The Combined Use of an Attractive and a Repellent Sex Pheromonal Component by a Gregarious Parasitoid.
Gregarious parasitoids usually clump their cocoons together and the adults emerge in a synchronized fashion. This makes it easy for them to find mating partners and most copulations indeed take place at the natal patch. Yet, males should leave such sites when females are no longer receptive. As yet, this decision-making process and the possible involvement of pheromones were poorly understood. Here we report on a remarkable use of attractive and repellent pheromones of the well-studied gregarious parasitoid species Cotesia glomerata (L.) (Hymenoptera: Braconidae). Virgin C. glomerata females were found to release an attractive as well as a repellent compound, which in combination arrest males on the natal patch, but after mating the females stop the production of the attractant and the males are repelled. The repellent compound was identified as heptanal, which was also released by males, probably reducing male-male competition on the natal patch. We also confirmed that the sex ratio of the emerging wasps can vary considerably among patches, depending on the relative quality of hosts and the number of females that parasitize a host. The newly revealed use of attractive and repellent pheromone compounds by C. glomerata possibly helps maximize mating success under these variable conditions.


The Effect of Early Positive Cultures on Mortality in Ventilated Trauma Patients.
The purpose was to examine the incidence of positive cultures in a highly susceptible subset of trauma patients admitted to the surgical intensive care unit (SICU) for mechanical ventilation and to examine the impact of their timing on outcomes. A retrospective review was conducted of blunt trauma patients admitted to the SICU for mechanical ventilation at a level I trauma center over a five-year period. All urine, blood, and sputum cultures were abstracted. Patients with at least one positive culture were compared with those with negative or no cultures. The primary outcome was mortality. A Cox regression model with a time-dependent variable was utilized to calculate the adjusted hazard ratio (AHR). The median age of 635 patients meeting inclusion criteria was 46 and 74.2% were male. A total of 298 patients (46.9%) had at least one positive culture, with 28.9% occurring within two days of admission. Patients with positive cultures were more likely to be severely injured with an injury severity score (ISS) ≥16 (68.5% vs. 45.1%, p < 0.001). Overall mortality was 22%. Patients who had their first positive culture within two and three days from admission had a significantly higher AHR for mortality (AHR: 14.46, p < 0.001 and AHR: 10.59, p = 0.028, respectively) compared to patients with a positive culture at day six or later. Early positive cultures are common among trauma patients requiring mechanical ventilation and are associated with higher mortality. Early identification with "damage control cultures" obtained on admission to aid with early targeted treatment might be justified.


The J-IDEA Pandemic Planner: A Framework for Implementing Hospital Provision Interventions During the COVID-19 Pandemic.
Planning for extreme surges in demand for hospital care of patients requiring urgent life-saving treatment for coronavirus disease 2019 (COVID-19), while retaining capacity for other emergency conditions, is one of the most challenging tasks faced by health care providers and policymakers during the pandemic. Health systems must be well-prepared to cope with large and sudden changes in demand by implementing interventions to ensure adequate access to care. We developed the first planning tool for the COVID-19 pandemic to account for how hospital provision interventions (such as cancelling elective surgery, setting up field hospitals, or hiring retired staff) will affect the capacity of hospitals to provide life-saving care. We conducted a review of interventions implemented or considered in 12 European countries in March to April 2020, an evaluation of their impact on capacity, and a review of key parameters in the care of COVID-19 patients. This information was used to develop a planner capable of estimating the impact of specific interventions on doctors, nurses, beds, and respiratory support equipment. We applied this to a scenario-based case study of 1 intervention, the set-up of field hospitals in England, under varying levels of COVID-19 patients. The Abdul Latif Jameel Institute for Disease and Emergency Analytics pandemic planner is a hospital planning tool that allows hospital administrators, policymakers, and other decision-makers to calculate the amount of capacity in terms of beds, staff, and crucial medical equipment obtained by implementing the interventions. Flexible assumptions on baseline capacity, the number of hospitalizations, staff-to-beds ratios, and staff absences due to COVID-19 make the planner adaptable to multiple settings. The results of the case study show that while field hospitals alleviate the burden on the number of beds available, this intervention is futile unless the deficit of critical care nurses is addressed first. The tool supports decision-makers in delivering a fast and effective response to the pandemic. The unique contribution of the planner is that it allows users to compare the impact of interventions that change some or all inputs.


