Applications for nuclear phenomena generated by ultra-intense lasers.
The amplification of laser light to generate powers large enough to affect the nucleus has been the desire of scientists since the invention of the laser 40 years ago. Many lasers, including tabletop varieties, now have pulse powers greater than the electrical power generated by all the world's power plants combined. When this power is focused to dimensions of a few microns, laser-driven nuclear phenomena can occur. Here we review the developments in this research field and describe the potential of laser produced proton, neutron, and heavy ion beams, together with isotope and isomer production.


Molecular dissection of the VHL gene in solitary capillary hemangioblastoma of the central nervous system.
Capillary hemangioblastomas (HGBs) of the CNS occur either sporadically or as part of the von Hippel-Lindau (VHL) syndrome. Molecular characterizations of the VHL gene in sporadic HGBs at the somatic level have been limited to date. We investigated the VHL gene in 57 patients most of whom (55 [96%] of 57) had a solitary CNS HGB at the time of surgery. Tissues from 23 HGBs of these patients (2 VHL related and 21 unrelated) were also investigated at genetic and epigenetic levels. Two of the 51 patients with apparently sporadic HGBs and no additional evidence of VHL (∼4%) were found to have a germline VHL gene mutation; both of these patients subsequently developed evidence of VHL syndrome. Somatic VHL gene mutations were found in 11 (52%) of the 21 non-VHL-related cases. A germline mutation was identified in 5 (84%) of 6 VHL-associated HGBs; double gene inactivation was observed in tumor tissue from VHL syndrome patients. Seven different previously unreported VHL gene alterations (6 somatic and 1 germline) were identified; double hits were identified in 7 (12%) of 57 cases. Our findings confirm the usefulness of VHL gene analysis at the germline level in patients who present with apparently solitary HGB. Moreover, the genetic and epigenetic VHL gene investigations performed support a key role for functional alterations of the VHL gene in sporadic neuraxial HGB.


Inhibitors of coenzyme A-independent transacylase induce apoptosis in human HL-60 cells.
ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine) is an antiproliferative agent, blocking the growth of cancer cells both in vitro and in vivo. However, there is controversy regarding the mechanism leading to its antiproliferative effects. CoA-independent transacylase (CoA-IT) is an enzyme that remodels arachidonate between specific phospholipid donor and acceptor molecules in a variety of mammalian cells. ET-18-O-CH3 was found to be a potent inhibitor of CoA-IT (IC50, 0.5 microM), and kinetic analysis revealed that its inhibition was competitive with the lyso-phospholipid substrate. The goal of the current study was to explore the connection between inhibition of CoA-IT and antiproliferative effects using several structurally distinct inhibitors of CoA-IT. ET-18-O-CH3 and other inhibitors of CoA-IT were found to inhibit cell proliferation and thymidine incorporation into the DNA, as well as to induce apoptosis in human HL-60 monocytic leukemia cells. The mechanism of apoptosis induced by ET-18-O-CH3 appeared to be different from that induced by tumor necrosis factor; the former failed to activate NF-kappa B, whereas tumor necrosis factor did. Closer examination of the pharmacology of apoptosis in this model revealed that compounds that were structurally related to CoA-IT inhibitors, but lacked CoA-IT inhibitory activity, also failed to induce apoptosis. In addition, compounds that inhibited other enzymes that participate in arachidonic acid metabolism, cyclooxygenase, 5-lipoxygenase and phospholipase A2, did not induce apoptosis. Taken together, these results demonstrate that inhibition of CoA-IT can be linked to blockade of proliferation and the induction of apoptosis in HL-60 cells.


Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations.
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.


Time series analysis of weekly influenza-like illness rate using a one-year period of factors in random forest regression.
Influenza, a disease caused by a respiratory virus, sickened over 5,043,127 citizens in Shenzhen, China, from January 2014 to April 2016. An accurate forecasting of outbreaks of influenza-like illness (ILI, here we refer to ILI as the upper respiratory infection) could facilitate public health officials to suggest public health actions earlier. In this study, a random forest regression constructed with a one-year period of factors was adopted to forecast the weekly ILI rate using the clinical data from Shenzhen Health Information Center. The following conclusions were drawn based on this method: i) Compared to the predication with 52 (one-year) history observations, the accuracy of the predication was improved by adding another 52 first-order difference variables: mean absolute percentage error (MAPE) decreased from 5.04% to 4.35% and mean squared error (MSE) decreased from 2.85E-04 to 1.97E-04. ii) The variables with the first-order difference seemed more significant than the original history observations during the predication. In addition, both the recent observations and the later observations seemed important in the predicating procedure. iii) Analysis using the Pearson correlation concluded that weather conditions, the influence of which could have been implied by history observations and seemed insignificant for the predication, showed correlation to the weekly average temperature and maximum temperature. The correlation coefficients were -0.3656 and -0.3583, respectively.


Transcriptional interference by independently regulated genes occurs in any relative arrangement of the genes and is influenced by chromosomal integration position.
Transcriptional interference is the influence, generally suppressive, of one active transcriptional unit on another unit linked in cis. Its wide occurrence in experimental systems suggests that it may also influence transcription in many loci, but little is known about its precise nature or underlying mechanisms. Here we report a study of the interaction of two nearly identical transcription units juxtaposed in various arrangements. Each reporter gene in the constructs has its own promoter and enhancer and a strong polyadenylation signal. We used recombinase-mediated cassette exchange (RMCE) to insert the constructs into previously tagged genomic sites in cultured cells. This strategy also allows the constructs to be assessed in both orientations with respect to flanking chromatin. In each of the possible arrangements (tandem, divergent, and convergent), the presence of two genes strongly suppresses expression of both genes compared to that of an identical single gene at the same integration site. The suppression is most severe with the convergent arrangement and least severe in total with the divergent arrangement, while the tandem arrangement is most strongly influenced by the integration site and the genes' orientation within the site. These results suggest that transcriptional interference could underlie some position effects and contribute to the regulation of genes in complex loci.


Misapplication of the Tarasoff duty to driving cases: a call for a reframing of theory.
In the years since the original Tarasoff cases created a new duty for psychotherapists toward third parties harmed by patients' violence, a series of cases nationwide--so called "driving cases"--have applied Tarasoff-like reasoning to situations where a patient injured others while driving a car. Our thesis in this paper is that such application is inappropriate since it represents an unjustified and largely unexamined assumption that driving injury is an expression of the mental-illness-derived intended violence that justifies the Tarasoff duty and its inevitable associated breach of confidentiality. We suggest to the contrary that driving cases almost invariably result from a patient's negligent driving rather than intentional violence stemming from mental illness; that clinicians in most instances have almost no capacity, training, or clinical bases on which to predict a patient's future negligence, violence aside; and that the theory of driving cases should be revised.


Predicting risk of ischemic heart disease and cerebrovascular disease from systolic and diastolic blood pressures.
The relative importance of systolic versus diastolic blood pressure in predicting risk of ischemic heart disease or cerebrovascular disease is controversial. Since 1948 we have observed in the Manitoba Study 3983 men (most between 25 to 34 years old at entry), in whom risk of both diseases was determined using the multiple logistic model. Systolic and diastolic blood pressures after adjustment for age and body weight were compared at entry and at four other examinations during the follow-up period. When both blood pressures were considered together, a stronger association with cerebrovascular disease was found for systolic compared to diastolic blood pressure at entry and at most of the other examinations. For ischemic heart disease, diastolic pressure showed a stronger association at the earlier examinations, whereas systolic pressure was more important when the majority of the cohort was between 40 to 50 years of age. In middle-aged men the general concept that diastolic is more important than systolic is not justified for cerebrovascular disease or for ischemic heart disease.


Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10-Dependent Apoptosis by Carfilzomib and Selinexor.
Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.


