interventions and had lengthier resuscitations. Adjusted for their clinical and resuscitation characteristics, procainamide recipients had a lower likelihood of survival to hospital discharge (OR = 0.52; 95% CI = 0.36 to 0.75). Further adjustment for receipt of other cardiac medications during resuscitation negated this apparent adverse association (OR = 1.02; 95% CI = 0.66 to 1.57). In this observational study of out-of-hospital VF and pulseless VT arrest, procainamide as second-line antiarrhythmic treatment was not associated with survival in models attempting to best account for confounding. The results suggest that procainamide, as administered in this investigation, does not have a large impact on outcome, but cannot eliminate the possibility of a smaller, clinically relevant effect on survival.


[Frontiers of anthropological research: ethics, autonomy, and trafficking in human organs. A commentary on The Global Traffic in Human Organs, by Nancy Scheper-Hughes].
The bioethical debate over the commercialization of the human body has intensified in recent years. This article discusses the principles of ethics and autonomy in the most important ethnography on international traffic in human organs, coordinated by anthropologist Nancy Scheper-Hughes. The author discusses how defending the ethics of non-commercialization of the human body entails absolute ethical principles pertaining to human life, a political premise whose legitimacy is not recognized by relativist anthropologists.


Proline-rich protein 11 regulates epithelial-to-mesenchymal transition to promote breast cancer cell invasion.
Breast cancer is the leading cause of cancer death in women world wide which is closely related to metastasis. Recent studies argue that breast cancer cells that have undergone epithelial-to-mesenchymal transition (EMT) acquire aggressive malignant properties, but the molecular mechanisms underlying this transition are poorly understood. In this study, we found that increased expression of proline-rich protein 11 (PRR11) was associated with the progression of breast cancer and that PRR11 protein levels were significantly elevated in breast cancer. High PRR11 levels also predict shorter overall survival of breast cancer patients. Moreover, we found that the forced expression of PRR11 decreased the expression of the epithelial marker E-cadherin but increased the mesenchymal markers in breast cancer cells. In contrast, silencing PRR11 in metastatic breast tumor cells promoted a shift toward an epithelial morphology concomitant with increased expression of E-cadherin and decreased expression of mesenchymal markers. PRR11 silencing also reduced the expression of EMT-inducing transcription factors (Snail, Slug, ZEB1 and ZEB2).


Ultraconserved coding regions outside the homeobox of mammalian Hox genes.
All bilaterian animals share a general genetic framework that controls the formation of their body structures, although their forms are highly diversified. The Hox genes that encode transcription factors play a central role in this framework. All Hox proteins contain a highly conserved homeodomain encoded by the homeobox motif, but the other regions are generally assumed to be less conserved. In this study, we used comparative genomic methods to infer possible functional elements in the coding regions of mammalian Hox genes. We identified a set of ultraconserved coding regions (UCRs) outside the homeobox of mammalian Hox genes. Here a UCR is defined as a region of at least 120 nucleotides without synonymous and nonsynonymous nucleotide substitutions among different orders of mammals. Further analysis has indicated that these UCRs occur only in placental mammals and they evolved apparently after the split of placental mammals from marsupials. Analysis of human SNP data suggests that these UCRs are maintained by strong purifying selection. Although mammalian genomes are known to contain ultraconserved non-coding elements (UNEs), this paper seems to be the first to report the UCRs in protein coding genes. The extremely high degree of sequence conservation in non-homeobox regions suggests that they might have important roles for the functions of Hox genes. We speculate that UCRs have some gene regulatory functions possibly in relation to the development of the intra-uterus child-bearing system.