Thrombolysis despite recent stroke: a case series.
Thrombolysis in ischemic stroke is contraindicated in patients who have had a stroke within 3 months. However, it is unclear whether thrombolytic therapy is associated with adverse outcomes in this population. We report the characteristics and outcomes of patients treated with systemic recombinant tissue-type plasminogen activator in the context of known or unknown recent stroke. We identified patients who received recombinant tissue-type plasminogen activator despite recent stroke (within 3 months of acute thrombolysis). Clinical and radiological findings were collected, including early neurological worsening and hemorrhagic transformation on unenhanced computed tomography at 24 hours. Clinical outcome measured by modified Rankin Scale was determined at 3 months from onset. Six patients presenting with acute stroke within 3 months of previous stroke were identified (median age, 76 years; median National Institutes of Health Stroke Scale, 8.5). Hemorrhagic transformation was seen in the follow-up computed tomography scan in 3 of 6 cases: all were hemorrhagic transformation 1 (petechial hemorrhage), asymptomatic, and mostly located within the area of subacute infarction. There was no early neurological deterioration, and 3 patients had modified Rankin Scale ≤ 2 after 3 months. In our center, we thrombolysed 6 patients despite recent stroke. Three patients had asymptomatic petechial hemorrhagic transformation within the area of subacute infarct, without apparent neurological worsening. Prospective studies are needed to explore the possible safety of tissue-type plasminogen activator in the context of previous subacute stroke in otherwise eligible patients.


Ontology of physics for biology: representing physical dependencies as a basis for biological processes.
In prior work, we presented the Ontology of Physics for Biology (OPB) as a computational ontology for use in the annotation and representations of biophysical knowledge encoded in repositories of physics-based biosimulation models. We introduced OPB:Physical entity and OPB:Physical property classes that extend available spatiotemporal representations of physical entities and processes to explicitly represent the thermodynamics and dynamics of physiological processes. Our utilitarian, long-term aim is to develop computational tools for creating and querying formalized physiological knowledge for use by multiscale "physiome" projects such as the EU's Virtual Physiological Human (VPH) and NIH's Virtual Physiological Rat (VPR). Here we describe the OPB:Physical dependency taxonomy of classes that represent of the laws of classical physics that are the "rules" by which physical properties of physical entities change during occurrences of physical processes. For example, the fluid analog of Ohm's law (as for electric currents) is used to describe how a blood flow rate depends on a blood pressure gradient. Hooke's law (as in elastic deformations of springs) is used to describe how an increase in vascular volume increases blood pressure. We classify such dependencies according to the flow, transformation, and storage of thermodynamic energy that occurs during processes governed by the dependencies. We have developed the OPB and annotation methods to represent the meaning-the biophysical semantics-of the mathematical statements of physiological analysis and the biophysical content of models and datasets. Here we describe and discuss our approach to an ontological representation of physical laws (as dependencies) and properties as encoded for the mathematical analysis of biophysical processes.


Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial.
Creatine supplementation improves glucose tolerance in healthy subjects. The aim was to investigate whether creatine supplementation has a beneficial effect on glycemic control of type 2 diabetic patients undergoing exercise training. A 12-wk randomized, double-blind, placebo-controlled trial was performed. The patients were allocated to receive either creatine (CR) (5 g·d) or placebo (PL) and were enrolled in an exercise training program. The primary outcome was glycosylated hemoglobin (HbA1c). Secondary outcomes included the area under the curve of glucose, insulin, and C-peptide and insulin sensitivity indexes. Physical capacity, lipid profile, and GLUT-4 protein expression and translocation were also assessed. Twenty-five subjects were analyzed (CR: n=13; PL: n=12). HbA1c was significantly reduced in the creatine group when compared with the placebo group (CR: PRE=7.4 ± 0.7, POST=6.4 ± 0.4; PL: PRE=7.5 ± 0.6, POST=7.6 ± 0.7; P=0.004; difference=-1.1%, 95% confidence interval=-1.9% to -0.4%). The delta area under the curve of glucose concentration was significantly lower in the CR group than in the PL group (CR=-7790 ± 4600, PL=2008 ± 7614; P=0.05). The CR group also presented decreased glycemia at times 0, 30, and 60 min during a meal tolerance test and increased GLUT-4 translocation. Insulin and C-peptide concentrations, surrogates of insulin sensitivity, physical capacity, lipid profile, and adverse effects were comparable between the groups. Creatine supplementation combined with an exercise program improves glycemic control in type 2 diabetic patients. The underlying mechanism seems to be related to an increase in GLUT-4 recruitment to the sarcolemma.