Nutrient uplift in a cyclonic eddy increases diversity, primary productivity and iron demand of microbial communities relative to a western boundary current.
The intensification of western boundary currents in the global ocean will potentially influence meso-scale eddy generation, and redistribute microbes and their associated ecological and biogeochemical functions. To understand eddy-induced changes in microbial community composition as well as how they control growth, we targeted the East Australian Current (EAC) region to sample microbes in a cyclonic (cold-core) eddy (CCE) and the adjacent EAC. Phototrophic and diazotrophic microbes were more diverse (2-10 times greater Shannon index) in the CCE relative to the EAC, and the cell size distribution in the CCE was dominated (67%) by larger micro-plankton [Formula: see text], as opposed to pico- and nano-sized cells in the EAC. Nutrient addition experiments determined that nitrogen was the principal nutrient limiting growth in the EAC, while iron was a secondary limiting nutrient in the CCE. Among the diazotrophic community, heterotrophic NifH gene sequences dominated in the EAC and were attributable to members of the gamma-, beta-, and delta-proteobacteria, while the CCE contained both phototrophic and heterotrophic diazotrophs, including Trichodesmium, UCYN-A and gamma-proteobacteria. Daily sampling of incubation bottles following nutrient amendment captured a cascade of effects at the cellular, population and community level, indicating taxon-specific differences in the speed of response of microbes to nutrient supply. Nitrogen addition to the CCE community increased picoeukaryote chlorophyll a quotas within 24 h, suggesting that nutrient uplift by eddies causes a 'greening' effect as well as an increase in phytoplankton biomass. After three days in both the EAC and CCE, diatoms increased in abundance with macronutrient (N, P, Si) and iron amendment, whereas haptophytes and phototrophic dinoflagellates declined. Our results indicate that cyclonic eddies increase delivery of nitrogen to the upper ocean to potentially mitigate the negative consequences of increased stratification due to ocean warming, but also increase the biological demand for iron that is necessary to sustain the growth of large-celled phototrophs and potentially support the diversity of diazotrophs over longer time-scales.


Direct and indirect effects of age on interoceptive accuracy and awareness across the adult lifespan.
Various aspects of physical and mental health have been linked to an individual's ability to perceive the physical condition of their body ('interoception'). In addition, numerous studies have demonstrated a role for interoception in higher-order cognitive abilities such as decision-making and emotion processing. The importance of interoception for health and typical cognitive functioning has prompted interest in how interoception varies over the lifespan. However, few studies have investigated interoception into older adulthood, and no studies account for the set of physiological changes that may influence task performance. The present study examined interoception from young to very late adulthood (until 90 years of age) utilising a self-report measure of interoception (Study One) and an objective measure of cardiac interoception (Study Two). Across both studies, interoception decreased with age, and changes in interoceptive accuracy were observed which were not explained by accompanying physiological changes. In addition to a direct effect of age on interoception, an indirect effect of ageing on cardiac interoceptive accuracy mediated by body mass index (BMI) was found, such that ageing was associated with increased BMI which was, in turn, associated with reduced interoceptive accuracy. Such findings support and extend previous research demonstrating interoceptive decline with advancing age, and highlight the importance of assessing whether decreasing interoceptive ability is responsible for some aspects of age-related ill-health and cognitive impairment.


Diode-pumped 100-W green Nd:YAG rod laser.
We developed a diode-pumped high-average-power Nd:YAG green laser. By use of a monolithic diffusive reflector having three slits and a rod with low doping concentration, uniform distribution of excited Nd ions could be achieved. Uniform distribution in the rod reduced thermal birefringence. We employed a Z-shaped cavity to have a constant beam size at the frequency-doubling crystal independent of thermal lensing in the rod. The pulse width and green power dependence on the pump power were analyzed. A maximum green power of 101 W was obtained when the total pump power was 398 W. The optical-to-optical conversion efficiency was as high as 25.4%.


Interventions for prudent antibiotic use in primary healthcare: an econometric analysis.
Rational antibiotic prescribing is crucial to combat antibiotic resistance. Optimal strategies to improve antibiotic use are not known. Strama, the Swedish strategic program against antibiotic resistance, has been successful in reducing antibiotic prescription rates. This study investigates whether two specific interventions directed toward healthcare centers, an informational visit and a self-evaluation meeting, played a role in observed reduction in rates of antibiotic prescriptions in primary healthcare. The study was a retrospective, observational, empirical analysis exploiting the variation in the timing of the interventions and considering past prescriptions through use of estimations from dynamic panel data models. Primary healthcare data from 2011 to 2014 were examined. Data were from public and private primary healthcare centers in western Sweden. The key variables were prescription of antibiotics and indicator variables for the two interventions. The first intervention, an educational information intervention, decreased the number of prescriptions among public healthcare centers, but this effect was only temporary. We found no proof that the second intervention, a self-evaluation meeting at the healthcare center, had an impact on the reduction of prescriptions. Single educational interventions aimed at influencing rates of antibiotic prescriptions have limited impact. A multifaceted approach is needed in efforts to reduce the use of antibiotics in primary health care.


Retracing the in vivo haematopoietic tree using single-cell methods.
The dynamic process by which self-renewing stem cells and their offspring proliferate and differentiate to create the erythroid, myeloid and lymphoid lineages of the blood system has long since been an important topic of study. A range of recent single cell and family tracing methodologies such as massively parallel single-cell RNA-sequencing, mass cytometry, integration site barcoding, cellular barcoding and transposon barcoding are enabling unprecedented analysis, dissection and re-evaluation of the haematopoietic tree. In addition to the substantial experimental advances, these new techniques have required significant theoretical development in order to make biological deductions from their data. Here, we review these approaches from both an experimental and inferential point of view, considering their discoveries to date, their capabilities, limitations and opportunities for further development.


Radiomics of Tumor Heterogeneity in Longitudinal Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Predicting Response to Neoadjuvant Chemotherapy in Breast Cancer.
Breast tumor morphological and vascular characteristics can be changed during neoadjuvant chemotherapy (NACT). The early changes in tumor heterogeneity can be quantitatively modeled by longitudinal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which is useful in predicting responses to NACT in breast cancer. In this retrospective analysis, 114 female patients with unilateral unifocal primary breast cancer who received NACT were included in a development (n = 61) dataset and a testing dataset (n = 53). DCE-MRI was performed for each patient before and after treatment (two cycles of NACT) to generate baseline and early follow-up images, respectively. Feature-level changes (delta) of the entire tumor were evaluated by calculating the relative net feature change (deltaRAD) between baseline and follow-up images. The voxel-level change inside the tumor was evaluated, which yielded a Jacobian map by registering the follow-up image to the baseline image. Clinical information and the radiomic features were fused to enhance the predictive performance. The area under the curve (AUC) values were assessed to evaluate the prediction performance. Predictive models using radiomics based on pre- and post-treatment images, Jacobian maps and deltaRAD showed AUC values of 0.568, 0.767, 0.630 and 0.726, respectively. When features from these images were fused, the predictive model generated an AUC value of 0.771. After adding the molecular subtype information in the fused model, the performance was increased to an AUC of 0.809 (sensitivity of 0.826 and specificity of 0.800), which is significantly higher than that of the baseline imaging- and Jacobian map-based predictive models (p = 0.028 and 0.019, respectively). The level of tumor heterogeneity reduction (evaluated by texture feature) is higher in the NACT responders than in the nonresponders. The results suggested that changes in DCE-MRI features that reflect a reduction in tumor heterogeneity following NACT could provide early prediction of breast tumor response. The prediction was improved when the molecular subtype information was combined into the model.


Potential effects of disruption to HIV programmes in sub-Saharan Africa caused by COVID-19: results from multiple mathematical models.
The COVID-19 pandemic could lead to disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimated that more than two-thirds of the approximately 38 million people living with HIV resided in 2018. We aimed to predict the potential effects of such disruptions on HIV-related deaths and new infections in sub-Saharan Africa. In this modelling study, we used five well described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, an Imperial College London model, and Epidemiological MODeling software [EMOD]) to estimate the effect of various potential disruptions to HIV prevention, testing, and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months over 1 year from April 1, 2020. We considered scenarios in which disruptions affected 20%, 50%, and 100% of the population. A 6-month interruption of supply of antiretroviral therapy (ART) drugs across 50% of the population of people living with HIV who are on treatment would be expected to lead to a 1·63 times (median across models; range 1·39-1·87) increase in HIV-related deaths over a 1-year period compared with no disruption. In sub-Saharan Africa, this increase amounts to a median excess of HIV deaths, across all model estimates, of 296 000 (range 229 023-420 000) if such a high level of disruption occurred. Interruption of ART would increase mother-to-child transmission of HIV by approximately 1·6 times. Although an interruption in the supply of ART drugs would have the largest impact of any potential disruptions, effects of poorer clinical care due to overstretched health facilities, interruptions of supply of other drugs such as co-trimoxazole, and suspension of HIV testing would all have a substantial effect on population-level mortality (up to a 1·06 times increase in HIV-related deaths over a 1-year period due to disruptions affecting 50% of the population compared with no disruption). Interruption to condom supplies and peer education would make populations more susceptible to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sexual behaviour (up to 1·19 times increase in new HIV infections over a 1-year period if 50% of people are affected). During the COVID-19 pandemic, the primary priority for governments, donors, suppliers, and communities should focus on maintaining uninterrupted supply of ART drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence. Bill & Melinda Gates Foundation.


Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts.
Although the sequence of the human cytomegalovirus (HCMV) genome is generally conserved among unrelated clinical strains, some open reading frames (ORFs) are highly variable. UL146 and UL147, which encode CXC chemokine homologues are among these variable ORFs. The region of the HCMV genome from UL146 through UL147A was analyzed in clinical strains for sequence variability, genotypic stability, and transcriptional expression. The UL146 sequences in clinical strains from two geographically distant sites were assigned to 12 sequence groups that differ by over 60% at the amino acid level. The same groups were generated by sequences from the UL146-UL147 intergenic region and the UL147 ORF. In contrast to the high level of sequence variability among unrelated clinical strains, the sequences of UL146 through UL147A from isolates of the same strain were highly stable after repeated passage both in vitro and in vivo. Riboprobes homologous to these ORFs detected multiple overlapping transcripts differing in temporal expression. UL146 sequences are present only on the largest transcript, which also contains all of the downstream ORFs including UL148 and UL132. The sizes and hybridization patterns of the transcripts are consistent with a common 3'-terminus downstream of the UL132 ORF. Early-late expression of the transcripts associated with UL146 and UL147 is compatible with the potential role of CXC chemokines in pathogenesis associated with viral replication. Clinical isolates from two different geographic sites cluster in the same groups based on the hypervariability of the UL146, UL147, or the intergenic sequences, which provides strong evidence for linkage and no evidence for interstrain recombination within this region. The sequence of individual strains was absolutely stable in vitro and in vivo, which indicates that sequence drift is not a mechanism for the observed sequence hypervariability. There is also no evidence of transcriptional splicing, although multiple overlapping transcripts extending into the adjacent UL148 and UL132 open reading frames were detected using gene-specific probes.


Sleep deprivation and its effects on communication during individual and collaborative tasks.
Sleep loss has been shown to cause impairments in a number of aspects central for successful communication, ranging from poorer linguistic comprehension to alterations in speech prosody. However, the effect of sleep loss on actual communication is unknown. This study investigated how a night of sleep deprivation affected performance during multiple tasks designed to test verbal communication. Healthy participants (N = 183) spent 8-9 hours per night in bed for three nights and were then randomised to either one night of total sleep deprivation or a fourth night with 8-9 hours in bed. The following day, participants completed two tasks together with another participant: a model-building task and a word-description task. Differences in performance of these tasks were assessed alongside speaking duration, speaking volume, and speaking volume consistency. Additionally, participants individually completed a verbal fluency assessment. Performance on the model-building task was worse if the model-builder was sleep deprived, whereas sleep deprivation in the instruction-giver predicted an improvement. Word-description, verbal fluency, speech duration, speaking volume, and speaking volume consistency were not affected. The results suggest that sleep deprivation leads to changes in communicative performance during instructive tasks, while simpler word-description tasks appear resilient.


Assessment of pain caused by invasive procedures in cancer patients.
Invasive procedures are commonly required in the diagnosis and management of cancer in adults. However, little is known regarding the prevalence and severity of procedure-related pain in this patient population. This prospective study was conducted to determine the frequency and types of invasive procedures performed in a large comprehensive cancer center, the intensity of pain associated with these procedures, the types of periprocedural analgesics administered, and how these patients would like their procedural pain to be managed in the future. During a 6-week period, 102 cancer patients were interviewed immediately after undergoing an invasive procedure. They were asked to rate the pain they experienced before, during, and after their procedure using a verbal descriptor scale (VDS) ranging from 0 to 10. They also were asked if they would want more, less, or the same amount of pain medication if they were to undergo the same procedure again. The most frequently performed procedures were bone marrow aspirates and biopsies (68%), lumbar punctures (14%), and placements of central venous catheters (10%). The average pain rating during these procedures was 4.2 (standard deviation [SD], 3.0). However, 26% of patients experienced severe pain (VDS score > or = 7) during the procedures. Twenty-four percent of patients surveyed received conscious sedation for their procedure. There was no statistical relationship between patients' pain ratings and their satisfaction with the pain control they received during the procedures. This study represents the largest descriptive study of procedural pain in adult cancer patients. As more than 50% of these patients experienced moderate to severe pain during procedures, further studies are needed to improve the control of procedure-related pain in patients with cancer.


Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos.
Asbestos exposure causes lung fibrosis and various malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos on immune cells have not been thoroughly investigated, although our previous reports showed that asbestos exposure reduced anti-tumor immunity. The effects of continuous exposure of regulatory T cells (Treg) to asbestos were examined using the HTLV-1 immortalized human T cell line MT-2, which possesses a suppressive function and expresses the Treg marker protein, Foxp3. Sublines were generated by the continuous exposure to low doses of asbestos fibers for more than one year. The sublines exposed to asbestos showed enhanced suppressive Treg function via cell-cell contact, and increased production of soluble factors such as IL-10 and transforming growth factor (TGF)-β1. These results also indicated that asbestos exposure induced the reduction of anti-tumor immunity, and efforts to develop substances to reverse this reduction may be helpful in preventing the occurrence of asbestos-induced tumors.


Consumer price sensitivity and social health insurer choice in Germany and The Netherlands.
In this paper, we examine the effects of the introduction of free choice and price competition in social health insurance in Germany and the Netherlands. Using panel data at the sickness fund level we estimate the price elasticity of sickness fund choice in both countries. We find that the price elasticity in Germany is high and rapidly increasing. Consistent with findings of other studies on health plan choice, the price elasticity is much lower for elderly than for non-elderly. In the Netherlands, by contrast, the price elasticity of fund choice is negligible. Only when people were forced to choose a sickness fund, they were quite sensitive to premium differences. Key factors in explaining the observed differences in switching behavior between both countries are the degree of financial risk for sickness funds, the features of the risk-adjustment mechanism and the role of employers.


Analysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells.
Statistical modelling, in combination with genome-wide expression profiling techniques, has demonstrated that the molecular state of the tumour is sufficient to infer its pathological state. These studies have been extremely important in diagnostics and have contributed to improving our understanding of tumour biology. However, their importance in in-depth understanding of cancer patho-physiology may be limited since they do not explicitly take into consideration the fundamental role of the tissue microenvironment in specifying tumour physiology. Because of the importance of normal cells in shaping the tissue microenvironment we formulate the hypothesis that molecular components of the profile of normal epithelial cells adjacent the tumour are predictive of tumour physiology. We addressed this hypothesis by developing statistical models that link gene expression profiles representing the molecular state of adjacent normal epithelial cells to tumour features in prostate cancer. Furthermore, network analysis showed that predictive genes are linked to the activity of important secreted factors, which have the potential to influence tumor biology, such as IL1, IGF1, PDGF BB, AGT, and TGFβ.


Periodic oscillation of ion conduction of nanofluidic diodes using a chemical oscillator.
Periodic ion-conduction oscillation of biological ion channels in a living system is essential for numerous life processes. Here we report an oscillatory nanofluidic system that can self-regulate its ion-conduction states under constant conditions. The oscillatory nanofluidic system is constructed by integrating a chemical oscillator into an artificial single nanochannel system. Oscillating chemical reactions of the pH oscillator carried out inside the nanochannel are used to switch the surface properties of the channel between highly and lowly charged states, thus realizing an autonomous, continuous and periodic oscillation of the ion conductance of the channel between high and low ion-conduction states. The ion-conduction switching is characterized by the periodic ion current oscillation of the nanochannel measured under constant conditions. The oscillation period of the nanofluidic devices decreased gradually with increasing the working temperature. This study is a potential step toward the ability to directly convert chemical energy to ion-conduction oscillation in nanofluidics. On the basis of these findings, we believe that a variety of artificial oscillatory nanofluidic systems will be achieved in future by integrating artificial functional nanochannels with diverse oscillating chemical reactions.


Decoupling of timescales reveals sparse convergent CPG network in the adult spinal cord.
During the generation of rhythmic movements, most spinal neurons receive an oscillatory synaptic drive. The neuronal architecture underlying this drive is unknown, and the corresponding network size and sparseness have not yet been addressed. If the input originates from a small central pattern generator (CPG) with dense divergent connectivity, it will induce correlated input to all receiving neurons, while sparse convergent wiring will induce a weak correlation, if any. Here, we use pairwise recordings of spinal neurons to measure synaptic correlations and thus infer the wiring architecture qualitatively. A strong correlation on a slow timescale implies functional relatedness and a common source, which will also cause correlation on fast timescale due to shared synaptic connections. However, we consistently find marginal coupling between slow and fast correlations regardless of neuronal identity. This suggests either sparse convergent connectivity or a CPG network with recurrent inhibition that actively decorrelates common input.


Make love to forget: two cases of transient global amnesia triggered by sexual intercourse.
Transient global amnesia (TGA) is characterized by a sudden onset and by a typical resolution within several hours. Several precipitating events have been proposed: physical exertion, emotional experiences, etc. The aim of this paper was to present two cases of TGA triggered by sexual intercourse and to suggest a possible mechanism for the development of TGA. In both patients, clinical examination revealed elevated blood pressure. Laboratory examinations and brain CTs were normal. EEG demonstrated diffuse dysrhythmia and slow spike-waves, respectively. SPECT revealed hypoperfusion in the left frontal and right medial temporal regions. Various explanations of the mechanism of TGA are discussed. Based on the observed hypoperfusion in the medial temporal regions, a new hypothesis is advanced, suggesting the possibility that TGA occurs due to a pathologically changed or less adaptable anterior chorioid artery, initially constricted by hypotension following a blood shift from the center towards periphery.


The use of tranexamic acid in spine surgery.
Patients undergoing surgical procedures of the spine with associated large volume blood loss often require perioperative blood conservation strategies. Synthetic antifibrinolytic medications such as tranexamic acid (TXA) may reduce blood transfusion requirements and postoperative complications following spinal procedures. Studies investigating the role of TXA in spine surgery have presented promising results and have proven its safety and efficacy. However, further investigation is needed to determine the optimal dosing regimen of TXA. In this article, we provide an overview of the basic science and pharmacology of TXA. A comprehensive summary of the findings from clinical trials and a review of the literature that demonstrate the risks and benefits of TXA in spine surgery are also presented.


P73a overexpression is associated with resistance to treatment with DNA-damaging agents in a human ovarian cancer cell line.
We examined the consequences of p73alpha overexpression on gene expression and cellular response to anticancer agents in clones from the human ovarian cancer cell line A2780. Using microarray filters, the expression of 588 genes in two clones overexpressing p73alpha (A2780/p73.4 and A2780/ p73.5) in comparison with empty vector-transfected cells was evaluated. There were clear differences in gene expression profiles. Both of the clones showed a marked increase in the expression of genes involved in DNA repair, including genes participating in nucleotide excision repair and mismatch repair. This was confirmed by reverse transcription-PCR and Northern blot analysis and was associated with an increase in the ability of p73alpha-expressing clones to repair two different DDP (cis-dichlorodiammine platinum)-damaged plasmids in a host reactivation assay. p73alpha overexpressing clones were less sensitive than parental cells to alkylating agents treatment or UV radiation but equally sensitive to the topoisomerase I inhibitor topotecan, which indicated that the increase in expression of DNA repair genes has implications for the response to DNA damaging agents.


Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.
Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.


PRR11 Is a Prognostic Marker and Potential Oncogene in Patients with Gastric Cancer.
PRR11 is a potential candidate oncogene that has been implicated in the pathogenesis of lung cancer, however the role of PRR11 in gastric cancer is currently unclear. In the present study, we investigated the role of PRR11 in gastric cancer by evaluating its expression status in samples from a cohort of 216 patients with gastric cancer. PRR11 was found to be overexpressed in 107 (49.5%) patients by immunohistochemistry of tissue microarrays generated using the patient samples. Furthermore, PRR11 overexpression was found to correlate significantly with clinicopathologic features such as tumor invasion, tumor differentiation, and disease stage. Survival analysis of the cohort revealed that PRR11 is an independent prognostic factor for gastric cancer patients. PRR11 was stably silenced in a gastric carcinoma cell line using an shRNA-based approach, and treated cells showed decreased cellular proliferation and colony formation in vitro and cell growth in vivo, companied by decreased expression of CTHRC1 and increased expression of LXN, proteins involved in tumor progression. Evaluation of human gastric cancer samples demonstrated that PRR11 expression was also associated with increased CTHRC1 and decreased LXN expression. These data indicate that PRR11 may be widely activated in human gastric cancer and are consistent with the hypothesis that PRR11 functions as an oncogene in the development and progression of gastric cancer.


Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily.
Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients. We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets. Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules. Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes, or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1r C57BL/6 (B6, resistant) and Cmv1s DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1. We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).


Practising evidence-based medicine: the design and implementation of a multidisciplinary team-driven extubation protocol.
Evidence from recent literature shows that protocol-directed extubation is a useful approach to liberate patients from mechanical ventilation (MV). However, research evidence does not necessarily provide guidance on how to implement changes in individual intensive care units (ICUs). We conducted the present study to determine whether such an evidence-based strategy can be implemented safely and effectively using a multidisciplinary team (MDT) approach. We designed a MDT-driven extubation protocol. Multiple meetings were held to encourage constructive criticism of the design by attending physicians, nurses and respiratory care practitioners (RCPs), in order to define a protocol that was evidence based and acceptable to all clinical staff involved in the process of extubation. It was subsequently implemented and evaluated in our medical/ surgical ICU. Outcomes included response of the MDT to the initiative, duration of MV and stay in the ICU, as well as reintubation rate. The MDT responded favourably to the design and implementation of this MDT-driven extubation protocol, because it provided greater autonomy to the staff. Outcomes reported in the literature and in the historical control group were compared with those in the protocol group, and indicated similar durations of MV and ICU stay, as well as reintubation rates. No adverse events were documented. An MDT approach to protocol-directed extubation can be implemented safely and effectively in a multidisciplinary ICU. Such an effort is viewed favourably by the entire team and is useful in enhancing team building.


From near-infrared and Raman to surface-enhanced Raman spectroscopy: progress, limitations and perspectives in bioanalysis.
Over recent decades, spreading environmental concern entailed the expansion of green chemistry analytical tools. Vibrational spectroscopy, belonging to this class of analytical tool, is particularly interesting taking into account its numerous advantages such as fast data acquisition and no sample preparation. In this context, near-infrared, Raman and mainly surface-enhanced Raman spectroscopy (SERS) have thus gained interest in many fields including bioanalysis. The two former techniques only ensure the analysis of concentrated compounds in simple matrices, whereas the emergence of SERS improved the performances of vibrational spectroscopy to very sensitive and selective analyses. Complex SERS substrates were also developed enabling biomarker measurements, paving the way for SERS immunoassays. Therefore, in this paper, the strengths and weaknesses of these techniques will be highlighted with a focus on recent progress.


Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion.
Defects in closure of embryonic tissues such as the neural tube, body wall, face and eye lead to severe birth defects. Cell adhesion is hypothesized to contribute to closure of the neural tube and body wall; however, potential molecular regulators of this process have not been identified. Here we identify an ENU-induced mutation in mice that reveals a molecular pathway of embryonic closure. Line2F homozygous mutant embryos fail to close the neural tube, body wall, face, and optic fissure, and they also display defects in lung and heart development. Using a new technology of genomic sequence capture and high-throughput sequencing of a 2.5Mb region of the mouse genome, we discovered a mutation in the grainyhead-like 2 gene (Grhl2). Microarray analysis revealed Grhl2 affects the expression of a battery of genes involved in cell adhesion and E-cadherin protein is drastically reduced in tissues that require Grhl2 function. The tissue closure defects in Grhl2 mutants are similar to that of AP-2α null mutants and AP-2α has been shown to bind to the promoter of E-cadherin. Therefore, we tested for a possible interaction between these genes. However, we find that Grhl2 and AP-2α do not regulate each other's expression, E-cadherin expression is normal in AP-2α mutants during neural tube closure, and Grhl2;AP-2α trans-heterozygous embryos are morphologically normal. Taken together, our studies point to a complex regulation of neural tube fusion and highlight the importance of comparisons between these two models to understand more fully the molecular pathways of embryonic tissue closure.


Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease.
In this study we segment the hippocampus according to functional connectivity assessed from resting state functional magnetic resonance images in healthy subjects and in patients with Alzheimer's disease (AD). We recorded the resting FMRI signal from 16 patients and 22 controls. We used seed-based functional correlation analyses to calculate partial correlations of all voxels in the hippocampus relative to characteristic regional signal changes in the thalamus, the prefrontal cortex (PFC) and the posterior cingulate cortex (PCC), while controlling for ventricular CSF and white matter signals. Group comparisons were carried out controlling for age, gender, hippocampal volume and brain volume. The strength of functional connectivity in each region also was correlated with neuropsychological measures. We found that the hippocampus can be segmented into three distinct functional subregions (head, body, and tail), according to the relative connectivity with PFC, PCC and thalamus, respectively. The AD group showed stronger hippocampus-PFC and weaker hippocampus-PCC functional connectivity, the magnitudes of which correlated with MMSE in both cases. The results are consistent with an adaptive role of the PFC in the context of progression of dysfunction in PCC during earlier stages of AD. Extension of our approach could integrate regional volume measures for the hippocampus with their functional connectivity patterns in ways that should increase sensitivity for assessment of AD onset and progression.


Researching Complex and Multi-Level Workplace Factors Affecting Disability and Prolonged Sickness Absence.
Purpose There is growing research evidence that workplace factors influence disability outcomes, but these variables reflect a variety of stakeholder perspectives, measurement tools, and methodologies. The goal of this article is to summarize existing research of workplace factors in relation to disability, compare this with employer discourse in the grey literature, and recommend future research priorities. Methods The authors participated in a year-long collaboration that ultimately led to an invited 3-day conference, "Improving Research of Employer Practices to Prevent Disability, held October 14-16, 2015, in Hopkinton, Massachusetts, USA. The collaboration included a topical review of the literature, group conference calls to identify key areas and challenges, drafting of initial documents, review of industry publications, and a conference presentation that included feedback from peer researchers and a question/answer session with a special panel of knowledge experts with direct employer experience. Results Predominant factors in the scientific literature were categorized as physical or psychosocial job demands, work organization and support, and workplace beliefs and attitudes. Employees experiencing musculoskeletal disorders in large organizations were the most frequently studied population. Research varied with respect to the basic unit of assessment (e.g., worker, supervisor, policy level) and whether assessments should be based on worker perceptions, written policies, or observable practices. The grey literature suggested that employers focus primarily on defining roles and responsibilities, standardizing management tools and procedures, being prompt and proactive, and attending to the individualized needs of workers. Industry publications reflected a high reliance of employers on a strict biomedical model in contrast to the more psychosocial framework that appears to guide research designs. Conclusion Assessing workplace factors at multiple levels, within small and medium-sized organizations, and at a more granular level may help to clarify generalizable concepts of organizational support that can be translated to specific employer strategies involving personnel, tools, and practices.


Antinociceptive and anti-inflammatory effect of sulfated polysaccharide fractions from Sargassum wightii and Halophila ovalis in male Wistar rats.
The aim of this objective is to evaluate the antinociceptive and anti-inflammatory potential of sulfated polysaccharide purified fractions isolated from brown seaweed Sargassum wightii and seagrass Halophila ovalis in male Wistar rats. Crude sulfated polysaccharide from S. wightii and H. ovalis was subjected to anion exchange chromatography, and the chemical composition was investigated. The antinociceptive activity of purified fractions was investigated using formalin and hot plate test. Carrageenan-induced paw edema, peritonitis model, and Freund's Complete Adjuvant-induced arthritis model were employed to determine the anti-inflammatory activity. In the formalin test, there was a significant reduction in licking time in both phases of the test at a dose of 10 mg/kg. In the hot plate test, the antinociceptive effect was observed only in animals treated with 5, 10 mg/kg suggesting that the analgesic effect occurs through a central action mechanism. Sw FrIV and Ho FrIV significantly inhibited paw edema induced by carrageenan, especially at 3 h after treatment and potentially decreased neutrophil migration at 10 mg/kg, respectively. In Freund's adjuvant-induced arthritic rats, a significant reduction in paw volume was observed in Sw FrIV and Ho FrIV-treated groups (10 mg/kg). Purified components from S. wightii and H. ovalis have strong antinociceptive and anti-inflammatory effect on animal model. However, to determine the molecular mechanism, it is necessary to investigate the effect of purified fractions on inhibition of nitric oxide synthase expression mediated by inhibiting the phosphorylation of various signal proteins in lipopolysaccharide-stimulated RAW264.7 cells.


PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.
Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients. However, a substantial proportion of patients eventually becomes refractory due to drug resistance. The detailed mechanisms remain unclear. We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC. In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway. Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo. Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay. The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression. Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo. Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy. Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo. Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.


Development and characterization of Brassica juncea--fruticulosa introgression lines exhibiting resistance to mustard aphid (Lipaphis erysimi Kalt).
Mustard aphid is a major pest of Brassica oilseeds. No source for aphid resistance is presently available in Brassica juncea. A wild crucifer, Brassica fruticulosa is known to be resistant to mustard aphid. An artificially synthesized amphiploid, AD-4 (B. fruticulosa × B. rapa var. brown sarson) was developed for use as a bridge species to transfer fruticulosa resistance to B. juncea. Using the selfed backcross we could select a large number of lines with resistance to mustard aphid. This paper reports cytogenetic stability of introgression lines, molecular evidence for alien introgression and their reaction to mustard aphid infestation. Majority of introgression lines had expected euploid chromosome number(2n= 36), showed normal meiosis and high pollen grain fertility. Well-distributed and transferable simple-sequence repeats (SSR) markers for all the 18 B. juncea chromosomes helped to characterize introgression events. Average proportions of recipient and donor genome in the substitution lines were 49.72 and 35.06%, respectively. Minimum alien parent genome presence (27.29%) was observed in the introgression line, Ad3K-280 . Introgressed genotypes also varied for their resistance responses to mustard aphid infestations under artificial release conditions for two continuous seasons. Some of the test genotypes showed consistent resistant reaction. B.juncea-fruticulosa introgression set may prove to be a very powerful breeding tool for aphid resistance related QTL/gene discovery and fine mapping of the desired genes/QTLs to facilitate marker assisted transfer of identified gene(s) for mustard aphid resistance in the background of commercial mustard genotypes.


Latest results from the UK trials evaluating prostate cancer screening and treatment: the CAP and ProtecT studies.
The European Randomised Study of Screening for Prostate Cancer (ERSPC) demonstrated a significant reduction in prostate cancer-specific mortality. The ongoing Comparison Arm for ProtecT (CAP) cluster randomised controlled trial (RCT) evaluates prostate cancer screening effectiveness by comparing primary care centres allocated to a round of prostate specific antigen (PSA) testing (intervention) or standard clinical care. Over 550 centres (around 450,000 men) were randomised in eight United Kingdom areas (2002-2008). Intervention group participants were also eligible for the ProtecT (Prostate testing for cancer and Treatment) RCT evaluating active monitoring, radiotherapy and radical prostatectomy treatments for localised prostate cancer. In ProtecT, over 1500 of around 3000 men with prostate cancer were randomised from over 10,000 with an elevated PSA in around 111,000 attendees at clinics. Investigation of the psychological impact of screening in a sub-sample showed that 10% of men still experienced high distress up to 3 months following prostate biopsies (22/227), although most were relatively unaffected. The risk of prostate cancer with a raised PSA was lower if urinary symptoms were present (frequent nocturia odds ratio (OR) 0.44, 95% confidence interval (CI) 0.22-0.83) or if a repeat PSA decreased by > or = 20% prior to biopsy (OR 0.43, 95% CI 0.35-0.52). Men aged 45-49 years attended PSA clinics less frequently (442/1299, 34%) in a nested cohort with a cancer detection rate of 2.3% (10/442). The CAP and ProtecT trials (ISRCTN92187251 and ISRCTN20141217) will help resolve the prostate cancer screening debate, define the optimum treatment for localised disease and generate evidence to improve men's health.


Clinical Framework and Medical Countermeasure Use During an Anthrax Mass-Casualty Incident.
In 2014, CDC published updated guidelines for the prevention and treatment of anthrax (Hendricks KA, Wright ME, Shadomy SV, et al. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20[2]. Available at http://wwwnc.cdc.gov/eid/article/20/2/13-0687_article.htm). These guidelines provided recommended best practices for the diagnosis and treatment of persons with naturally occurring or bioterrorism-related anthrax in conventional medical settings. An aerosolized release of Bacillus anthracis spores over densely populated areas could become a mass-casualty incident. To prepare for this possibility, the U.S. government has stockpiled equipment and therapeutics (known as medical countermeasures [MCMs]) for anthrax prevention and treatment. However, previously developed, publicly available clinical recommendations have not addressed the use of MCMs or clinical management during an anthrax mass-casualty incident, when the number of patients is likely to exceed the ability of the health care infrastructure to provide conventional standards of care and supplies of MCMs might be inadequate to meet the demand required. To address this gap, in 2013, CDC conducted a series of systematic reviews of the scientific literature on anthrax to identify evidence that could help clinicians and public health authorities set guidelines for intravenous antimicrobial and antitoxin use, diagnosis of anthrax meningitis, and management of common anthrax-specific complications in the setting of a mass-casualty incident. Evidence from these reviews was presented to professionals with expertise in anthrax, critical care, and disaster medicine during a series of workgroup meetings that were held from August 2013 through March 2014. In March 2014, a meeting was held at which 102 subject matter experts discussed the evidence and adapted the existing best practices guidance to a clinical use framework for the judicious, efficient, and rational use of stockpiled MCMs for the treatment of anthrax during a mass-casualty incident, which is described in this report. This report addresses elements of hospital-based acute care, specifically antitoxins and intravenous antimicrobial use, and the diagnosis and management of common anthrax-specific complications during a mass-casualty incident. The recommendations in this report should be implemented only after predefined triggers have been met for shifting from conventional to contingency or crisis standards of care, such as when the magnitude of cases might lead to impending shortages of intravenous antimicrobials, antitoxins, critical care resources (e.g., chest tubes and chest drainage systems), or diagnostic capability. This guidance does not address primary triage decisions, anthrax postexposure prophylaxis, hospital bed or workforce surge capacity, or the logistics of dispensing MCMs. Clinicians, hospital administrators, state and local health officials, and planners can use these recommendations to assist in the development of crisis protocols that will ensure national preparedness for an anthrax mass-casualty incident.


Visual clutter causes high-magnitude errors.
Perceptual decisions are often made in cluttered environments, where a target may be confounded with competing "distractor" stimuli. Although many studies and theoretical treatments have highlighted the effect of distractors on performance, it remains unclear how they affect the quality of perceptual decisions. Here we show that perceptual clutter leads not only to an increase in judgment errors, but also to an increase in perceived signal strength and decision confidence on erroneous trials. Observers reported simultaneously the direction and magnitude of the tilt of a target grating presented either alone, or together with vertical distractor stimuli. When presented in isolation, observers perceived isolated targets as only slightly tilted on error trials, and had little confidence in their decision. When the target was embedded in distractors, however, they perceived it to be strongly tilted on error trials, and had high confidence of their (erroneous) decisions. The results are well explained by assuming that the observers' internal representation of stimulus orientation arises from a nonlinear combination of the outputs of independent noise-perturbed front-end detectors. The implication that erroneous perceptual decisions in cluttered environments are made with high confidence has many potential practical consequences, and may be extendable to decision-making in general.


Influence of C-terminal amidation on the efficacy of modelin-5.
To gain insight into the effects of amidation on the mechanism of membrane interaction, we studied two peptides modelin-5-COOH and modelin-5-CONH(2) and found they exhibit high surface activities (23.2 and 27.1 mN/m, respectively). When they were tested against Escherichia coli, amidation was seen to increase efficacy approximately 10-fold. Our results demonstrated that both peptides adopted low levels of α-helix in solution (<20%); however, in the presence of E. coli lipid extract, modelin-5-CONH(2) had a greater propensity (69%) than modelin-5-COOH (32%) to generate α-helical structure. The binding coefficient for both peptides was ∼10 μM, and the Hill coefficient approximated 1, suggesting that for both peptides the interactions with E. coli membranes were monomeric and comparable in strength. The peptides showed a clear preference for anionic lipid, with monolayer data showing that enhanced levels of helicity were associated with a greater pressure change (∼6 mN/m). Use of fluorescein-phosphatidylethanolamine showed the amidated version was able to generate greater levels of membrane disruption, which was confirmed by thermodynamic analysis. The data would imply that both peptides are able to initially bind to bilayer structures, but upon binding, the amidation stabilizes helix formation. This would be expected to help overcome a key rate-limiting step and generate higher local concentrations of peptide at the bilayer interface, which in turn would be predicted to increase efficacy.


Global dynamics of bipedal macaques during grounded and aerial running.
Macaques trained to perform bipedally use grounded running, skipping and aerial running, but avoid walking. The preference for grounded running across a wide range of speeds is substantially different from the locomotion habits observed in humans, which may be the result of differences in leg compliance. In the present study, based on kinematic and dynamic observations of three individuals crossing an experimental track, we investigated global leg properties such as leg stiffness and viscous damping during grounded and aerial running. We found that, in macaques, similar to human and bird bipedal locomotion, the vector of the ground reaction force is directed from the center of pressure (COP) to a virtual pivot point above the center of mass (COM). The visco-elastic leg properties differ for the virtual leg (COM-COP) and the effective leg (hip-COP) because of the position of the anatomical hip with respect to the COM. The effective leg shows damping in the axial direction and positive work in the tangential component. Damping does not prevent the exploration of oscillatory modes. Grounded running is preferred to walking because of leg compliance. The transition from grounded to aerial running is not accompanied by a discontinuous change. With respect to dynamic properties, macaques seem to be well placed between bipedal specialists (humans and birds). We speculate that the losses induced in the effective leg by hip placement and slightly pronograde posture may not pay off by facilitating stabilization, making bipedal locomotion expensive and insecure for macaques.


DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels.
Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5'-cytosine-phosphate-guanine-3' (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations (P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.


Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data.
Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. We used individual records from 13 European cohort studies (1985-2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. 30,214 (15%) of 197,473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10-1·37). This effect estimate was higher in published (1·43, 1·15-1·77) than unpublished (1·16, 1·02-1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15-1·48) and 5 years (1·30, 1·13-1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.


Follow-up study of implants with turned or oxidized surfaces placed after sinus augmentation.
To compare long-term survival and clinical outcomes of endosseous implants with different surface characteristics in patients with sinus elevation procedures, autologous bone grafting, and delayed implant placement. Implant survival, peri-implant soft tissue conditions, marginal bone level, intrasinus apical bone level, and sinus health were studied in patients subjected to autologous bone graft and delayed placement of implants with turned or oxidized surfaces. After a minimum of 5 years of functional loading, all patients were clinically examined regarding gingival pocket depth (PD) and bleeding on probing (BoP). The marginal bone level (MBL) was measured in intraoral radiographs. Cone beam computed tomography was used to evaluate the apical bone level (ABL) of the implants and intrasinus conditions. Twenty-eight patients received sinus elevation and a total of 92 dental implants. Thirteen patients received 47 implants with a turned surface, and 15 patients received 45 implants with an oxidized surface. Mean follow-up was 10 years (range, 5 to 19 years). No significant difference was found between the two implant surfaces in terms of PD, BoP, MBL, or ABL. Four patients (14%) exhibited radiographic signs of sinus pathology, with opacification, polyp-like structures, and thickening of the sinus membrane. Radiographic signs of sinus pathology were not correlated to implant survival or to the investigated parameters. Grafting of the maxillary sinus floor with intraorally harvested bone and delayed placement of either turned or oxidized implants results in equally high long-term survival rates, stable marginal and apical bone levels, and good peri-implant soft tissue health.


Sustained delivery of nicotinamide limits cortical injury and improves functional recovery following traumatic brain injury.
Previously, we have demonstrated that nicotinamide (NAM), a neuroprotective soluble B-group vitamin, improves recovery of function following traumatic brain injury (TBI). However, no prior studies have examined whether NAM is beneficial following continuous infusions over 7 days post-TBI. The purpose of this study was to investigate the preclinical efficacy of NAM treatment as it might be delivered clinically; over several days by slow infusion. Rats were prepared with either unilateral controlled cortical impact (CCI) injuries or sham procedures and divided into three groups: CCI-NAM, CCI-vehicle, and sham. Thirty minutes following CCI, Alzet osmotic mini-pumps were implanted subcutaneously. NAM was delivered at a rate of 50 mg/kg/day for 7 days immediately post-CCI. On day 7 following injury, the pumps were removed and blood draws were collected for serum NAM and nicotinamide adenine dinucleotide (NAD+) analyses. Starting on day 2 post-CCI, animals were tested on a battery of sensorimotor tests (bilateral tactile adhesive removal, locomotor placing, and limb-use asymmetry). Continuous infusion of NAM resulted in a significant serum elevation in NAM, but not NAD+. Statistical analyses of the tactile removal and locomotor placing data revealed that continuous administration of NAM significantly reduced the initial magnitude of the injury deficit and improved overall recovery compared to the vehicle-treated animals. NAM treatment also significantly decreased limb-use asymmetries compared to vehicle-treated animals. The overall extent of the cortical damage was also reduced by NAM treatment. No detrimental effects were seen following continuous infusion. The present results suggest that NAM delivered via a clinically relevant therapeutic regimen may truncate behavioral damage following TBI. Thus our results offer strong support for translation into the clinical population.


The value of magnetic resonance imaging in the detection of type II hemorrhagic lacunes.
Lacunar infarcts (lacunes) are small necrotic/cystic lesions of the brain associated with hypertension. Many are clinically silent, but some are associated with localizing symptoms and signs. Lacunes recently were classified into three types, namely, those resulting from small infarcts (type I), those arising as small hemorrhages (type II), and those due to dilatation of perivascular spaces (type III). The type II lacunes are thought to be much less common than those of type I. Type II lacunes have not previously been reported during life. We report a case of subacute type II lacune in the pontine tegmentum that was detected by magnetic resonance imaging and later verified by histopathologic examination. The patient was hypertensive and had numerous other type I lacunes. This case shows that the magnetic resonance imaging features of hemorrhagic lacunes are identical to those of small hemorrhages or small hemorrhagic infarcts and that magnetic resonance imaging is a useful tool in the detection of lacunes and their correlation with clinical neurologic symptoms and signs.


eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling.
The Drosophila melanogaster genes Passover and l(1)ogre and the Caenorhabditis elegans gene unc-7 define a gene family whose function is not known. We have isolated and characterized the C. elegans gene eat-5, which is required for synchronized pharyngeal muscle contractions, and find that it is a new member of this family. Simultaneous electrical and video recordings reveal that in eat-5 mutants, action potentials of muscles in the anterior and posterior pharynx are unsynchronized. Injection of carboxyfluorescein into muscles of the posterior pharynx demonstrates that all pharyngeal muscles are dye-coupled in wild-type animals; in eat-5 mutants, however, muscles of the anterior pharynx are no longer dye-coupled to posterior pharyngeal muscles. We show that a gene fusion of eat-5 to the green fluorescent protein is expressed in pharyngeal muscles. unc-7 and eat-5 are two of at least sixteen members of this family in C. elegans as determined by database searches and PCR-based screens. The amino acid sequences of five of these members in C. elegans have been deduced from cDNA sequences. Polypeptides of the family are predicted to have four transmembrane domains with cytoplasmic amino and carboxyl termini. We have constructed fusions of one of these polypeptides with beta-galactosidase and with green fluorescent protein. The fusion proteins appear to be localized in a punctate pattern at or near plasma membranes. We speculate that this gene family is required for the formation of gap junctions.


Vascular resistance and Kf in normal and PMA-injured rabbit lungs: effects of adenosine.
The effects of adenosine (ADO) on pulmonary vascular resistance (PVR) distribution, vascular compliance (C), and permeability were determined in normal and PMA-injured isolated rabbit lungs perfused with a 1:1 mixture of 6% albumin in Krebs-Henseleit buffer and autologous blood. ADO or vehicle was continuously infused into the reservoir at 1,4, or 5 mumol/min after a 1-mumol bolus of ADO or vehicle. The capillary filtration coefficient (Kf) and arterial, venous, and double occlusion pressures were measured at baseline and 30 min after phorbol myristate acetate (PMA; 4 x 10(-8) M) or vehicle. Perfusate differential and total leukocyte counts as well as adenine nucleotides, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) concentrations were determined at each measurement period. ADO was recovered as hypoxanthine and inosine in the perfusate. ADO alone did not alter PVR, C, Kf, or TxB2 but reduced 6-keto-PGF1 alpha levels. PMA induced an increase in Kf (0.024 +/- 0.002 to 0.040 +/- 0.006 g.cmH2O-1.min-1, P less than 0.05) that was completely blocked by 4 or 5 mumol/min ADO. PVR increased by 63 +/- 11% after PMA, primarily in the arteries and arterial and venous microvessels. The postcapillary resistance increase was blunted by 4 mumol/min ADO; 5 mumol/min ADO prevented the PVR increase in all segments. ADO did not affect the initial adherence of neutrophils in the lung or the PMA-induced 87 +/- 2% decrease in circulating leukocytes (greater than 98% lymphocytes) or threefold increase in TxB2 levels. These results suggest that protection by ADO is not mediated by the altering of cyclooxygenase products or by leukocyte adherence.


Alpha-actinin from sea urchin eggs: biochemical properties, interaction with actin, and distribution in the cell during fertilization and cleavage.
A protein similar to alpha-actinin has been isolated from unfertilized sea urchin eggs. This protein co-precipitated with actin from an egg extract as actin bundles. Its apparent molecular weight was estimated to be approximately 95,000 on an SDS gel: it co-migrated with skeletal-muscle alpha-actinin. This protein also co-eluted with skeletal muscle alpha-actinin from a gel filtration column giving a Stokes radius of 7.7 nm, and its amino acid composition was very similar to that of alpha-actinins. It reacted weakly but significantly with antibodies against chicken skeletal muscle alpha-actinin. We designated this protein as sea urchin egg alpha-actinin. The appearance of sea urchin egg alpha-actinin as revealed by electron microscopy using the low-angle rotary shadowing technique was also similar to that of skeletal muscle alpha-actinin. This protein was able to cross-link actin filaments side by side to form large bundles. The action of sea urchin egg alpha-actinin on the actin filaments was studied by viscometry at a low-shear rate. It gelled the F-actin solution at a molar ratio to actin of more than 1:20, at pH 6-7.5, and at Ca ion concentration less than 1 microM. The effect was abolished by the presence of tropomyosin. Distribution of this protein in the egg during fertilization and cleavage was investigated by means of microinjection of the rhodamine-labeled protein in the living eggs. This protein showed a uniform distribution in the cytoplasm in the unfertilized eggs. Upon fertilization, however, it was concentrated in the cell cortex, including the fertilization cone. At cleavage, it seemed to be concentrated in the cleavage furrow region.


Hair-sparing whole brain radiotherapy with volumetric arc therapy in patients treated for brain metastases: dosimetric and clinical results of a phase II trial.
To report the dosimetric results and impact of volumetric arc therapy (VMAT) on temporary alopecia and hair-loss related quality of life (QOL) in whole brain radiotherapy (WBRT). The potential of VMAT-WBRT to reduce the dose to the hair follicles was assessed. A human cadaver was treated with both VMAT-WBRT and conventional opposed field (OF) WBRT, while the subcutaneously absorbed dose was measured by radiochromic films and calculated by the planning system. The impact of these dose reductions on temporary alopecia was examined in a prospective phase II trial, with the mean score of hair loss at 1 month after VMAT-WBRT (EORTC-QOL BN20) as a primary endpoint and delivering a dose of 20 Gy in 5 fractions. An interim analysis was planned after including 10 patients to rule out futility, defined as a mean score of hair loss exceeding 56.7. A secondary endpoint was the global alopecia areata severity score measured with the "Severity of Alopecia Tool" (SALT) with a scale of 0 (no hair loss) to 100 (complete alopecia). For VMAT-WBRT, the cadaver measurements demonstrated a dose reduction to the hair follicle volume of 20.5% on average and of 41.8% on the frontal-vertex-occipital medial axis as compared to OF-WBRT. In the phase II trial, a total of 10 patients were included before the trial was halted due to futility. The EORTC BN20 hair loss score following WBRT was 95 (SD 12.6). The average median dose to the hair follicle volume was 12.6 Gy (SD 0.9), corresponding to a 37% dose reduction compared to the prescribed dose. This resulted in a mean SALT-score of 75. Compared to OF-WBRT, VMAT-WBRT substantially reduces hair follicle dose. These dose reductions could not be related to an improved QOL or SALT score.


Protein-protein interactions in the tetraspanin web.
Tetraspanins are evolutionarily conserved membrane proteins that tend to associate laterally with one another and to cluster dynamically with numerous partner proteins in membrane microdomains. Consequently, members of this family are involved in the coordination of intracellular and intercellular processes, including signal transduction; cell proliferation, adhesion, and migration; cell fusion; and host-parasite interactions.


Validation and characterization of DNA microarray gene expression data distribution and associated moments.
The data from DNA microarrays are increasingly being used in order to understand effects of different conditions, exposures or diseases on the modulation of the expression of various genes in a biological system. This knowledge is then further used in order to generate molecular mechanistic hypotheses for an organism when it is exposed to different conditions. Several different methods have been proposed to analyze these data under different distributional assumptions on gene expression. However, the empirical validation of these assumptions is lacking. Best fit hypotheses tests, moment-ratio diagrams and relationships between the different moments of the distribution of the gene expression was used to characterize the observed distributions. The data are obtained from the publicly available gene expression database, Gene Expression Omnibus (GEO) to characterize the empirical distributions of gene expressions obtained under varying experimental situations each of which providing relatively large number of samples for hypothesis testing. All data were obtained from either of two microarray platforms--the commercial Affymetrix mouse 430.2 platform and a non-commercial Rosetta/Merck one. The data from each platform were preprocessed in the same manner. The null hypotheses for goodness of fit for all considered univariate theoretical probability distributions (including the Normal distribution) are rejected for more than 50% of probe sets on the Affymetrix microarray platform at a 95% confidence level, suggesting that under the tested conditions a priori assumption of any of these distributions across all probe sets is not valid. The pattern of null hypotheses rejection was different for the data from Rosetta/Merck platform with only around 20% of the probe sets failing the logistic distribution goodness-of-fit test. We find that there are statistically significant (at 95% confidence level based on the F-test for the fitted linear model) relationships between the mean and the logarithm of the coefficient of variation of the distributions of the logarithm of gene expressions. An additional novel statistically significant quadratic relationship between the skewness and kurtosis is identified. Data from both microarray platforms fail to identify with any one of the chosen theoretical probability distributions from an analysis of the l-moment ratio diagram.


Reliability and validity testing of a single-item physical activity measure.
To develop and test a new single-item physical activity screening tool, suitable for assessing respondents' eligibility for behaviour change interventions. Two single-item assessment tools were developed, one using a "past week" recall period, the other using a "past month" recall period. A quota sampling system was used to recruit 480 adults from across England, Scotland and Wales. Half the sample completed the past-week question and half completed the past-month version. Test-retest reliability was assessed over a 2- to 5-day period. Concurrent validity was assessed using the Global Physical Activity Questionnaire and the UK Active People Survey. All surveys were completed via telephone interviews. Both versions of the single-item instrument demonstrated strong reproducibility (r=0.72-0.82), using Spearman's rank correlation coefficients. The past-week recall question showed strong agreement in the classification of respondents meeting the current physical activity recommendation (kappa=0.63, 95% CI 0.54 to 0.72).Concurrent validity over the past week compared to the Global Physical Activity Questionnaire was modest (r=0.53) and slightly weaker for the past month compared to the Active People Survey (r=0.33-0.48). Both versions of the new single-item measure performed as well as other short physical activity tools in terms of reliability and concurrent validity. Criterion validity testing of the single-item measure is recommended to establish its ability to assess objectively measured physical activity levels. In addition, further research to assess the responsiveness of the single-item measure in detecting changes in physical activity will inform its usefulness in programme evaluation.


Informative Disagreements: Associations Between Relationship Distress, Depression, and Discrepancy in Interpersonal Perception Within Couples.
This study evaluated the associations between relationship distress, depression symptoms, and discrepancy in interpersonal perception within couples. After completing a series of discussion tasks, couples (N = 88) rated their behavior using the circumplex-based Structural Analysis of Social Behavior Model (SASB; Benjamin, 1979, 1987, 2000). Overall, couple members were strikingly similar in their interpersonal perceptions, and tended to see themselves as friendly, reciprocal in their focus, and balanced between connection and separateness. As hypothesized, however, perceptual discrepancy was related to relationship distress and depression. Relationship distress was associated with discrepancy regarding transitive behavior focused on the partner, while depression was associated with disagreement about intransitive, self-focused behavior. Analysis of affiliation and autonomy revealed that relationship distress was associated with seeing oneself as reacting with more hostility than the partner sees, and perceiving one's partner as more hostile, more controlling, and less submissive than he or she does. Partners of depressed individuals viewed themselves as more controlling than their mate did. Men's depression was associated with disagreement between partners regarding men's self-focused behavior. Results underscore the importance of considering interpersonal perception when conceptualizing relationship distress and depression within intimate relationships.


Growth hormone, enhancement and the pharmaceuticalisation of short stature.
This paper takes the biological drug human Growth Hormone (hGH) as a case study to investigate processes of pharmaceuticalisation and medicalisation in configuring childhood short stature as a site for pharmaceutical intervention. Human growth hormone is considered to have legitimate applications in treating childhood growth hormone deficiency and short stature associated with other recognised conditions. It is also regarded by bioethicists and others as a form of human biomedical enhancement when applied to children with idiopathic or 'normal' short stature. The purpose of this study is not to evaluate whether treatment of idiopathic short stature is enhancement or not, but to evaluate how some applications of hGH in treating short stature have come to be accepted and stabilised as legitimate 'therapies' while others remain contested as 'enhancements'. A comparative, historical approach is employed, drawing on approaches from medical sociology and Science and Technology Studies (STS) to set out a socio-technical history of hGH in the US and UK. Through this history the relative influence and interplay of drivers of pharmaceuticalisation, including industry marketing and networks of drug distribution, and processes of medicalisation will be employed to address this question and simultaneously query the value of enhancement as a sociological concept.


Joint report on terminology for surgical procedures to treat pelvic organ prolapse.
Surgeries for pelvic organ prolapse (POP) are common, but standardization of surgical terms is needed to improve the quality of investigation and clinical care around these procedures. The American Urogynecologic Society and the International Urogynecologic Association convened a joint writing group consisting of 5 designees from each society to standardize terminology around common surgical terms in POP repair including the following: sacrocolpopexy (including sacral colpoperineopexy), sacrocervicopexy, uterosacral ligament suspension, sacrospinous ligament fixation, iliococcygeus fixation, uterine preservation prolapse procedures or hysteropexy (including sacrohysteropexy, uterosacral hysteropexy, sacrospinous hysteropexy, anterior abdominal wall hysteropexy, Manchester procedure), anterior prolapse procedures (including anterior vaginal repair, anterior vaginal repair with graft, and paravaginal repair), posterior prolapse procedures (including posterior vaginal repair, posterior vaginal repair with graft, levator plication, and perineal repair), and obliterative prolapse repairs (including colpocleisis with hysterectomy, colpocleisis without hysterectomy, and colpocleisis of the vaginal vault). Each of these terms is clearly defined in this document including the required steps of the procedure, surgical variations, and recommendations for procedural terminology.


An ecosystem approach to human health and the prevention of cutaneous leishmaniasis in Tumaco, Colombia.
A study was conducted during 1996-1997 in 20 villages of Tumaco, Colombia, to evaluate the effectiveness of personal protective measures against cutaneous leishmaniasis (CL). The intervention was effective, but the high costs of the preventive measures and the lack of a more holistic approach hampered the intervention's sustainability. This paper analyzes the results using an ecosystem approach to human health. Using this approach, we found that CL has been present in the study area for a long time and affects farmers and those living closest to the forest. The forest constitutes the habitat for insect vectors (sandflies) and parasite reservoirs (wild mammals). Four spatial scales were identified in this ecosystem: residential, village, regional, and global. From the ecosystem perspective, three interventions are proposed to prevent CL in the 20 villages: improve housing construction, organize village housing in clusters, and make diagnosis and treatment of CL more accessible. The design and implementation of these interventions require active involvement by people with the disease (village inhabitants) and decision-makers (local authorities).


Mouse DNA primase plays the principal role in determination of permissiveness for polyomavirus DNA replication.
We have investigated the species-specific replication of polyomavirus DNA in the cell-free system that was established previously (Y. Murakami, T. Eki, M. Yamada, C. Prives, and J. Hurwitz, Proc. Natl. Acad. Sci. USA 83:6347-6351, 1986). Extracts from various species of cells supported polyomavirus DNA replication in a species-specific manner that was consistent with the host range specificity of polyomavirus; extracts prepared from mouse and hamster cells were active, whereas extracts prepared from human, monkey, and insect cells were inactive. The addition of DNA polymerase alpha-primase purified from mouse cells induced the replication of polyomavirus DNA in a cell-free system containing polyomavirus large tumor antigen and nonpermissive cell extracts, such as human and insect cell extracts. Isolated mouse DNA primase alone also induced polyomavirus DNA replication in human cell extracts but not in insect cell extracts, indicating that mouse DNA primase plays the principal role in determining permissiveness for polyomavirus DNA replication.


Excitonic Diffusion in InGaN/GaN Core-Shell Nanowires.
We report on the direct observation of the diffusion of carriers in graded InGaN/GaN quantum wells in a nanowire. By probing the local dynamics at the nanoscale, along the wire for different temperatures between 4 and 250 K, we conclude that this diffusion process is thermally activated. In addition, the analysis of the cathodoluminescence lifetime for different temperatures shows that the carrier motion is isotropic and does not follow the indium gradient. Our observations are interpreted in terms of a hopping process between localized states. We find that the random alloy fluctuations prevent any directional drift of excitons along the In gradient and therefore any carrier accumulation. Our results therefore confirm the potential of core-shell nanowires for lighting devices. Indeed, the short lifetime of m-plane quantum wells together with their large active area and the homogeneous distribution of carrier along the quantum well will decrease influence of any high carrier density effect on the efficiency of these light-emitting diodes.