Superoxide dismutase plus catalase improve contractile function in the canine model of the "stunned myocardium".
Fifteen minutes of coronary occlusion followed by reperfusion does not result in myocardial necrosis; however, the contractile function and high energy phosphate content of the previously ischemic myocardium remains depressed or "stunned" for several hours to days after reperfusion. Oxygen-derived free radicals have been implicated in ischemia and reperfusion-induced injury in a variety of tissues. We wished to determine whether administration of free radical scavengers superoxide dismutase plus catalase before and during occlusion, and throughout reperfusion, could attenuate the "stunning" produced by 15 minutes of left anterior descending coronary artery occlusion in anesthetized, open-chest dogs. Segment shortening in the previously ischemic zone recovered to within only +/- 10% of preinfusion values in the control group during 3 hours of reperfusion, while, in the treated dogs, segment shortening returned to a maximum of 56 +/- 16% of preinfusion at 1 1/2 hours post-reperfusion (P less than 0.0003 compared to controls). Similarly, superoxide dismutase + catalase-treated dogs exhibited improved wall thickening during reperfusion (+30% to +70% of preinfusion values), compared to controls (0% to +10%). However, this improvement in contractile function in the treated group was not accompanied by increased adenosine triphosphate stores in the previously ischemic zone (31.8 +/- 0.8 vs. 28.2 +/- 2.2 nmol/mg protein for control vs. treated groups). Infusion of superoxide dismutase + catalase did not influence blood flow during occlusion or reperfusion. However, the treated group did exhibit a significant decrease in blood pressure during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Platelet-derived growth factor is detected in human blastocyst culture medium but not in human follicular fluid--a preliminary report.
The content of PDGF in human blastocyst culture medium (n = 8), serum (n = 12), and FF (n = 17) from natural IVF cycles was determined by an RIA specific for PDGF B-chain. The blastocysts were cultured under serum-free conditions throughout development. The findings show that PDGF B-chain is released into the culture medium of human blastocysts and that serum is positive, whereas FF is negative for PDGF.


Intracellular Ca(2+) signaling: A novel player in the canonical mTOR-controlled autophagy pathway.
Functional intracellular Ca(2+) signaling is essential for the upregulation of the canonical mTOR-controlled autophagy pathway triggered by rapamycin or by nutrient deprivation. Moreover, modifications in the Ca(2+)-signaling machinery coincide with autophagy stimulation. This results in enhanced intracellular Ca(2+) signaling essential for driving the autophagy process. Yet, the mechanisms upstream (the players causing the changes in Ca(2+) signaling) and downstream (the targets of the altered Ca(2+) signals) of this Ca(2+)-dependent autophagy pathway remain elusive. Here, we speculate about these mechanisms based on our current knowledge.


Natural products as safeguards against monosodium glutamate-induced toxicity.
Monosodium glutamate is a sodium salt of a nonessential amino acid, L-glutamic acid, which is widely used in food industry. Glutamate plays an important role in principal brain functions including formation and stabilization of synapses, memory, cognition, learning, as well as cellular metabolism. However, ingestion of foodstuffs rich in monosodium glutamate can result in the outbreak of several health disorders such as neurotoxicity, hepatotoxicity, obesity and diabetes. The usage of medicinal plants and their natural products as a therapy against MSG used in food industry has been suggested to be protective. Calendula officinalis, Curcuma longa, Green Tea, Ginkgo biloba and vitamins are some of the main natural products with protective effect against mentioned monosodium glutamate toxicity through different mechanisms. This review provides a summary on the toxicity of monosodium glutamate and the protective effects of natural products against monosodium glutamate -induced toxicity.


Calculations of pKa's and redox potentials of nucleobases with explicit waters and polarizable continuum solvation.
The SMD implicit solvation model augmented with one and four explicit water molecules was used to calculate pKa's and redox potentials of N-methyl-substituted nucleic acid bases guanine, adenine, cytosine, thymine, and uracil. Calculations were carried out with the B3LYP/6-31+G(d,p) level of theory. The same numbers of water molecules were hydrogen bonded to the neutral, protonated, and deprotonated nucleobases in their unoxidized and oxidized forms. The improvement in pKa1 involving neutrals and cations was modest. By contrast, the improvement in pKa2 involving neutrals and anions was quite significant, reducing the mean absolute error from 4.6 pKa units with no waters, to 2.6 with one water and 1.7 with four waters. For the oxidation of nucleobases, adding explicit waters did little to improve E(X(•),H(+)/XH), possibly because both species in the redox couple are neutral molecules at pH 7.