Validity and reliability of OIDP and OHIP-14: a survey of Chinese high school students.
To determine the impact of oral diseases on everyday life, measures of oral quality of life are needed. In complementing traditional disease-based measures, they assess the need for oral care to evaluate oral health care programs and management of treatment. To assess the reliability and validity of the Oral Impact of Daily Performance (OIDP) and the short-form Oral Health Impact Profile (OHIP-14) among high school students in Xi'an, the capital of Shanxi province, China. Cross-sectional one-stage stratified random cluster sample using high schools as the primary sampling unit. Students completed self-administered questionnaires at school. The survey included the OHIP-14 and OIDP inventories, translated and culturally adapted for China, and global oral health and socio-behavioral measures. A total of 5,608 students participated in the study, with a 93% response rate (mean age 17.2, SD 0.8, 52% females, 45.3% urban residents).The proportion experiencing at least one impact (at any frequency) during the previous six months was 62.9% for the OHIP-14 and 45.8% for the OIDP. Cronbach's alpha measured internal consistency at 0.85 for OHIP-14 and 0.75 for OIDP while Cohen's kappa varied between 0.27 and 0.58 for OHIP-14 items and between 0.23 and 0.65 for OIDP items. Kappa scores for the OHIP-14 and OIDP additive scores were 0.52 and 0.66, respectively. Both measures varied systematically and in the expected direction, with global oral health measures showing criterion validity. The correlation between OIDP and OHIP-14 was rs +0.65. That both measures varied systematically with socio-behavioral factors indicates construct validity. Both the OIDP and OHIP-14 inventories had reasonable reliability and construct validity in relation to subjective global oral health indicators among adolescents attending high schools in China and thus appear to be useful oral health -related quality of life measures in this context. Overall, the OHIP-14 and OIDP performed equally well, although OHIP-14 had superior content validity due to its sensitivity towards less severe impacts.


Identifying redundancy and exposing provenance in crowdsourced data analysis.
We present a system that lets analysts use paid crowd workers to explore data sets and helps analysts interactively examine and build upon workers' insights. We take advantage of the fact that, for many types of data, independent crowd workers can readily perform basic analysis tasks like examining views and generating explanations for trends and patterns. However, workers operating in parallel can often generate redundant explanations. Moreover, because workers have different competencies and domain knowledge, some responses are likely to be more plausible than others. To efficiently utilize the crowd's work, analysts must be able to quickly identify and consolidate redundant responses and determine which explanations are the most plausible. In this paper, we demonstrate several crowd-assisted techniques to help analysts make better use of crowdsourced explanations: (1) We explore crowd-assisted strategies that utilize multiple workers to detect redundant explanations. We introduce color clustering with representative selection--a strategy in which multiple workers cluster explanations and we automatically select the most-representative result--and show that it generates clusterings that are as good as those produced by experts. (2) We capture explanation provenance by introducing highlighting tasks and capturing workers' browsing behavior via an embedded web browser, and refine that provenance information via source-review tasks. We expose this information in an explanation-management interface that allows analysts to interactively filter and sort responses, select the most plausible explanations, and decide which to explore further.


Incremental value of contrast enhanced computed tomography on diagnostic accuracy in evaluation of small pulmonary ground glass nodules.
To evaluate the information gain by the application of both non-contrast and contrast enhanced computed tomography (CT) with extended mediastinal display window settings in the evaluation of pure ground glass nodules (pGGNs) and or mixed ground glass nodules (mGGNs) in the context of pre-invasive or early stage lung adenocarcinoma. One hundred and fifty patients with ground glass nodules (GGNs) and mGGNs, with contrast enhanced CT scans within 2 weeks of thoracic surgery were included in the study. Quantitative evaluation of all nodules was performed in a conventional mediastinal window (CMW) and an extended mediastinal window (EMW) both on non-contrast images and contrast-enhanced images. Contrast-enhanced images with CMW demonstrated amplification of solid portion in 23 (43%), 41 (77%) with EMW out of 53 minimally invasive adenocarcinoma (MIA) nodules, and in 34 of 37 (91%) of invasive adenocarcinoma (IAC) nodules. Using the increase in size of solid portion of the nodule measured on the enhanced CT images with EMW, area under the receiver operating characteristic (ROC) curve of 0.872 and 0.899 was utilized for differentiating between the pre-invasive nodules and MIA and between MIA and IAC nodules, respectively. Statistically significant differences existed between the pre-invasive and the MIA groups, and MIA and the IAC groups in smaller nodules (P<0.01). Comparative quantitative analysis of the pre and post contrast images can help differentiate between atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), MIAs, and IACs. Extension of the CT mediastinal window setting improves the evaluation of small GGNs, and can augment the diagnostic accuracy when evaluating small pGGNs and mGGNs.


Antibacterial potential of essential oils of Zataria multiflora and Mentha piperita, micro- and nano-formulated forms.
Plant-derived essential oils (EOs) shave many usages in health and medicine, such as antibacterial agents. The aim of this study was the improvement of antibacterial activities of two EOs using nanotechnology. Antibacterial activity was investigated on four important human pathogenic bacteria using the 96-well plate microdilution method, a quantitative approach. Eleven formulations were prepared using each of the EOs. Eventually, the best nanoformulation with the smallest particle size and polydispersive indices (PDI and SPAN) was selected using each EO for further investigations. Moreover, two microemulsions with similar ingredients and the same portion in comparison with two selected nanoemulsions were also prepared. Antibacterial activity of each EO was compared with its micro- and nano-emulsions. The antibacterial efficacy of Zataria multiflora EO (ZMEO) was significantly better than Mentha piperita EO (MPEO). Besides, the antibacterial activity of nanoemulsion of ZMEO with a particle size of 129 ± 12 nm was significantly better than no- and micro-formulated forms of ZMEO. Interestingly, the efficiency of MPEO nanoemulsion (160 ± 25 nm) was also significantly better than MPEO and its micro-formulated form. Regardless of the intrinsic antibacterial property of two examined EOs, by formulating to nanoemulsion, their efficiencies were improved. Nanoemulsion of ZMEO introduced as an inexpensive, potent and green antibacterial agent.


Corrosion and late infection causing delayed paraparesis after spinal instrumentation.
A 28-year-old female patient came to our hospital 14 years after surgical correction of adolescent idiopathic scoliosis with a 316L stainless-steel instrumentation. She presented progressive paraparesis during the last 2 months. Plain radiography, computed tomography scan and computed tomography-scan-guided needle biopsy revealed that a metallotic mass penetrated into the spinal canal, causing compression of the spinal cord at the T5-T6 level. The patient's symptoms were related to corrosion of the implant and infection by Propionibacterium acnes. Through a posterior approach, the instrumentation was retrieved and the metallotic mass and tissues were excised. Six months after the surgery, the patient is completely asymptomatic. Corrosion of stainless-steel implants is a finding more common than supposed. Biocorrosion--or microbially influenced corrosion--is a concept to be taken into account. It is possible that bacteria may modify the rate of corrosion of metals. Early diagnosis of corrosion is essential in order to prevent cases like the one we report, and perhaps, as suggested for total hip arthroplasties, metal levels could be useful to monitor spinal implants.


Tires as habitats for mosquitoes: a review of studies within the eastern United States.
Discarded vehicle tires are a common habitat for a variety of container mosquito species. I reviewed the literature from the last 50 yr on mosquitoes collected within tires in the eastern United States with four objectives: to examine the historical and contemporary issues of tires as a habitat for mosquitoes, to identify tire-inhabiting species, to summarize findings from studies that focused on biotic and abiotic characteristics of tires, and to offer future directions to aid our understanding of tire-inhabiting mosquitoes. Thirty-two species have been documented, including seven invasives, with the most frequently encountered being Aedes triseriatus, Ae. albopictus, Ae. atropalpus, Culex restuans, Cx. pipiens, Cx. territans, Anopheles punctipennis, and Toxorhynchites rutilus. The proclivity of these species to occupy small containers is one possible explanation for their occurrence in tires. The native species Ae. triseriatus was abundant and the most often collected, particularly in central and northern regions, whereas the invasive Ae. albopictus was most abundant in the south. One half of the studies investigating aspects of the tire environment compared mosquito populations between sunlit and shaded tires, with the general finding that this factor alone led to dramatic differences in larval species composition and abundance patterns. Less frequently investigated factors, e.g., tire orientation, detritus, and proximity to humans, also were found to affect patterns of occupancy by mosquitoes. For the future, I suggest more surveys are needed in understudied areas, as well as quantitative experiments to determine habitat associations and community dynamics in tires, which are especially necessary to assist in understanding invasions. Discarded tires are important for studies of vector dynamics, because of their abundance near human populations and because they expand the habitat range of mosquitoes that vector pathogens.


Impact of Medical Scribes in Primary Care on Productivity, Face-to-Face Time, and Patient Comfort.
Medical scribes are a clinical innovation increasingly being used in primary care. The impact of scribes in primary care remain unclear. We aimed to examine the impact of medical scribes on productivity, time spent facing the patient during the visit, and patient comfort with scribes in primary care. We conducted a prospective observational pre-post study of 5 family and internal medicine-pediatrics physicians and their patients at an urban safety net health clinic. Medical scribes accompanied providers in the examination room and documented the clinical encounter. After an initial phase-in period, we added an additional 20-minute patient slot per 200-minute session. We examined productivity by using electronic medical record data on the number of patients seen and work relative value units (work RVUs) per hour. We directly observed clinical encounters to measure the amount of time providers spent facing patients and other visit components. We queried patient comfort with scribes by using surveys administered after the visit. Work RVUs per hour increased by 10.5% from 2.59 prescribe to 2.86 post-scribe (P < .001). Patients seen per hour increased by 8.8% from 1.82 to 1.98 (P < .001). Work RVUs per patient did not change. After scribe implementation, time spent facing the patient increased by 57% (P < .001) and time spent facing the computer decreased by 27% (P = .003). The proportion of the visit time that was spent face-to-face increased by 39% (P < .001). Most (69%) patients reported feeling very comfortable with the scribe in the room, while the proportion feeling very comfortable with the number of people in the room decreased from 93% to 66% (P < .001). Although the full implications of medical scribe implementation remain to be seen, this initial study highlights the promising opportunity of medical scribe implementation in primary care.


Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma.
Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM. In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity. MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor, selectively impairs chemotherapy-resistant MPM cells by activating the PERK/eIF2α/ATF4-mediated UPR and augmenting apoptosis. We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.


Inhibition of glucose-stimulated insulin release by alpha 2-adrenoceptor activation is parallelled by both a repolarization and a reduction in cytoplasmic free Ca2+ concentration.
Effects of the alpha 2-adrenergic agonist clonidine on insulin release, membrane potential, and cytoplasmic free Ca2+ concentration ([Ca2+]i) were investigated using pancreatic beta-cells isolated from obese hyperglycemic mice. Addition of 2 microM clonidine promptly inhibited glucose-stimulated insulin release, an effect accompanied by a lowering in both membrane potential and [Ca2+]i. Within minutes, the effect on Ca2+ was partly reversed, [Ca2+]i attaining a new level, although still significantly lower than in the absence of agonist. This late increase in [Ca2+]i was inhibited by 50 microM D-600, a blocker of voltage-activated Ca2+ channels. The inhibitory effects of clonidine on membrane potential, [Ca2+]i, and insulin release were abolished by 5 microM of the alpha 2-adrenergic antagonist yohimbine. Depolarization with high K+ increased [Ca2+]i also in the presence of clonidine, conditions accompanied by only a minute release of insulin. Secretion was, however, partly restored by subsequent addition of 20 mM glucose. