Towards integrated modeling of the long-term impacts of oil spills.
Although great progress has been made to advance the scientific understanding of oil spills, tools for integrated assessment modeling of the long-term impacts on ecosystems, socioeconomics and human health are lacking. The objective of this study was to develop a conceptual framework that could be used to answer stakeholder questions about oil spill impacts and to identify knowledge gaps and future integration priorities. The framework was initially separated into four knowledge domains (ocean environment, biological ecosystems, socioeconomics, and human health) whose interactions were explored by gathering stakeholder questions through public engagement, assimilating expert input about existing models, and consolidating information through a system dynamics approach. This synthesis resulted in a causal loop diagram from which the interconnectivity of the system could be visualized. Results of this analysis indicate that the system naturally separates into two tiers, ocean environment and biological ecosystems versus socioeconomics and human health. As a result, ocean environment and ecosystem models could be used to provide input to explore human health and socioeconomic variables in hypothetical scenarios. At decadal-plus time scales, the analysis emphasized that human domains influence the natural domains through changes in oil-spill related laws and regulations. Although data gaps were identified in all four model domains, the socioeconomics and human health domains are the least established. Considerable future work is needed to address research gaps and to create fully coupled quantitative integrative assessment models that can be used in strategic decision-making that will optimize recoveries from future large oil spills.


Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis.
Emerging evidence has implicated reactive oxygen species (ROS) in the pathogenesis of inflammatory bowel disease (IBD). Although intestinal epithelial cells produce the ROS-neutralizing enzyme superoxide dismutase (SOD), the protein and activity levels of copper/zinc (Cu/Zn) and manganese (Mn) SOD are perturbed in inflamed tissues of IBD patients. Thus we investigated the ability of MnSOD from Streptococcus thermophilus to reduce colitis symptoms in interleukin (IL) 10-deficient mice using Lactobacillus gasseri as a delivery vehicle. Cohorts of 13-15 IL-10-deficient mice were left untreated or supplemented with native L. gasseri or L. gasseri expressing MnSOD for 4 wk. Colonic tissue was collected and inflammation was histologically scored. The presence of innate immune cells was investigated by immunohistochemistry and the host antioxidant response was determined by quantitative PCR. It was demonstrated that L. gasseri was stably maintained in mice for at least 3 days. L. gasseri producing MnSOD significantly reduced inflammation in IL-10-deficient mice compared with untreated controls (P < 0.05), whereas the anti-inflammatory effects of both native and MnSOD producing L. gasseri were more pronounced in males. The anti-inflammatory effects of L. gasseri were associated with a reduction in the infiltration of neutrophils and macrophages. Transcripts of antioxidant genes were equivalent in colonic tissues obtained from control and probiotic-treated IL-10-deficient mice. This study demonstrates that L. gasseri producing MnSOD has significant anti-inflammatory activity that reduces the severity of colitis in the IL-10-deficient mouse.


The impact of apical and basolateral albumin on intestinal zinc resorption in the Caco-2/HT-29-MTX co-culture model.
The molecular mechanisms of intestinal zinc resorption and its regulation are still topics of ongoing research. To this end, the application of suitable in vitro intestinal models, optimized with regard to their cellular composition and medium constituents, is of crucial importance. As one vital aspect, the impact of cell culture media or buffer compounds, respectively, on the speciation and cellular availability of zinc has to be considered when investigating zinc resorption. Thus, the present study aims to investigate the impact of serum, and in particular its main constituent serum albumin, on zinc uptake and toxicity in the intestinal cell line Caco-2. Furthermore, the impact of serum albumin on zinc resorption is analyzed using a co-culture of Caco-2 cells and the mucin-producing goblet cell line HT-29-MTX. Apically added albumin significantly impaired zinc uptake into enterocytes and buffered its cytotoxicity. Yet, undigested albumin does not occur in the intestinal lumen in vivo and impairment of zinc uptake was abrogated by digestion of albumin. Interestingly, zinc uptake, as well as gene expression studies of mt1a and selected intestinal zinc transporters after zinc incubation for 24 h, did not show significant differences between 0 and 10% serum. Importantly, the basolateral application of serum in a transport study significantly enhanced fractional apical zinc resorption, suggesting that the occurrence of a zinc acceptor in the plasma considerably affects intestinal zinc resorption. This study demonstrates that the apical and basolateral medium composition is crucial when investigating zinc, particularly its intestinal resorption, using in vitro cell culture.


Putting Safety in the Frame: Nurses' Sensemaking at Work.
Current patient safety policy focuses nursing on patient care goals, often overriding nurses' safety. Without understanding how nurses construct work health and safety (WHS), patient and nurse safety cannot be reconciled. Using ethnography, we examine social contexts of safety, studying 72 nurses across five Australian hospitals making decisions during patient encounters. In enacting safe practice, nurses used "frames" built from their contextual experiences to guide their behavior. Frames are produced by nurses, and they structure how nurses make sense of their work. Using thematic analysis, we identify four frames that inform nurses' decisions about WHS: (a) communicating builds knowledge, (b) experiencing situations guides decisions, (c) adapting procedures streamlines work, and (d) team working promotes safe working. Nurses' frames question current policy and practice by challenging how nurses' safety is positioned relative to patient safety. Recognizing these frames can assist the design and implementation of effective WHS management.


Damage to the fronto-polar cortex is associated with impaired multitasking.
A major question in understanding the functional organization of the brain is to delineate the functional divisions of the prefrontal cortex. Of particular importance to the cognitive capacities that are uniquely human is the fronto-polar cortex (Brodmann's area 10), which is disproportionally larger in humans relative to the rest of the brain than it is in the ape's brain. The specific function of this brain region remains poorly understood, but recent neuroimaging studies have proposed that it may hold goals in mind while exploring and processing secondary goals. Here we show that the extent of damage to the fronto-polar cortex predicts impairment in the management of multiple goals. This result reveals that the integrity of the fronto-polar cortex is necessary to perform tasks that require subjects to maintain a primary goal in mind while processing secondary goals, an ability which is crucial for complex human cognitive abilities. These results provide important new insights concerning the cerebral basis of complex human cognition such as planning and multitasking.


Effect of an industrial waste water on the nitrification in fixed-bed biofilm reactors--use of fluorescence in-situ hybridization (FISH).
The influence of an industrial waste water containing partly toxic and poorly biodegradable substances on an autotrophic biocenosis was investigated. Nitrifying bacteria were identified using fluorescently-labeled oligonucleotide probes and epifluorescence microscopy. Industrial waste water was used untreated and after ozonation to simulate the effects of indirect discharge to municipal waste water treatment plants. Results were compared to those obtained with acetate as a non-toxic and easily biodegradable substance and a mixture of acetate and pyruvate. The degradation of ammonium and the formation of nitrite and nitrate were measured and compared with the results obtained by fluorescence in-situ hybridization (FISH). The untreated waste water, containing higher amounts of refractory substances, disturbed nitrification, which was restored after reaching higher elimination of the organic substances. However, it showed only minor effects on the bacterial composition. These findings were similar to those reached by the addition of acetate and pyruvate. On the other hand, the ozonated waste water, showing higher toxicity than the untreated waste water, caused a stabilization in nitrification, but the composition of the population of ammonium-oxidizing bacteria changed significantly. In all cases, nitrite-oxidizing bacteria were only little affected both in activity and abundance.


Thermal transport in au-core polymer-shell nanoparticles.
Thermal transport in aqueous suspensions of Au-core polymer-shell nanoparticles is investigated by time-resolved measurements of optical absorption. The addition of an organic cosolvent to the suspension causes the polystyrene component of the polymer shell to swell, and this change in the microstructure of the shell increases the effective thermal conductivity of the shell by a factor of approximately 2. The corresponding time scale for the cooling of the nanoparticle decreases from 200 ps to approximately 100 ps. The threshold concentration of cosolvent that creates the changes in thermal conductivity, 5 vol % tetrahydrofuran in water or 40 vol % N,N-dimethylformamide in water, is identical to the threshold concentrations for producing small shifts in the frequency of the plasmon resonance. Because the maximum fraction of solvent in the polymer shell is less than 20 vol %, the increase in the effective thermal conductivity of the shell cannot be easily explained by contributions to heat transport by the solvent or enhanced alignment of the polystyrene backbone along the radial direction.


What mechanisms coordinate leg movement in walking arthropods?
The construction of artificial walking machines has been a challenging task for engineers for several centuries. Advances in computer technology have stimulated this research in the past two decades, and enormous progress has been made, particularly in recent years. Nevertheless, in comparing the walk of a six-legged robot with the walk of an insect, the immense differences are immediately obvious. The walking of an animal is much more versatile, and seems to be more effective and elegant. Thus it is useful to consider the corresponding biological mechanisms in order to apply these or similar mechanisms to the control of walking legs in machines. Until recently, little information on this paper summarizes recent developments.


Talking about sunbed tanning: Social representations and identity-work.
Despite the publicised health risks associated with its usage, sunbed tanning remains popular in many Western countries. Previous research indicates that knowledge of the harmful effects does not necessarily lead to a reduction in sunbed use. The aim of this study was to develop a more extensive social psychological understanding of sunbed use, in the United Kingdom, by exploring the social representations of sunbed tanning held by both those who use and who have never used sunbeds. Semi-structured interviews were conducted with 15 sunbed users and 10 who had never used a sunbed. A thematic analysis identified two dimensions in the social representations of both the users and non-users; these were concerned with a) health and b) beauty. However, whereas non-users emphasised the health risks, users downplayed and minimised them, instead emphasising the health benefits. Similarly, whereas non-users emphasised the negative aspects of excessive concern with beauty, sunbed users challenged and distanced themselves from this negativity. Sunbed users were engaged in a form of identity-work to protect themselves from the wider negativity and disapproval of which they were aware. Theoretically, social representations theory has provided a unique lens through which to explore this topic, highlighting the importance of taking into consideration the wider environment in which sunbed use takes place. Preliminary practical suggestions include that health workers should consider identity-work when designing interventions aimed at reducing sunbed use. Findings also suggest that, rather than continuing to educate sunbed users about the risks, campaigns and interventions should challenge the commonly drawn upon arguments about the health benefits. These benefits emerged as a particularly powerful discursive tool for the sunbed users in helping to justify their behaviour, but also to counteract negative stereotypes and assumptions they knew others held of them.


Esthetic evaluation of implants vs canine substitution in patients with congenitally missing maxillary lateral incisors: Are there any new insights?
The aims of the study were to determine how a panel of orthodontists, dentists, and laypersons rated the esthetic appeal of dentitions after orthodontic space closure by canine substitution compared with space opening and replacement of missing maxillary lateral incisors by implant-borne crowns and to compare the outcome with the results of a study in the United States in 2005. A series of 9 posttreatment intraoral frontal photographs was presented to 87 orthodontists, 100 general dentists, and 100 laypersons. The photographs represented dentitions with either single-tooth implants or canine substitutions for missing maxillary lateral incisors and dentitions with no missing teeth. Each photograph was rated independently by assigning a number between 1 (best) and 5 (worst) for a series of 7 bipolar adjectives. Two-way analysis of variance and Tukey post hoc tests were performed to assess differences in intragroup and intergroup preferences for the various treatment options. Subsequently, the mean scores were compared with the mean scores in the study from 2005. Highly significant improvements (P <0.0001) in the esthetic outcome for implants were found in all respondent groups when compared with the study from 2005. To date, orthodontists and dentists rank implants and canine substitution as equally pleasing, but laypersons prefer space closure. Perceptions of dental esthetics can vary between dental professionals and laypersons. Investigating each patient's esthetic expectations is thus important, but in the patient's best interest, esthetic and functional aspects should be carefully weighed during comprehensive treatment planning.


An evaluation of effect of airborne dust from a cotton mill on the guinea-pig ileum with reference to byssinosis.
The effect of airborne dust on the guinea-pig ileum was studied. Tyrode extracts of airborne dust collected freshly in the cardroom of a cotton mill, and extracts of air pollutant samples drawn on the roof of the mill and of the local town hall were all found to induce the guinea-pig ileum to contract when applied in a tissue-bath. However, the force of contraction with air pollutants was rather greater than that with the cardroom dust. Considering the variables involved, the ileum response to the cardroom dust may have been due to ordinary air pollutants which constitute a significant part of the dust. It is concluded that this pharmacological phenomenon is probably not relevant in the context of byssinosis.


[Free radical processes in the embryogenesis of Anura].
The localization of free radical processes and changes in their level during the common frog development have been studied by means of grafted copolymerisation and autoradiography. The maps of distribution of relative concentrations of free radicals were obtained for the beginning of cleavage, blastula, gastrula and neurula. The distinct regionalization was found in the beginning of cleavage: the concentration of the free radicals in the cortical layer and dorsal half of embryo is lower than in the central area and ventral half, resp. At the early blastula stage this regionalization is preserved in its general features. The region of embryo characterized by active free radical processes corresponds to the presumptive endo- and mesoderm in the period of inductive interaction. The possible participation of regional changes in oxidative metabolism in the fertilized egg in the determination of cytoplasmic localization of morphogenetic potencies is discussed. At the later stages there were variations observed in free radicals concentration, which are discussed as being related to the determination and morphogenesis of some rudiments of embryo. A local rise of free radicals concentration was also found out in the eye rudiment just before the onset of its components differentiation.


Partial life-cycle toxicity and bioconcentration modeling of perfluorooctanesulfonate in the northern leopard frog (Rana pipiens).
A number of recent monitoring studies have demonstrated elevated concentrations of perfluorooctanesulfonate (PFOS) in humans and wildlife throughout the world. Although no longer manufactured in the United States, the global distribution and relative persistence of PFOS indicates a need to understand its potential ecological effects. Presently, little is known concerning toxicity of PFOS in chronic exposures with aquatic species. Therefore, we evaluated the effects of PFOS on survival and development of the northern leopard frog (Rana pipiens) from early embryogenesis through complete metamorphosis. Exposures were conducted via water at measured PFOS concentrations ranging from 0.03 to 10 mg/L. Animals exposed to 10 mg/L began dying within approximately two weeks of test initiation. Survival was not affected by PFOS at lower concentrations; however, time to metamorphosis was delayed and growth reduced in the 3-mg/L treatment group. Tadpoles readily accumulated PFOS directly from water. Using a one-compartment bioaccumulation model, growth was shown to have a modest impact on steady-state PFOS concentrations. Variability in observed growth rates and the possible contribution of a size-dependent decrease in PFOS elimination rate contributed uncertainty to modeling efforts. Nevertheless, fitted uptake and elimination rate constants were comparable to those determined in earlier studies with juvenile rainbow trout. Overall, our studies suggest that R. pipiens is not exceptionally sensitive to PFOS in terms of either direct toxicity or bioconcentration potential of the chemical.


Right precordial-directed electrocardiographical markers identify arrhythmogenic right ventricular cardiomyopathy in the absence of conventional depolarization or repolarization abnormalities.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) carries a risk of sudden death. We aimed to assess whether vectorcardiographic (VCG) parameters directed toward the right heart and a measured angle of the S-wave would help differentiate ARVD/C with otherwise normal electrocardiograms from controls. Task Force 2010 definite ARVD/C criteria were met for all patients. Those who did not fulfill Task Force depolarization or repolarization criteria (-ECG) were compared with age and gender-matched control subjects. Electrocardiogram measures of a 3-dimentional spatial QRS-T angle, a right-precordial-directed orthogonal QRS-T (RPD) angle, a root mean square of the right sided depolarizing forces (RtRMS-QRS), QRS duration (QRSd) and the corrected QT interval (QTc), and a measured angle including the upslope and downslope of the S-wave (S-wave angle) were assessed. Definite ARVD/C was present in 155 patients by 2010 Task Force criteria (41.7 ± 17.6 years, 65.2% male). -ECG ARVD/C patients (66 patients) were compared to 66 control patients (41.7 ± 17.6 years, 65.2% male). All parameters tested except the QRSd and QTc significantly differentiated -ECG ARVD/C from control patients (p < 0.004 to p < 0.001). The RPD angle and RtRMS-QRS best differentiated the groups. Combined, the 2 novel criteria gave 81.8% sensitivity, 90.9% specificity and odds ratio of 45.0 (95% confidence interval 15.8 to 128.2). ARVD/C disease process may lead to development of subtle ECG abnormalities that can be distinguishable using right-sided VCG or measured angle markers better than the spatial QRS-T angle, the QRSd or QTc, in the absence of Taskforce ECG criteria.


Does Student-Led Faculty Development Have A Place in Health Professions Education?
This article was migrated. The article was marked as recommended. Background: Instructors at health sciences universities typically transition directly from the clinical to academic setting, limiting their ability to formally develop proficiency in the science of teaching. We assess the effectiveness of a student-led faculty development course and faculty perceptions of the program. Methods: Faculty from a clinical graduate program participated in a longitudinal student-led faculty development course. The course was offered in four separate 90-minute modules led by a student facilitator. Faculty completed course evaluations after each module, a knowledge assessment before and after the course, and a comprehensive evaluation upon completion of the course. Descriptive statistics were used to explore the effectiveness of the course and faculty perceptions. Results: Faculty (N=5) exhibited increased knowledge in teaching and learning principles after the course (p < 0.01). The highest-rated area on the module evaluations was the relevance of the topics to the participants' roles as instructors (4.31 ± 0.22). The lowest-rated area was pace of the modules (3.55 ± 0.62). The final course evaluation results showed that faculty rated the overall curriculum delivery very high (4.20 ± 0.46). Overall, faculty rated the student's instructional quality at or above what they would expect from a peer faculty member (3.80 ± 0.72). Faculty expressed that the most valuable parts of the curriculum were applicable content, the introduction to evidence-based learning and teaching concepts, and the group discussions. Conclusions: A student-led faculty development course improved faculty knowledge of learning, teaching, and assessment principles.


Regional Differences in Prevalence of Macrolide Resistance among Pediatric Mycoplasma pneumoniae Infections in Hokkaido, Japan.
Recently, macrolide-resistant (MR) Mycoplasma pneumonia appeared, and prevalence of macrolide resistance among M. pneumoniae infections varies by country. However, reports on regional differences in the prevalence of MR M. pneumonia within a country are scarce. In this study, 617 nasopharyngeal swab samples were collected from 617 pediatric patients, and DNA of M. pneumoniae was identified in 95 samples. In 51 of the 95 M. pneumonia positive samples, we detected the presence of mutation A2063G mutation (conferring macrolide resistance) in the 23S rRNA gene. The overall macrolide resistance rate was 53.7%, but there were regional differences: 0.0% in Muroran, 5.3% in Asahikawa, 55.3% in Sapporo, and 100.0% in Kushiro. Statistically significant pairwise differences in the prevalence of MR M. pneumoniae were observed among these cities except for the pair of Muroran and Asahikawa. After exclusion (in order to avoid the influence of macrolides) of patients who were prescribed macrolides before collection of nasopharyngeal swab samples, statistically significant differences persisted: 0.0% in Muroran, 5.6% in Asahikawa, 38.5% in Sapporo, and 100.0% in Kushiro.


Partial differential equation modeling of rumor propagation in complex networks with higher order of organization.
Mathematical modeling is an important approach to research rumor propagation in online social networks. Most of prior work about rumor propagation either carried out empirical studies or focus on ordinary differential equation models with only consideration of temporal dimension; little attempt has been given on understanding rumor propagation over both temporal and spatial dimensions. This paper primarily addresses an issue related to how to define a spatial distance in online social networks by clustering and then proposes a partial differential equation model with a time delay to describing rumor propagation over both temporal and spatial dimensions. Theoretical analysis reveals the existence of equilibrium points, a priori bound of the solution, the local stability and the global stability of equilibrium points of our rumor propagation model. Finally, numerical simulations have analyzed the possible influence factors on rumor propagation and proved the validity of the theoretical analysis.


Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A.
The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl- transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.


Essentialist beliefs about bodily transplants in the United States and India.
Psychological essentialism is the belief that some internal, unseen essence or force determines the common outward appearances and behaviors of category members. We investigated whether reasoning about transplants of bodily elements showed evidence of essentialist thinking. Both Americans and Indians endorsed the possibility of transplants conferring donors' personality, behavior, and luck on recipients, consistent with essentialism. Respondents also endorsed essentialist effects even when denying that transplants would change a recipient's category membership (e.g., predicting that a recipient of a pig's heart would act more pig-like but denying that the recipient would become a pig). This finding runs counter to predictions from the strongest version of the "minimalist" position (Strevens,2000), an alternative to essentialism. Finally, studies asking about a broader range of donor-to-recipient transfers indicated that Indians essentialized more types of transfers than Americans, but neither sample essentialized monetary transfer. This suggests that results from bodily transplant conditions reflect genuine essentialism rather than broader magical thinking.


Critical role of canonical transient receptor potential channel 7 in initiation of seizures.
Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel.


Blood pressure lowering effect of Korea ginseng derived ginseol K-g1.
We investigated the effect of Panax ginseng extract, which is rich in the ginsenoside protopanaxatriol (Ginseol K-g1), on blood pressure (BP). Adults over 20 years old with a systolic BP (SBP) between 120 and 159 mm Hg or a diastolic BP (DBP) between 80 and 99 mm Hg were included. At the end of an initial 2-week washout period, the patients were divided into three groups: the control group (placebo), the low-dose Ginseol K-g1 group (100 mg), and the high-dose Ginseol K-g1 (300 mg) group. The primary end point was the difference in seated SBP (seSBP) and seated DBP (seDBP) changes between the placebo and Ginseol K-g1 groups after 8 weeks of treatment. A total of 90 subjects participated in the study (mean age; 55.2 ± 11.8 years, 43 males). At week 8, levels of seSBP and seDBP were significantly decreased from baseline in the high-dose Ginseol K-g1 group (-3.1 mm Hg and -2.3 mm Hg, respectively, p < 0.05). In contrast, there was no significant decrease in seSBP or seDBP in the control or low-dose Ginseol K-g1 groups. No significant difference of seSBP and seDBP was identified among the three treatment groups at week 8. In patients who had a seSBP ≥ 130 mm Hg or an seDBP ≥ 85 mm Hg, the high dose of Ginseol K-g1 decreased the BP compared with the control group at week 4; however, there was no significant difference at week 8. The proportions of patients who experienced adverse events were comparable among the treatment groups. In conclusion, Ginseol K-g1 has a favorable effect on BP after 4 weeks of treatment, especially at a high dose. However, the effect is not maintained over 8 weeks. (Clinical trial registration information is available at http://www.clinicaltrials.gov , identifier: NCT01483430.).


Stem cell quiescence.
Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress. The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells (CSCs) to chemotherapy and targeted therapies. Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic. Thus, an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers. Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence. It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence. Other intrinsic regulatory mechanisms include the FoxO, HIF-1α, and NFATc1 transcription factors and signaling through ATM and mTOR. Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1, TGF-β, bone morphogenic protein, thrombopoietin, N-cadherin, and integrin adhesion receptors; Wnt/β-catenin signaling; and osteopontin. In this article, we review current advances in understanding normal stem cell quiescence, their significance for CSC quiescence and drug resistance, and the potential clinical applications of these findings.


Diagnostic value of IL-22, IL-23, and IL-17 for NK/T cell lymphoma.
NK/T cell lymphoma (NKTCL) is a common blood cancer, and early diagnosis of this disease is crucial. This study is aimed to investigate the roles of IL-17, IL-22 as well as IL-23 for the diagnosis of NKTCL. Sixty-five patients with NKTCL were included and the blood samples were collected, and sixty healthy objectives served as the controls. Serums of the patients and controls were collected. The expression levels of IL-17, IL-22, and IL-23 were examined using enzyme-linked immunosorbent (ELISA) assay. The receiver operator characteristic (ROC) curve was drawn for determining the potential diagnostic value of these cytokines. The serum levels of IL-17 (156.0 ± 67.75 pg/mL), IL-22 (39.98 ± 23.88 pg/mL), and IL-23 (43.05 ± 25.69 pg/mL) were all markedly increased in NKTCL patients (P<0.001); ROC analysis showed the serum level of IL-17, IL-22, and IL-23 could serve as the potential diagnostic biomarker for NKTCL with high sensitivity and specificity. The AUC of IL-17 was 0.9487 (95% confidence interval (CI), 0.9052 to 0.9922). Area under the curve (AUC) of IL-22 was 0.7321 (95% CI, 0.6449 to 0.8192). The AUC of IL-23 was 0.7885 (95% CI, 0.7070 to 0.8699). Our data indicated that IL-17, IL-22, and IL-23 were all increased in NKTCL and may function as potential diagnostic biomarkers for NKTCL.


Vascular Transcriptome Profiling Reveals Aging-Related Genes in Angiotensin Ⅱ-Induced Hypertensive Mouse Aortas.
Objective Angiotensin Ⅱ (Ang Ⅱ)-induced vascular damage is a major risk of hypertension. However, the underlying molecular mechanism of AngⅡ-induced vascular damage is still unclear. In this study, we explored the novel mechanism associated with Ang II-induced hypertension. Methods We treated 8- to 12-week-old C57BL/6J male mice with saline and Ang Ⅱ(0.72 mg/kg·d) for 28 days, respectively. Then the RNA of the media from the collected mice aortas was extracted for transcriptome sequencing. Principal component analysis was applied to show a clear separation of different samples and the distribution of differentially expressed genes was manifested by Volcano plot. Functional annotations including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to reveal the molecular mechanism of Ang Ⅱ-induced hypertension. Finally, the differentially expressed genes were validated by using quantitative real-time PCR. Results The result revealed that a total of 773 genes, including 599 up-regulated genes and 174 down-regulated genes, were differentially expressed in the aorta of Ang Ⅱ-induced hypertension mice model. Functional analysis of differentially expressed genes manifested that various cellular processes may be involved in the Ang Ⅱ-induced hypertension, including some pathways associated with hypertension such as extracellular matrix, inflammation and immune response. Interestingly, we also found that the differentially expressed genes were enriched in vascular aging pathway, and further validated that the expression levels of insulin-like growth factor 1 and adiponectin were significantly increased (P<0.05). Conclusion We identify that vascular aging is involved in Ang Ⅱ-induced hypertension, and insulin-like growth factor 1 and adiponectin may be important candidate genes leading to vascular aging.


Construction and characterization of extrachromosomal probes for mutagenesis by carcinogens: site-specific incorporation of O6-methylguanine into viral and plasmid genomes.
Organic synthesis and recombinant DNA technology were used to situate a putatively premutagenic DNA lesion, O6-methylguanine (O6MeGua), at a specific location in the genomes of two bacterial viruses, M13mp8 and phi X174, and of the bacterial plasmid pBR322. In each genome the first guanine residue in the unique recognition sequence for restriction endonuclease Pst I (5'-C-T-G-C-A-G-3') was replaced with O6MeGua. This was accomplished by ligating a chemically synthesized tetranucleotide, 5'-pTpm6GpCpA-3', into a circular, genome-length heteroduplex in which the four internal nucleotides of the Pst I recognition site had been removed from one strand of the DNA double helix (ligation yield, approximately equal to 50%). It was established that the tetranucleotide was located specifically at the Pst I site and that the presence of O6MeGua rendered the ligation product resistant to cleavage by Pst I. Sensitivity of the genome to Pst I was restored upon treatment with purified Escherichia coli O6MeGua DNA-methyltransferase, a repair protein that removes the methyl group from DNA-bound O6MeGua. This result, in combination with other data, showed unambiguously that O6MeGua was incorporated with high yield into the Pst I recognition sequence.


Bridging language barriers in developing valid health policy research tools: insights from the translation and validation process of the SHEMESH questionnaire.
The use of research tools developed and validated in one cultural and linguistic context to another often faces challenges. One major challenge is poor performance of the tool in the new context. This potentially impact the legitimacy of health policy research conducted with informal adaptations of existing tools which have not been subjected to formal validation. Best practices exist to guide researchers in adapting and validating research tools effectively. We present here, as an extended example, our validation of the SHEMESH questionnaire ('Organizational Readiness to Change Assessment'; In Hebrew: 'SHE'elon Muchanut Ergunit le'SHinuy'), a Hebrew-language version of the Organizational Readiness to Change Assessment (ORCA). SHEMESH is tailored to support implementation science projects, whose aim is to promote a more rapid and complete adoption of evidence-based health policies and practices. The SHEMESH included originally eleven questions from the Evidence (item 1-4) and Context (items 5-11) domains. We validated SHEMESH through the following steps: 1. Professional translation to Hebrew and discussion of the translation by multidisciplinary committee; 2. Back-translation into English by a different translator to detect discrepancies; 3. Eleven cognitive interviews with psychiatric emergency department physicians and nurses; and 4. Pilot testing and psychometric analyses, including Cronbach's alpha for subscales and factor analyses. Following translation and cognitive interviews, SHEMESH was administered to 222 psychiatrists and nurses. Pearson correlation showed significant and strong correlations of items 1-4 to the Evidence construct and items 6-11 to the Context construct. Item 5 did not correlate with the other items, and therefore was removed from the other psychometric procedures and eventually from the SHEMESH. Factor analysis with the remaining 10 items yielded two factors, which together explained a total of 69.7% of variance. Cronbach's Alpha scores for the two subscales were high (Evidence, 0.887, and Context, 0.852). This multi-step validation process of the SHEMESH questionnaire may serve as a comprehensive guideline for others who are willing to adapt research tools that were developed in other languages. Practically, SHEMESH has been validated for use in implementation science research projects in Israel.


Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).
The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.


Construction of pBR322-ara hybrid plasmids by in vivo recombination.
In vivo recombination was used to clone deletions of the araBAD-araC genes of Escherichia coli onto a hybrid pBR322-ara plasmid. Genetic and physical analyses demonstrated that the desired deletions had been recombined onto the plasmid. In addition to permitting a detailed physical analysis of various ara deletions, this procedure has generated a series of plasmid cloning vehicles that can be used to clone, by in vivo recombination, any ara point mutation located within the region covered by the deletions. Hybrid plasmids containing the cloned point mutation can be distinguished from the original cloning vehicle by genetic complementation. The desired recombinant plasmid can be easily obtained because the frequency of recombination between the plasmid ara region and the chromosomal ara region is 0.025%--3%. A plasmid containing a deletion which removes the ara controlling site region and the araC gene was used to clone two types of araBAD promoter mutations and an araC mutation by in vivo recombination. Genetic and physical analysis of these plasmids established that the mutations in question had been recombined on to the ara deletion plasmid. The application of this procedure to the ara genes and to other genetic systems is discussed.


The effect of cigarette smoke exposure and ascorbic acid intake on gene expression of antioxidant enzymes and other related enzymes in the livers and lungs of Shionogi rats with osteogenic disorders.
Cigarette smoking causes many chronic diseases but is a preventable risk factor in developing countries. However, it may be possible to relieve the smoke-induced damage by increasing the protective defense system. As vitamin C intake reduces smoking risk, it is recommended that smokers should take more vitamin C. However, the molecular mechanism of vitamin C intake on smokers has not been thoroughly investigated. We have found there to be suppression of smoke-induced cytochrome P-450 1A1 (CYP1A1) mRNA expression by high-dose ascorbic acid administration. Therefore, we surveyed other genes, the expressions of which were altered by the administration of high-dose ascorbic acid. As cigarette smoking increases oxidative stress, we investigated the effect on antioxidative enzyme expression. The osteogenic disorder Shionogi (ODS) rat, which lacks ascorbic acid synthesis enzyme, was administered either minimal amounts (4 mg/day, S4) or high-dose amounts (40 mg/day, S40) of ascorbic acid, and were exposed to cigarette smoke daily for 25 days. The effect on antioxidative enzymes mRNA expression in the liver was measured by competitive reverse transcription-polymerase chain reaction method (competitive RT-PCR). CuZn-superoxide dismutase (SOD), MnSOD, catalase and protein disulfide isomerase (PDI) were significantly decreased by high-dose ascorbic acid administration, and plasma glutathione peroxidase was also decreased, but not significantly. Cigarette smoke exposure slightly increased gene expression of PDI and catalase, but not significantly. The differently expressed 27 genes in the liver were found by differential display methods. From 27 genes, altered expression of plasma proteinase inhibitor, alpha-1-inhibitor III and CYP1A2 were confirmed by competitive RT-PCR. These results show that ascorbic acid intake influences gene expression of antioxidative enzymes, an ascorbic acid recycle enzyme, and xenobiotic metabolizing enzymes.


Capturing habitual, in-home gait parameter trends using an inexpensive depth camera.
Results are presented for measuring the gait parameters of walking speed, stride time, and stride length of five older adults continuously, in their homes, over a four month period. The gait parameters were measured passively, using an inexpensive, environmentally mounted depth camera, the Microsoft Kinect. Research has indicated the importance of measuring a person's gait for a variety of purposes from fall risk assessment to early detection of health problems such as cognitive impairment. However, such assessments are often done infrequently and most current technologies are not suitable for continuous, long term use. For this work, a single Microsoft Kinect sensor was deployed in four apartments, containing a total of five residents. A methodology for generating trends in walking speed, stride time, and stride length based on data from identified walking sequences in the home is presented, along with trend estimates for the five participants who were monitored for this work.


Interactions among endocrine control systems in the regulation of ovarian function.
During sequential physiologic maturation of an individual follicle, the number of granulosa cells increases in excess of 1000-fold, while intra-ovarian concentrations of sex steroids escalate by 100-fold. The recent development of several in vitro ovarian systems has permitted a more extensive and direct assessment of specific mechanisms that control growth and steroidogenesis in granulosa and thecal cells. For example, estradiol and follicle stimulating-hormone seem to promote the production by ovarian cells of low-molecular-weight growth factors, that may participate in granulosa cell proliferation. Luteinizing hormone stimulates the de novo synthesis of prostacyclin by granulosa cells in vitro. Prostacyclin, in turn, may regulate the microvasculature of the maturing follicle and directly stimulate steroidogenesis. The effects of individual hormones are markedly modified by other intraovarian endocrine factors, and by the precise status of cytodifferentiation of the ovarian cells. For example, the actions of prolactin on granulosa-cell steroidogenesis are influenced strikingly by both agonistic and antagonistic interactions between prolactin and estradiol, as well as by the level of granulosa-cell cytodifferentiation attained in vivo. Similar bihormonal intrafollicular interactions are recognizable between estrogen and follicle-stimulating hormone in the early follicle, and between estradiol and luteinizing hormone in the maturing follicle. These interactions are susceptible to more precise examination under defined in vitro conditions. Overall, recent advances in biomedical research continue to elucidate basic molecular mechanisms of hormone action in ovarian cell physiology. Such advances are likely to continue to provide important insights into the pathophysiology of clinical disorders of human reproduction.


Force-Length Relationship Modeling of Wrist and Finger Flexor Muscles.
Because the hand joints possess a broad range of motion, the muscle length can vary importantly which might result in significant variations of the muscle force-generating capacities. However, facing the complexity of this musculoskeletal system, no study has examined the effect of hand muscle length change on muscle force. This study aimed to characterize the force-length relationship of muscles involved in wrist and metacarpophalangeal flexion. Eleven participants performed two sessions: (i) one for the wrist flexor muscles and (ii) one for the finger flexor muscles. For each session, the participants performed two maximal voluntary contractions and then two progressive isometric ramps from 0% to 100% of their maximal force capacity at five different wrist/metacarpophalangeal angles. Torque, kinematic, and electromyographic data were recorded. An ultrasound scanner was used to measure the myotendinous junction displacement of flexor carpi radialis (FCR) and flexor digitorum superficialis (FDS) during isometric contractions. A three-dimensional relationship between muscle length, force, and activation level was modeled using optimization procedure. Globally, the FCR was stronger and shorter compared with FDS. The results showed that the three-dimensional relationships fitted well the experimental data (mean R = 0.92 ± 0.07 and 0.87 ± 0.11 for FCR and FDS, respectively). Using joint angle and EMG data, this approach allows to estimate the muscle force with low estimation errors (<9% of Fmax). This study proposes a new method to investigate the force-length relationship by combining ultrasound measurement, musculoskeletal modeling and optimization procedures. The data and relationships provide a new insight into hand biomechanics and muscle function that could be useful for designing hand tools or surgical operations.


TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity.
The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.


MR findings in Tay-Sachs disease.
MR and CT findings in two patients of Tay-Sachs disease are reported. In two patients of Tay-Sachs disease, MR and CT studies were conducted in the early phase (11 and 10 months of age, respectively) and one was followed-up with MR in the late phase at the age of 5 years and 8 months. Six MR studies on this disease (including 3 other cases documented in the literature) were reviewed and correlated with the pathological phases of this disease. MRI findings drastically changed during the phases of disease process in one case. In the early phase, T2-weighted MR images demonstrated hyperintensity in both basal ganglia and thalamus. MR images obtained in the late phase demonstrated markedly advanced brain atrophy and diffuse white matter lesions, which were hyperintense on the T2-weighted images. T1-weighted images exhibited hyperintensity in the basal ganglia, thalamus, and along the cortical layer of the cerebrum, which appeared to by hypointense on T2-weighted images. MR was apparently superior to CT in clearly delineating lesions of this disease. These abnormal signal intensities in the late phase may reflect the pathological findings, marked accumulation of GM2 ganglioside in the basal ganglia and thalamus and along the cerebral gray matter.


CSI: a severity index for Clostridium difficile infection at the time of admission.
Clostridium difficile is a common cause of nosocomial diarrhoea in the USA. To develop a score model that would help to identify severe versus mild or moderate C. difficile infection (CDI) upon admission we performed a retrospective cohort study. Between January 2004 and December 2007, 255 patients met inclusion criteria for this study. Severe CDI was defined as cases that required colectomy, intensive care unit management, ended in death, or hospitalisation of >10 days. Data recorded included past medical history, physical examination on admission, laboratory data and imaging/colonoscopy data. To create the CDI severity index (CSI) score, we included four risk factors for severe CDI that were identified by univariate analysis: history of malignancy, white blood cell count at admission >20,000/dL, blood albumin <3.0mg/dL, and creatinine at admission >1.5-fold the baseline value. One point was assigned to each of the risk factors. As indicated by a c-statistic of 0.78, the CSI score predicted severe CDI much better than chance (c-statistics of 0.50). The risk of developing severe CDI increased by a factor of 2.9 (95% CI: 1.82-4.59) for each 1-point increase in the CSI score. A CSI score with a cut-off value of 2 had a sensitivity and specificity of 82% and 65%, respectively. The CSI score may quantify the risk of severe CDI at the time of admission, and help in early identification of patients who may benefit from more aggressive treatment.


Arl3 and RP2 regulate the trafficking of ciliary tip kinesins.
Ciliary trafficking defects are the underlying cause of many ciliopathies, including Retinitis Pigmentosa (RP). Anterograde intraflagellar transport (IFT) is mediated by kinesin motor proteins; however, the function of the homodimeric Kif17 motor in cilia is poorly understood, whereas Kif7 is known to play an important role in stabilizing cilia tips. Here we identified the ciliary tip kinesins Kif7 and Kif17 as novel interaction partners of the small GTPase Arl3 and its regulatory GTPase activating protein (GAP) Retinitis Pigmentosa 2 (RP2). We show that Arl3 and RP2 mediate the localization of GFP-Kif17 to the cilia tip and competitive binding of RP2 and Arl3 with Kif17 complexes. RP2 and Arl3 also interact with another ciliary tip kinesin, Kif7, which is a conserved regulator of Hedgehog (Hh) signaling. siRNA-mediated loss of RP2 or Arl3 reduced the level of Kif7 at the cilia tip. This was further validated by reduced levels of Kif7 at cilia tips detected in fibroblasts and induced pluripotent stem cell (iPSC) 3D optic cups derived from a patient carrying an RP2 nonsense mutation c.519C > T (p.R120X), which lack detectable RP2 protein. Translational read-through inducing drugs (TRIDs), such as PTC124, were able to restore Kif7 levels at the ciliary tip of RP2 null cells. Collectively, our findings suggest that RP2 and Arl3 regulate the trafficking of specific kinesins to cilia tips and provide additional evidence that TRIDs could be clinically beneficial for patients with this retinal degeneration.


Relationship between mucosal levels of Helicobacter pylori-specific IgA, interleukin-8 and gastric inflammation.
Mucosal IgA is important in local immune defence. Helicobacter pylori induces a specific IgA response in antral mucosa, but its immunopathology is unknown. Interleukin-8 (IL-8) has been suggested to be important in H. pylori-induced inflammation. Current information on the relationship between H. pylori-induced IgA and mucosal inflammation is limited. To investigate possible associations between mucosal-specific IgA, the toxinogenicity of H. pylori, mucosal levels of IL-8 and gastric inflammation, 52 endoscoped patients were studied. These comprised 28 patients with peptic ulcer and 24 with non-ulcer dyspepsia. Of these patients, 38 had H. pylori infection: 28 with peptic ulcer and 10 with non-ulcer dyspepsia. Antral biopsies were taken for histology, H. pylori culture and measurement of mucosal levels of IL-8 (pg/mg) and specific IgA (A450x1000) by ELISA. Mucosal H. pylori IgA was detectable in 35 out of 38 patients with H. pylori infection, with a median (interquartile) level of 220 (147, 531) units. There was no significant difference in mucosal levels of the IgA antibodies between patients infected with cytotoxin-positive or cagA-positive strains of H. pylori and those with toxin-negative or cagA-negative strains. The IgA levels in those patients with severe neutrophil infiltration were lower than in those with mild or moderate infiltration (P<0.05). There was a weak inverse correlation between antral mucosal IgA and IL-8 in infected patients (r=-0.36; P=0.04). H. pylori infection induced a significant local mucosal IgA response in most infected patients. The level of IgA antibodies does not appear to be correlated with the toxinogenicity of H. pylori. However, patients with severe active inflammation appear to have decreased levels of IgA. An inverse correlation between mucosal IL-8 and IgA may suggest that IL-8-induced inflammation compromises the mucosal IgA defence and renders the mucosa susceptible to further damage.


GDF15 and Cardiac Cells: Current Concepts and New Insights.
Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily of proteins. Glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) is an endogenous receptor for GDF15 detected selectively in the brain. GDF15 is not normally expressed in the tissue but is prominently induced by "injury". Serum levels of GDF15 are also increased by aging and in response to cellular stress and mitochondrial dysfunction. It acts as an inflammatory marker and plays a role in the pathogenesis of cardiovascular diseases, metabolic disorders, and neurodegenerative processes. Identified as a new heart-derived endocrine hormone that regulates body growth, GDF15 has a local cardioprotective role, presumably due to its autocrine/paracrine properties: antioxidative, anti-inflammatory, antiapoptotic. GDF15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and in the heart within hours after myocardial infarction (MI). Recent studies show associations between GDF15, inflammation, and cardiac fibrosis during heart failure and MI. However, the reason for this increase in GDF15 production has not been clearly identified. Experimental and clinical studies support the potential use of GDF15 as a novel therapeutic target (1) by modulating metabolic activity and (2) promoting an adaptive angiogenesis and cardiac regenerative process during cardiovascular diseases. In this review, we comment on new aspects of the biology of GDF15 as a cardiac hormone and show that GDF15 may be a predictive biomarker of adverse cardiac events.


Optical chirality without optical activity: How surface plasmons give a twist to light.
Light interacts differently with left and right handed three dimensional chiral objects, like helices, and this leads to the phenomenon known as optical activity. Here, by applying a polarization tomography, we show experimentally, for the first time in the visible domain, that chirality has a different optical manifestation for twisted planar nanostructured metallic objects acting as isolated chiral metaobjects. Our analysis demon-strate how surface plasmons, which are lossy bidimensional electromagnetic waves propagating on top of the structure, can delocalize light information in the just precise way for giving rise to this subtle effect.


[Cytophotometric determination of the relationship between the chief isoenzyme forms of lactate dehydrogenase in the neuron--neuroglia system in different fuctional states of the nervous system].
In white mice, unlike the Wistar rats, the ratio of activities of H- and M-forms of lactate dehydrogenase (LDH) is lower in the cerebral cortex neurons but higher in the spinal cord motoneurons within the limits of sensitivity and correctness of the cytospectro-photometric method. No statistically significant species differences in the activity ratios of H- to M-forms of LDH were found in the Purkinje cells of the cerebellum, as well as in the perineuronal glia of all the areas studied. Rats of the Krushinsky--Molodkina strain with a hereditary high sensitivity to audiogenic convulsions differed from the Wistar rats only with a higher H- to M-form activity ratio in the Purkinje cells and in their glial satellite cells. The ratio of H-forms to M-forms of LDH did not differ significantly in the majority of the neuron types studied as well as in the neurons as compared with their glial satellite cells. Histotoxic hypoxia in mice due to KCN injection gave rise to activation of M-forms of LDH in spinal cord motoneurons and spinal ganglia neurons, of H-forms in cerebral and cerebellar cortex neurons and of both forms in the neuroglial cells adjacent to the cerebellum Purkinje neurons. Audiogenic convulsions in the Krushinsky--Molodkina rats induced an increase of the H-form activity of LDH in perineuronal glia of spinal cord anterior horns, and of the M-form activity in the cerebellum Purkinje cells with a decrease in the M-forms of the cerebellum neuroglia. An importance of multiple forms of enzymes for the functional regulation of the cell biochemical pattern is discussed.


MicroRNAs in alcoholic liver disease.
Alcoholic liver disease (ALD) is characterized by hepatocyte damage, inflammatory cell activation and increased intestinal permeability leading to the clinical manifestations of alcoholic hepatitis. Selected members of the family of microRNAs are affected by alcohol, resulting in an abnormal miRNA profile in the liver and circulation in ALD. Increasing evidence suggests that mRNAs that regulate inflammation, lipid metabolism and promote cancer are affected by excessive alcohol administration in mouse models of ALD. This communication highlights recent findings in miRNA expression and functions as they relate to the pathogenesis of ALD. The cell-specific distribution of miRNAs, as well as the significance of circulating extracellular miRNAs, is discussed as potential biomarkers. Finally, the prospects of miRNA-based therapies are evaluated in ALD.


Making ceramics "ductile".
Distributed irreversible deformation in otherwise brittle ceramics (specifically, in silicon carbide and micaceous glass-ceramic) has been observed in Hertzian contacts. The deformation takes the form of an expanding microcrack damage zone below the contact circle, in place of the usual single propagating macrocrack (the Hertzian "cone fracture") outside. An important manifestation of this deformation is an effective "ductility" in the indentation stress-strain response. Control of the associated brittle-ductile transition is readily effected by appropriate design of weak interfaces, large and elongate grains, and high internal stresses in the ceramic microstructure.


LDA/SVM driven nearest neighbor classification.
Nearest neighbor (NN) classification relies on the assumption that class conditional probabilities are locally constant. This assumption becomes false in high dimensions with finite samples due to the curse of dimensionality. The NN rule introduces severe bias under these conditions. We propose a locally adaptive neighborhood morphing classification method to try to minimize bias. We use local support vector machine learning to estimate an effective metric for producing neighborhoods that are elongated along less discriminant feature dimensions and constricted along most discriminant ones. As a result, the class conditional probabilities can be expected to be approximately constant in the modified neighborhoods, whereby better classification performance can be achieved. The efficacy of our method is validated and compared against other competing techniques using a number of datasets.


An overview of biomarkers in Alzheimer's disease.
Alzheimer's disease (AD) is the commonest progressive, dementing neurodegenerative disease in elderly, which affects innumerable people each year, and these numbers are likely to further increase as the population ages. In addition to the financial burden of AD on health care system, the disease has powerful emotional impact on caregivers and families of those afflicted. In this advancing era of AD research, with the availability of new treatment strategies having disease-modifying effects, there is growing need for the early diagnosis in AD, often hampered by paucity of biomarkers of AD. Various candidate biomarkers for AD have been developed that can detect patients with AD at an early stage. In the recent years, the search for an ideal biomarker has undergone a rapid evolution. Novel technologies in proteomics, genomics, and imaging techniques further expand the role of a biomarker not only in early diagnosis, but also in monitoring the response to various treatments. However, the availability of sensitive and specific biomarkers requires the method to be standardized so as to be able to compare the results across studies. Inspite of tremendous advances in this field the quest for an "ideal biomarker" still continues. In this review, we will discuss the various candidate markers in five spheres namely biochemical, neuroanatomical, metabolic, genetic and neuropsychological, and their current status and limitations in AD diagnosis.


Re-evaluating dissociations between implicit and explicit category learning: an event-related fMRI study.
Recent fMRI studies have found that distinct neural systems may mediate perceptual category learning under implicit and explicit learning conditions. In these previous studies, however, different stimulus-encoding processes may have been associated with implicit versus explicit learning. The present design was aimed at decoupling the influence of these factors on the recruitment of alternate neural systems. Consistent with previous reports, following incidental learning in a dot-pattern classification task, participants showed decreased neural activity in occipital visual cortex (extrastriate region V3, BA 19) in response to novel exemplars of a studied category compared to members of a foil category, but did not show this decreased neural activity following explicit learning. Crucially, however, our results show that this pattern was primarily modulated by aspects of the stimulus-encoding instructions provided at the time of study. In particular, when participants in an implicit learning condition were encouraged to evaluate the overall shape and configuration of the stimuli during study, we failed to find the pattern of brain activity that has been taken to be a signature of implicit learning, suggesting that activity in this area does not uniquely reflect implicit memory for perceptual categories but instead may reflect aspects of processing or perceptual encoding strategies.


Potential factors associated with resilience among older adults in rural China: a multilevel analysis.
Resilience is crucial for older adults who experience adversities, but research on the issue in rural China remains limited. This study aims to examine factors associated with resilience among older adults in rural China, as related to different types of resilience, and under different levels of adversity. Data were taken from the eight-wave (2001-2021) Longitudinal Study of Older Adults in Anhui Province, China. We used data from the eighth wave (2021) for the outcome variables and lagged predictors (2018) to avoid reverse causal effects. The study sample included individuals 60 years and above, excluding new participants from 2021, those without any adverse events, and any respondents with incomplete analytic data. Resilience was operationalized as residuals of the regressions of life satisfaction (Life Satisfaction Scale) and depressive symptoms (CES-D) on adversity, referred to as Type-1 and Type-2 resilience respectively. These two types of resilience were then treated as the outcome variables in subsequent multilevel regressions, with the predictors focusing on individual, social, and environmental characteristics and resources. This study adheres to STROBE guidelines. 43% of rural older adults exhibited both Type-1 and Type-2 resilience, whereas 18% exhibited only Type-1 resilience and 7% exhibited only Type-2 resilience. Common factors associated with both types of resilience included self-rated health, satisfaction with one's own financial situation, and the prestigiousness of social networks. Predictors for higher levels of Type-1 resilience included higher levels of financial and emotional support and more options for places of leisure. Predictors for higher levels of Type-2 resilience included greater access to medical care. The prestigiousness of social networks, higher levels of emotional support and instrumental support, access to medical care, and more options of places of leisure were positively associated with resilience in the low-adversity group (first tertile of adversity), only satisfaction with financial situation was positively correlated with the resilience of the middle-adversity group (second tertile), while better self-rated health, satisfaction with financial situation, and financial support yielded greater resilience in the high-adversity group (third tertile). We examined two types of resilience among older adults in rural China, and found that they have shared and unique associated factors. In addition, the potential factors influencing resilience varied with the level of adversity.


Aviation dentistry.
With the rapid expansion of the airline industry in all sectors, dentists should pay special attention to crews and frequent flyers, due to change of pressure in-flight, that cause different types of oro-facial pain. Aviation dentistry deals with evaluation, principles of prevention, treatment of diseases, disorders or conditions which are related to oral cavity and maxillofacial area or adjacent and associated structures and their impact on people who travel or on aircrew members and flight restrictions. Dentists should prevent the creation of in-flight hazards when they treat aircrew members and frequent flyers.


Failure of Surgical Equipoise in Posterior Cord Syndrome Myelopathy.
We suggest that a clinical diagnosis of posterior cord syndrome indicates primary posterior decompression in cervical spondylotic myelopathy cases. We present two unique cases of failed anterior decompression in neutrally aligned necks with compressive myelopathy and a literature review. Two recent cases of cervical spondylotic myelopathy that failed to respond after anterior surgical decompression and fusion surgery were observed at our institution. Both patients had motor strength preservation but were unable to stand and walk independently and had other clinical findings consistent with posterior cord syndrome rather than the more common anterior or central cord syndromes, and both responded well to staged posterior decompression. Posterior cervical decompression successfully relieved posterior cord syndrome symptoms after a failed anterior decompression in both of our cases. Posterior cord syndrome is a rare syndrome best diagnosed clinically and should be considered in cases of cervical spondylotic myelopathy in which motor strength testing is preserved.


Regulation of differentiation to the infective stage of the protozoan parasite Leishmania major by tetrahydrobiopterin.
A critical step in the infectious cycle of Leishmania is the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H4B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H4B, remained infectious to mice, and induced larger cutaneous lesions (hypervirulence). Thus, the control of pteridine metabolism has relevance to the mechanism of Leishmania differentiation and the limitation of virulence during evolution.


Core competencies for clinical ethics committees.
Clinical ethics committees (CECs) are increasing in number in the UK and have mostly developed in response to local interest, as opposed to being mandated as in the USA. However, there is no regulatory framework for UK CECs with no defined educational requirements or specification of core competencies for their members. The UK Clinical Ethics Network has consulted extensively with its members to set out, for the first time in the UK, the core competencies necessary for the provision of clinical ethics support. Recommendations for educational and membership requirements for CECs have also been made. Given the appropriate resources the standards proposed can be appropriately evaluated and are consistent with principles of ethical governance.


Gastrointestinal stromal tumor of the stomach: How to manage?
Gastrointestinal stromal tumor (GIST) is one of the most common malignant mesenchymal tumors of the stomach. Prognosis of this disease is related to tumor size and mitotic activity and early diagnosis is the only way to improve it. Diagnosis of GIST always requires histological and immunohistochemical confirmation as no imaging modalities can diagnose it conclusively. Endoscopic forceps biopsy results are frequently negative. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a technique which allows tissue samples to be obtained with minimal risks and is accurate in the diagnosis of GIST. From the point of view of the endoscopist, aggressive use of EUS-FNA is the only promising way to allow early diagnosis and early treatment of this disease.


[Assessment of risk for occupationally induced diseases in purification plant workers at a petroleum refinery].
The risk for occupationally induced diseases was assessed in purification plant workers at a petroleum refinery. The auxiliary process (purification and prepurification plants, biochemical purification) of the refinery OAO "Naftan" was the study object. Epidemiological, sanitary-and-hygienic studies were conducted to examine the negative influence of dangerous and harmful production factors on the workers' health status. The harmful and dangerous production factors recorded at this enterprise have been found to have a negative influence on the workers' health workers, which leads to the development of occupationally induced diseases in them.


Clinical phenotype of drug-naïve Parkinson's disease based on nonmotor symptoms.
Nonmotor symptoms in Parkinson's disease (PD) are heterogeneous and can result in a variety of symptoms at various disease stages. The objective of the present study was to identify clinically meaningful nonmotor symptoms and to assess the relationship between changes in nonmotor symptoms and cognition and motor symptoms. A total of 159 patients who had drug-naïve PD participated in this study. Nonmotor symptoms (Nonmotor Symptoms Scale), PD status (Unified Parkinson's Disease Rating Scale), depression (Geriatric Depression Scale or Montgomery-Asberg Depression Scale) and health-related quality of life (39-item Parkinson's Disease Questionnaire) were assessed. An exploratory factor analysis was performed to establish a nonmotor symptom factor, which was analyzed to evaluate whether the results were associated with the clinical severity measures. Exploratory factor analysis revealed one factor comprised of sleep/fatigue, attention/memory and mood/cognition. The modified Hoehn and Yahr Stage, Unified Parkinson's Disease Rating Scale Part III, Montgomery-Asberg Depression Scale and the 39-item Parkinson's Disease Questionnaire Summary Index were independently associated with the sleep/fatigue, attention/memory and mood/cognition domains. The presence of these domains was associated with advanced Parkinson's disease or depressed mood. This study shows that motor impairment and depressed mood in PD are related to sleep/fatigue, attention/memory and mood/cognition. Sleep/fatigue, attention/memory and mood/cognition also had a major impact on health-related quality of life. It is appropriate to identify patients with severe motor symptoms and depressed mood in order to signify the need to consider more detailed care and further assessment.


Dorsal Augmentation Using Autologous Costal Cartilage or Microfat-Infused Soft Tissue Augmentation.
Costal cartilage grafting is increasing in popularity with increased demand for augmentation rhinoplasty and increased need for grafting material for structure rhinoplasty techniques. Use of costal cartilage for dorsal grafting is both art and science. The art is demonstrated in the act of carving a dorsal graft that will reflect the actual contour of the nasal dorsum. The science is linked to the methodology of how the grafts are contoured to match the patient's desires and how the graft is fixed to the bony dorsum to minimize the risk of warping and displacement. Variations in dorsal graft design and methods of fixation are described. Use of the perichondrial interface between dorsal graft and perforated/rasped nasal dorsum acts to ossify the dorsal graft to the underlying bone, creating an immobile and natural appearing nasal dorsum. The fixation of the dorsal graft limits movement and hence decreases the likelihood of warping or deformity. Use of microfat in rhinoplasty has tremendous potential for camouflage and to promote healing of compromised tissues. Using microfat-infused soft tissue augmentation (MISTA), the surgeon is able to deliver microfat to an open surgical field, promote healing, and provide soft tissue augmentation. In this technique, microfat is injected into soft tissue carriers (perichondrium, temporalis fascia, etc.) and then implanted into the surgical field. MISTA has tremendous potential utility in many areas of cosmetic and reconstructive surgery.


Calcium silicate as a graft material for bone fractures: a systematic review.
Objective The goal of this review was to determine whether calcium silicate (wollastonite) as a bone graft material is a viable alternative to autogenous bone or whether the evidence base for its use is weak. Methods In this systematic review, electronic databases (MEDLINE/PubMed and BVS) were searched for relevant articles in indexed journals. Articles published in a 10-year period were identified (n = 48). After initial selection, 17 articles were assessed for eligibility; subsequently, seven articles were excluded and 10 articles were included. Results Among the studies included, 20% emphasized the importance of randomization, which adds reliability to the study, minimizing the risk of bias. High variability was observed in the material used, such as additives, amounts, dosage, and chemical alterations, rendering direct comparison among these studies impossible. The experimental periods varied considerably; one of the studies did not include statistical analysis, weakening the evaluation. Nonetheless, the true potential of wollastonite as a graft material conducive to new bone formation was reported in all studies. Conclusion The results support the use of wollastonite as a bone graft material. The initial research question was answered despite the significant variability observed among these preclinical studies, which hindered the precision of this analysis.


Image-based Gait Spatiotemporal Parameters Estimation using a Single Camera and CNN-Transformer Hybrid Network.
Vision-based gait analysis can play an important role in the remote and continuous monitoring of the elderly's health conditions. However, most vision-based approaches compute gait spatiotemporal parameters using human pose information and provide average parameters. This study aimed to propose a straightforward method for stride-by-stride gait spatiotemporal parameters estimation. A total of 160 elderly individuals participated in this study. Data were gathered with a GAITRite system and a mobile camera simultaneously. Three deep learning networks were trained with a few RGB frames as input and a continuous 1D signal containing both spatial and temporal gait parameters as output. The trained networks estimated the stride lengths with correlations of 0.938 and more and detected gait events with F1-scores of 0.914 and more.Clinical relevance- The proposed method showed excellent agreements with the GAITRite system in analyzing spatiotemporal gait parameters. Our approach can be applied to monitor the elderly's health conditions based on their gait parameters for early diagnosis of diseases, proper treatment, and timely intervention.


Time to clearance of Chlamydia trachomatis ribosomal RNA in women treated for chlamydial infection.
The dynamics of chlamydia clearance after treatment administration for chlamydial urogenital infection are unknown. We estimated the time to clearance of Chlamydia trachomatis (CT) ribosomal RNA (rRNA) after administration of azithromycin for cervical chlamydial infection using APTIMA Combo 2 (Gen-Probe, Inc., San Diego, CA, USA). A total of 115 women diagnosed with urogenital chlamydial infection, defined as a positive APTIMA urine or endocervical specimen, were enrolled in the present study. Vaginal swabs on the day of treatment (Day 0) and on Days 3, 7, 10 and 14 after treatment with 1 g of azithromycin were self-obtained by participants. Specimens were tested in a single laboratory. Our analysis was limited to women who were CT-confirmed by vaginal swab at baseline, who returned all follow-up swabs, and who reported sexual abstinence during the follow-up period (n = 61). Among 61 participants, 48 (79%) had a negative APTIMA at Day 14. Subjects with a negative APTIMA at each time-point were as follows: 0/61 (0%) on Day 0, 7/61 (12%) on Day 3, 28/61 (46%) on Day 7, 40/61 (66%) on Day 10, and 48/61 (79%) on Day 14. Multiple linear regression analysis predicted time to clearance at 17 days (95% confidence interval, 16-18 days) after administration of azithromycin. Seventeen of the 94 participants (18.1%) who screened positive for chlamydia had a negative vaginal swab on Day 0, indicating possible spontaneous clearance of CT. After treatment, CT rRNA declined with time. As rRNA was still detectable in 21% of the women 14 days after treatment, APTIMA should not be used as a test-of-cure in the 14-day period following azithromycin administration.


Erythropoietin and GDNF enhance ventral mesencephalic fiber outgrowth and capillary proliferation following neural transplantation in a rodent model of Parkinson's disease.
Low dopaminergic cell survival and suboptimal fiber reinnervation are likely major contributing factors for the limited benefits of neural transplantation in Parkinson's disease (PD) patients. Glial cell lined-derived neurotrophic factor (GDNF) has been shown to enhance dopaminergic cell survival and fiber outgrowth of the graft site as well as promote behavioral recovery in rodent models of PD, while erythropoietin (EPO) can produce dopaminergic neuroprotective effects against 6-hydroxydopamine (6-OHDA) exposure on cultured neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. The aim of this study was to determine if fetal ventral mesencephalic (FVM) tissue exposed to hibernation media containing a combination of GDNF and EPO could enhance dopaminergic graft survival, striatal reinnervation and functional recovery in a 6-OHDA rodent model of PD. FVM tissue was dissected from 14-day-old rat fetuses and placed for 6 days in hibernation media alone, and in hibernation media that received either a daily administration of GDNF, EPO or a combination of GDNF and EPO. Following hibernation, FVM cells were transplanted as a single cell suspension into the striatum of unilateral 6-OHDA-lesioned rats. Rotational behavioral assessment revealed animals that received FVM tissue exposed to GDNF, EPO or the combination of both drugs had accelerated functional recovery. Immunohistochemical and stereological assessment revealed a significant increase in graft fiber density and angiogenesis into the graft when compared with control. These findings suggest that the hibernation of FVM tissue in a combination of GDNF and EPO can enhance graft efficacy and may have important implications for tissue preparation protocols for clinical neural transplantation in PD.


Prevention of liver-tumor colonization by combined immunomodulation and liver lectin blocking.
The protective effect of combined treatment (immunomodulation with Propionibacterium avidum KP-40; liver lectin blocking by D-galactose administration) on the liver colonization of RAW 117-H10 lymphosarcoma was investigated in BALB/c-mice. Both, immunomodulation with P. avidum KP-40 as well as liver lectin blocking by D-galactose treatment significantly decreased the number of liver tumor colonies in this experimental model. However, the combination of P. avidum KP-40 and D-galactose obviously proved to be superior to each monotherapy since the liver colonization by RAW 117-H 10 lymphosarcoma could be completely inhibited.


Hospital admissions for bleeding events associated with treatment with apixaban, dabigatran and rivaroxaban.
To analyse the hospital admissions for bleeding events associated with treatment with direct oral anticoagulants (DOACs). To describe the characteristics and outcomes of those patients. A retrospective observational study was carried out in the framework of an integral risk management plan of drugs and proactive pharmacovigilance of hospital admissions for bleeding associated with apixaban, dabigatran and rivaroxaban from April 2015 through December 2016. Cases were identified using the information management tool of Orion Clinic (hospital electronic medical history) and by reviewing the hospital discharge reports. Various biometric, clinical and pharmacotherapeutic variables of each patient were registered. 37 hospitalisation episodes for DOAC-induced bleeding in 32 patients (15 received rivaroxaban, 9 apixaban and 8 dabigatran) were detected, representing an incidence rate of 3.44 per 100 person-years (95% CI 2.35 to 4.86). The most common bleeding site was gastrointestinal (27 cases, 73.0%). Intracranial bleeding was rare (three cases, 8.1%). Four patients (12.5%) were receiving DOACs at full doses and had a 'dose reduction indication'. The mean (SD) length of stay was 8.4 (5.2) days. Three patients (8.1%) died during the hospitalisation. Among bleeding episodes without fatal outcome, DOACs were stopped in 14 cases, continued in 14 cases, switched for another DOAC in two cases and the dose was reduced in four cases. DOACs are associated with serious bleeding events that require hospitalisation. The risk/benefit ratio assessment considering patient preferences and an individualised follow-up, especially in patients who are elderly, polymedicated or have impaired renal function, can help to reinforce the safe use of DOACs.


Infant Effortful Control Mediates Relations Between Nondirective Parenting and Internalising-Related Child Behaviours in an Autism-Enriched Infant Cohort.
Internalising problems are common within Autism Spectrum Disorder (ASD); early intervention to support those with emerging signs may be warranted. One promising signal lies in how individual differences in temperament are shaped by parenting. Our longitudinal study of infants with and without an older sibling with ASD investigated how parenting associates with infant behavioural inhibition (8-14 months) and later effortful control (24 months) in relation to 3-year internalising symptoms. Mediation analyses suggest nondirective parenting (8 months) was related to fewer internalising problems through an increase in effortful control. Parenting did not moderate the stable predictive relation of behavioural inhibition on later internalising. We discuss the potential for parenting to strengthen protective factors against internalising in infants from an ASD-enriched cohort.


Two simple and rapid methods to detect monoclonal antibodies with identical epitope specificities in a large population of monoclonal antibodies.
Two novel and simple methods have been developed for detecting monoclonal antibodies (MAbs) with identical epitope specificities from a large population of MAbs against human chorionic gonadotropin (hCG). The first method was based on the observation that following radioiodination many molecules of an antigen are altered in such a manner that they cannot be recognized by MAbs. The proportion of radiolabelled antigen (Bmax) able to bind to a MAb was characteristic of that MAb and MAbs having identical specificities showed identical Bmax values. Using this principle it was possible to identify MAbs having identical epitope specificities within a large population of MAbs against hCG. In the second method one test MAb was immobilized on a plastic surface through an immunochemical bridge. This MAb was then incubated with 125I-hCG previously complexed with a second MAb. Such a complex could bind to the solid phase MAb only if the two MAbs were not identical. The results obtained with both methods were concordant. With such methods it is possible to identify MAbs with identical epitope specificities immediately after the initial screening of the fusion. These methods do not require subcloning, ascites production, or the purification and iodination of large number of MAbs.


The chief strategy officer.
They're nominally and ultimately responsible for strategy, but today's CEOs have less and less time to devote to it. As a result, CEOs are appointing "chief strategy officers"--executives specifically tasked with creating, communicating, executing, and sustaining a company's strategic initiatives. In this article, three authors from Accenture share the results of their research on this emerging organizational role. The typical CSO or top strategy executive is not a pure strategist, conducting long-range planning in relative isolation. Most CSOs consider themselves doers first, with the mandate, credentials, and desire to act as well as advise. They are seasoned executives with a strong strategy orientation who have usually worn many operations hats before taking on the role. Strategy executives are charged with three critical jobs that together form the very definition of strategy execution. First, they must clarify the company's strategy for themselves and for every business unit and function, ensuring that all employees understand the details of the strategic plan and how their work connects to corporate goals. Second, CSOs must drive immediate change. The focus of the job almost always quickly evolves from creating shared alignment around a vision to riding herd on the ensuing change effort. Finally, a CSO must drive decision making that sustains organizational change. He or she must be that person who, in the CEO's stead, can walk into any office and test whether the decisions being made are aligned with the strategy and are creating the desired results. When decisions below the executive suite aren't being made in accordance with strategy, much of the CSO's job involves learning why and quickly determining whether to stay the course or change tack.


Cost-Effectiveness and Effects of a Home-Based Exercise Intervention for Female Caregivers of Relatives with Dementia: Study Protocol for a Randomized Controlled Trial.
Previous research has proposed a range of support interventions to mitigate the adverse impact of caregiving on the daily life of caregivers of relatives with dementia. However, the effectiveness of these interventions shows a high variability. Informal caregivers usually lack the time and/or live too far from conventional facilities to do physical exercise, especially those who live in rural areas. Thus, home-based interventions may be more efficacious due to their greater convenience for this population. The present work proposes and describes a study protocol for a randomized control trial that will analyze the efficacy and cost-effectiveness of a home-based, structured individual physical exercise intervention to improve the health-related quality of life and the mental health of female informal caregivers of relatives with dementia. The nine-month-long intervention will comprise participation in two supervised physical exercise sessions per week at the caregiver's home. The proposed study outcomes will be: (1) feasibility of and adherence to the home-based provision of the intervention; (2) improvement in physical fitness and quality of life; and (3) reduction in subjective burden, psychological symptomatology and depression. Analyses will also be performed to determine the cost-effectiveness after the intervention. In conclusion, this intervention might thus represent a tailored and feasible strategy to help caregivers cope with the physical and psychological stress resulting from caregiving-related responsibilities, and it could represent a novel cost-effective support home-based intervention for caregivers.


[Euthanasia].
Technological progress in medicine regarding the application of life-sustaining treatment in the critical patient and the cultural changes that have taken place in contemporary society with respect to the patients' right to decide over the end of their lives, demand the existence of a definition of euthanasia that will acknowledge this new scenario. The concept of euthanasia would be very specifically limited by the exclusion of so-called passive forms of euthanasia and of omission as a possible procedure to cause death and the need for the explicit request of the patient involved. Likewise, the definition of euthanasia should include a specific reference to the means through which death is to be achieved. Euthanasia would thus be defined basically as causing the death of a patient suffering from a mortal disease, upon his or her request and for his or her own benefit, by administering a toxic or poisonous substance in mortal doses. This restrictive definition would differentiate euthanasia from cases of refusal to receive treatment, even if death is the consequence of such refusal, and also from cases in which life-sustaining treatment is withheld or withdrawn to enable the occurrence of death.


Nucleic acids of respiratory syncytial virus.
Analysis of purified respiratory syncytial virus revealed that the virion RNA was composed of 50S, 28S, 18S, and 4S species. The 18S and 28S species were presumed to represent host rRNA since virus grown in actinomycin D-treated cells contained only 50S and 4S RNAs. Actinomycin D treatment stimulated production of infectious respiratory syncytial virus 5- to 10-fold. The 50S virion RNA was shown to hybridize with polyadenylated mRNA's isolated from infected cells, indicating that respiratory syncytial virus RNA is of negative-strand sense. Six mRNA's were identified by polyacrylamide gel electrophoresis.


Construction and comparison of three reference-quality genome assemblies for soybean.
We report reference-quality genome assemblies and annotations for two accessions of soybean (Glycine max) and for one accession of Glycine soja, the closest wild relative of G. max. The G. max assemblies provided are for widely used US cultivars: the northern line Williams 82 (Wm82) and the southern line Lee. The Wm82 assembly improves the prior published assembly, and the Lee and G. soja assemblies are new for these accessions. Comparisons among the three accessions show generally high structural conservation, but nucleotide difference of 1.7 single-nucleotide polymorphisms (snps) per kb between Wm82 and Lee, and 4.7 snps per kb between these lines and G. soja. snp distributions and comparisons with genotypes of the Lee and Wm82 parents highlight patterns of introgression and haplotype structure. Comparisons against the US germplasm collection show placement of the sequenced accessions relative to global soybean diversity. Analysis of a pan-gene collection shows generally high conservation, with variation occurring primarily in genomically clustered gene families. We found approximately 40-42 inversions per chromosome between either Lee or Wm82v4 and G. soja, and approximately 32 inversions per chromosome between Wm82 and Lee. We also investigated five domestication loci. For each locus, we found two different alleles with functional differences between G. soja and the two domesticated accessions. The genome assemblies for multiple cultivated accessions and for the closest wild ancestor of soybean provides a valuable set of resources for identifying causal variants that underlie traits for the domestication and improvement of soybean, serving as a basis for future research and crop improvement efforts for this important crop species.


Somatomedins.
An intact pituitary gland capable of secreting growth hormone has long been considered the prime requirement for the achievement of skeletal growth potential in man. Recent studies have revealed that the growth-promoting action of growth hormone is an in-vivo phenomenon which cannot be mimicked by the addition of the hormone to skeletal tissue in vitro. The humoral agent responsible for skeletal growth has now been identified as somatomedin, a peptide produced in the liver under the stimulus of pituitary growth hormone. Serum levels of somatomedin are measured in a bioassay system by monitoring the stimulation of uptake of labelled sulphate by cartilage. Low levels of somatomedin activity are detected in the serum of children with growth hormone deficiency and short stature; the levels are high in acromegalics and low in patients with cirrhosis of the liver or chronic renal failure. Undernourished children also have low levels despite reaised serum levels of growth hormone; this suggests the presence of an inhibitor which lowers the growth-promoting activity of the somatomedin molecule. Adequate nutrition in these children results in the restoration of serum somatomedin levels to normal. Attempts to isolate and purify somatomedin have led to the identification of a group of substances sharing similar actions on skeletal tissue. Insulin has also been demonstrated to share some of these growth-promoting activities but varies in its organ specificity. Nerve growth factor, epidermal growth factor and proinsulin are other molecules which form a large group of growth promoting peptides which may all be related to the somatomedins.