Partnering with the black church: recipe for promoting heart health in the stroke belt.
Health disparities related to cardiovascular disease (e.g., heart disease, high blood pressure, diabetes, and stroke) have remained higher in the African-American community than in other populations. African Americans living in the stroke belt are at an even higher risk for these conditions. Recently, increasing numbers of health agencies and researchers have successfully partnered with the black church to respond to the troubling statistics regarding these health disparities. Because the black church has a long history of being in the forefront of addressing critical social, economic, political, and health issues of African Americans, it is clear they are the principal gatekeepers in reversing these negative health trends. Working with churches to reduce cardiovascular disease is not a new concept. Hypertension screening programs were established at churches approximately 30 years ago. This article shares findings of elements to improve relations between community agencies and pastors, explores the strengths and challenges of working with churches, examines the role of the pastors in establishing successful programs, and identifies model programs. This article will identify key factors that are essential to cardiovascular health programs that purport to reach high-risk populations for cardiovascular disease with life saving environmental policies and behavior change strategies. Suggestions are provided for working with pastors, churches, and church resources to maximize the desired outcomes of future health promotion interventions. Examples of strategies include serving healthier choices during church meals; the inclusion of relevant scriptural citations in promotional materials; the implementation of instruction, training, and exercise programs; and, the provision of tangible compensation to the churches and congregants facilitating the health initiatives.


Quasi-Two-Dimensional Se-Terminated Bismuth Oxychalcogenide (Bi2O2Se).
Since the discovery of graphene, van der Waals (vdW) two-dimensional (2D) materials have attracted considerable attention for various potential applications. Recently, a Se-terminated bismuth oxychalcogenide, Bi2O2Se, has been fabricated using the vapor deposition method. Bi2O2Se is not a vdW 2D material, but the as-grown substance shows 2D characteristics. For example, Bi2O2Se exhibits layer number-dependent absorption spectra in experiments, but until now, there has been no reasonable explanation as to why. Here, we propose a 50% Se-passivation surface model, which elucidates the production of such spectra. Our model is also consistent with recent observations using scanning tunneling microscopy. Moreover, high-resolution transmission electron microcopy observations show a broken zipper-like structure in Bi2O2Se. We ascribe Bi2O2Se as a zipper 2D material, and we summarize the characteristics of zipper 2D materials while proposing the development of others. Zipper 2D materials not only are an important subset of 2D materials but also bridge the gap between vdW 2D materials and traditional 3D materials. Because they are a big family, including insulators, semiconductors, and magnetic metals, zipper 2D materials lend themselves to a plethora of applications.


Behçet's disease-like syndrome secondary to microbial infection: a case report and review of the literature.
Behçet's disease (BD)-like syndrome is an extremely rare situation occurred after Mycobacterium tuberculosis infection and virus infection. We reported a 45-year-old woman who visited our hospital complaining of swollen left ankle, painful genital ulcer, redness in the left eye and skin rash on lower limbs. The patient had a history of pleural tuberculosis and had received anti-tuberculous therapy for one year. Her left cervical lymph node sample demonstrated tubercle bacilli DNA fragmentation. The diagnosis of tuberculous lymphadenitis and Behçet's disease (BD)-like syndrome were made. This patient's symptoms remitted following treatment with anti-tuberculous therapy. This case indicates that some microbial infection can trigger the onset of BD-like syndrome in genetically susceptible subjects. However, treatment strategy of BD-like syndrome secondary to infection is totally different from primary BD. The aim of this case report is to present our experience of the different clinical signs and treatment of BD-like syndrome to expedite its early diagnosis in future. Combination of clinical, radiological, immunophenotypic, pathological, and genetic data contribute to improving the rate of diagnosis.


Darier's disease: a commonly misdiagnosed cutaneous disorder.
Darier's disease is a rare disorder of keratinization of the epidermis, nails, and mucous membranes. Patients usually present with pruritus and pain along with multiple small, red-brown papules on the seborrheic areas. Other cutaneous signs include punctate keratotic pits of the palms and soles and dystrophy of the nails. Darier's disease is the result of a mutation in the ATP2A2 gene. A case which was difficult to diagnose because its presentation resembled more commonly seen skin conditions is reported. The patient was misdiagnosed with acne, eczema, and seborrheic dermatitis, and was treated without improvements. This case highlights the fact that skin disorders that do not respond to conventional therapy should lead physicians to suspect an uncommon or even serious cutaneous disorder. The diagnosis of Darier's disease, based on family history, clinical appearance, and histopathology, expedited the appropriate treatment.


The spontaneous mutation frequencies of Prochlorococcus strains are commensurate with those of other bacteria.
The marine cyanobacterium Prochlorococcus, the smallest and most abundant oxygenic phototroph, has an extremely streamlined genome and a high rate of protein evolution. High-light adapted strains of Prochlorococcus in particular have seemingly inadequate DNA repair systems, raising the possibility that inadequate repair may lead to high mutation rates. Prochlorococcus mutation rates have been difficult to determine, in part because traditional methods involving quantifying colonies on solid selective media are not straightforward for this organism. Here we used a liquid dilution method to measure the approximate number of antibiotic-resistant mutants in liquid cultures of Prochlorococcus strains previously unexposed to antibiotic selection. Several antibiotics for which resistance in other bacteria is known to result from a single base pair change were used. The resulting frequencies of antibiotic resistance in Prochlorococcus cultures allowed us to then estimate maximum spontaneous mutation rates, which were similar to those in organisms such as E. coli (∼5.4 × 10(-7) per gene per generation). Therefore, despite the lack of some DNA repair genes, it appears unlikely that the Prochlorcoccus genomes studied here are currently being shaped by unusually high mutation rates.


Propagation characteristics of the supermode based on two coupled semi-infinite rib plasmonic waveguides.
We report on the propagation characteristics of a plasmonic waveguide structure based on two coupled rectangular wedges. Dispersion, propagation loss, and field distributions are investigated by three-dimensional finite-difference time-domain method. The considered structure supports only one supermode over 30THz bandwidth, and the calculated propagation loss at lambda=1.55mum is 0.0257dB/mum, which is lower than the existing report by 1.7 times while keeping comparable field localizations. The all-planar structure in conjunction with the linearly dispersive characteristic over a wide operational bandwidth signifies its great potential for optical signal transporting in nanophotonic circuits.


Long-term outcomes after vestibuloplasty with a porcine collagen matrix (Mucograft® ) versus the free gingival graft: a comparative prospective clinical trial.
Porcine collagen matrices are proclaimed being a sufficient alternative to autologous free gingival grafts (FGG) in terms of augmenting the keratinized mucosa. The collagen matrix Mucograft® (CM) already showed a comparable clinical performance in the early healing phase, similar histological appearance, and even a more natural appearance of augmented regions. Predictability for long-term stability does not yet exist due to missing studies reporting of a follow-up >6 months. The study included 48 patients with atrophic edentulous or partially edentulous lower jaw situations that had undergone an implant treatment. In the context of implant exposure, a vestibuloplasty was either performed with two FGGs from the palate (n = 21 patients) or with the CM (n = 27 patients). Surgery time was recorded from the first incision to the last suture. Follow-up examinations were performed at the following time points: 10, 30, 90, and 180 days and 1, 2, 3, 4, and 5 years after surgery. The width of keratinized mucosa was measured at the buccal aspect of each implant, and augmented sites were evaluated in terms of their clinical appearances (texture and color). The groups showed similar healing with increased peri-implant keratinized mucosa after surgery (FGG: 13.06 mm ± 2.26 mm and CM: 12.96 mm ± 2.86 mm). The maximum follow-up was 5 years (5 patients per group). After 180 days, the width of keratinized mucosa had decreased to 67.08 ± 13.85% in the FGG group and 58.88 ± 14.62% in the CM group with no statistically significant difference. The total loss of the width of keratinized mucosa after 5 years was significant between the FGG (40.65%) and the CM group (52.89%). The CM group had significantly shorter operation times than the FGG group. Augmented soft tissues had a comparable clinical appearance to adjacent native gingiva in the CM group. FGGs could still be defined after 5 years. The FGG and the CM are both suitable for the regeneration of the peri-implant keratinized mucosa with a sufficient long-term stability. With the CM, tissue harvesting procedures are invalid, surgery time can be reduced, and regenerated tissues have a more esthetic appearance.


The attachment system and physiology in adulthood: normative processes, individual differences, and implications for health.
Attachment theory provides a conceptual framework for understanding intersections between personality and close relationships in adulthood. Moreover, attachment has implications for stress-related physiology and physical health. We review work on normative processes and individual differences in the attachment behavioral system, as well as their associations with biological mechanisms related to health outcomes. We highlight the need for more basic research on normative processes and physiology and discuss our own research on individual differences in attachment and links with physiology. We then describe a novel perspective on attachment and physiology, wherein stress-related physiological changes may also be viewed as supporting the social-cognitive and emotion regulatory functions of the attachment system through providing additional energy to the brain, which has implications for eating behavior and health. We close by discussing our work on individual differences in attachment and restorative processes, including sleep and skin repair, and by stressing the importance of developing biologically plausible models for describing how attachment may impact chronic illness.


Acid rain on Acid soil: a new perspective.
Acid rain is widely believed to be responsible for acidifying soil and water in areas of North America and northern Europe. However, factors commonly considered to make landscapes susceptible to acidification by acid rain are the same factors long known to strongly acidify soils through the natural processes of soil formation. Recovery from extreme and widespread careless land use has also occurred in regions undergoing acidification. There is evidence that acidification by acid rain is superimposed on long-term acidification induced by changes in land use and consequent vegetative succession. Thus, the interactions of acid rain, acid soil, and vegetation need to be carefully examined on a watershed basis in assessing benefits expected from proposed reductions in emissions of oxides of sulfur and nitrogen.


Ag-NOR studies in a human lymphocyte culture: are variants localized to specific chromosomes?
The genomic activity and polymorphisms of nucleolus organizer regions (NORs) were studied in an individual with routinely used AgNO3 and Q-banding techniques. The results demonstrate that (a) the mean number of NORs per metaphase spread was 7.4, (b) chromosomes 14, 13, 15, and 21 showed variations of Ag-NOR in decreasing order, (c) chromosome 22 did not show a polymorphism in any cell examined, and (d) both chromosomes 14 showed silver staining in most cells. Unlike many earlier reports indicating that NOR variants were constitutional in each individual, our present case represented a mosaic pattern of polymorphism involving most of the D- and G-group chromosomes.


Platelet endothelial cell adhesion molecule-1 expression modulates endothelial cell migration in vitro.
Endothelial cell migration is an important process that occurs during embryonic vasculogenesis and angiogenesis, wound healing, and tumor growth and metastasis, and after denudation injury following angioplasty and bypass grafting. Mechanisms regulating this process involve a complex interplay of cytoskeletal reorganization, cell-cell adhesion, and cell-extracellular matrix interactions. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is constitutively expressed in endothelial cells, leukocytes, monocytes, lymphocytes, and platelets. PECAM-1 undergoes dynamic dephosphorylation during endothelial cell migration in vitro and during vasculogenesis in the murine conceptus. In transfected 3T3 cells, in cultured endothelial cells, and in the murine conceptus undergoing vasculogenesis, the tyrosine phosphorylation state of PECAM-1 Y686 correlates with the migratory state of the cells. In the present study, we investigate the role of PECAM-1 in modulating endothelial cell migration in vitro using retroviral transduction of c-myc epitope-tagged, wild-type, Y686 to F-mutated PECAM-1 and extracellular domain-deleted PECAM-1 constructs in endothelial cells devoid of endogenous PECAM-1 (ECV304 cells) and in endothelial cells expressing high levels of endogenous PECAM-1 (bovine aortic endothelial cells, BAEC). In ECV304 cells, the expression of wild-type PECAM-1 inhibited migration rates, whereas in BAEC, overexpression of wild-type PECAM-1 had no effect. Expression of Y686 to F-mutated PECAM-1 or extracellular domain-deleted PECAM-1 in BAEC increased migration rates. These data support the concept that endothelial cell migration is modulated, in part, by a balance between PECAM-1 cytoplasmic domain-mediated "inside-out" and "outside-out" signaling resulting from PECAM-1-mediated cell-cell interactions and integrin-extracellular matrix interactions.


Emerging Computational Methods for the Rational Discovery of Allosteric Drugs.
Allosteric drug development holds promise for delivering medicines that are more selective and less toxic than those that target orthosteric sites. To date, the discovery of allosteric binding sites and lead compounds has been mostly serendipitous, achieved through high-throughput screening. Over the past decade, structural data has become more readily available for larger protein systems and more membrane protein classes (e.g., GPCRs and ion channels), which are common allosteric drug targets. In parallel, improved simulation methods now provide better atomistic understanding of the protein dynamics and cooperative motions that are critical to allosteric mechanisms. As a result of these advances, the field of predictive allosteric drug development is now on the cusp of a new era of rational structure-based computational methods. Here, we review algorithms that predict allosteric sites based on sequence data and molecular dynamics simulations, describe tools that assess the druggability of these pockets, and discuss how Markov state models and topology analyses provide insight into the relationship between protein dynamics and allosteric drug binding. In each section, we first provide an overview of the various method classes before describing relevant algorithms and software packages.


Cost-effectiveness of clopidogrel treatment in percutaneous coronary intervention: a European model based on a meta-analysis of the PCI-CURE, CREDO and PCI-CLARITY trials.
Our objective was to conduct a comprehensive cost-effectiveness analysis of pre-treatment and long-term treatment with clopidogrel in percutaneous coronary intervention (PCI) in three European countries based on a meta-analysis of the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO) and PCI-Clopidogrel as Adjunctive Therapy (CLARITY) trials. This analysis adds to existing knowledge by providing further data on the cost-effectiveness of clopidogrel in PCI across a wide spectrum of patients. A combined decision tree and Markov model was created. The relative risks of myocardial infarction, cardiovascular death and of major bleedings with clopidogrel were based on a fixed-effects meta-analysis. The risk of ischaemic events in untreated patients and long-term survival were taken from the Swedish hospital and death registers. A societal perspective was used in Sweden and a payer perspective in Germany and France. Costs are stated in euro2006 and effectiveness measured in quality-adjusted life-years (QALYs). The pooled effects of clopidogrel on the combined endpoint showed a relative risk of 0.711 (p=0.003) at 30 days and 0.745 (p=0.002) at end of follow-up (up to 1 year). Pre-treatment with clopidogrel compared with aspirin alone is a dominant strategy. Long-term treatment with clopidogrel compared with 1-month treatment leads to approximately 0.09 QALYs at an incremental cost of euro393 in Sweden, euro709 in Germany and euro494 in France. The corresponding incremental cost-effectiveness ratios range from euro4225/QALY to euro7871/QALY. The results of this modelling analysis suggest that pre-treatment and long-term treatment in PCI with clopidogrel for up to 1 year are cost-effective in a range of patient groups and settings given commonly accepted thresholds.


In vivo 17O NMR approaches for brain study at high field.
17O is the only stable oxygen isotope that can be detected by NMR. The quadrupolar moment of 17O spin (I = 5/2) can interact with local electric field gradients, resulting in extremely short T1 and T2 relaxation times which are in the range of several milliseconds. One unique NMR property of 17O spin is the independence of 17O relaxation times on the magnetic field strength, and this makes it possible to achieve a large sensitivity gain for in vivo 17O NMR applications at high fields. In vivo 17O NMR has two major applications for studying brain function and cerebral bioenergetics. The first application is to measure the cerebral blood flow (CBF) through monitoring the washout of inert H2 17O tracer in the brain tissue following an intravascular bolus injection of the 17O-labeled water. The second application, perhaps the most important one, is to determine the cerebral metabolic rate of oxygen utilization (CMRO2) through monitoring the dynamic changes of metabolically generated H2 17O from inhaled 17O-labeled oxygen gas in the brain tissue. One great merit of in vivo 17O NMR for the determination of CMRO2 is that only the metabolic H2 17O is detectable. This merit dramatically simplifies both CMRO2 measurement and quantification compared to other established methods. There are two major NMR approaches for monitoring H2 17O in vivo, namely direct approach by using 17O NMR detection (referred as direct in vivo 17O NMR approach) and indirect approach by using 1H NMR detection for measuring the changes in T2- or T1rho-weighted proton NMR signals caused by the 17O-1H scalar coupling and proton chemical exchange (referred as indirect in vivo 17O NMR approach). Both approaches are suitable for CBF measurements. However, recent studies indicated that the direct in vivo 17O NMR approach at high/ultrahigh fields appears to offer significant advantages for quantifying and imaging CMRO2. New developments have further demonstrated the feasibility for establishing a completely noninvasive in vivo 17O NMR approach for imaging CMRO2 in a rat brain during a brief 17O2 inhalation. This approach should be promising for studying the central role of oxidative metabolism in brain function and neurological diseases. Finally, the similar approach could potentially be applied to image CMRO2 noninvasively in human brain.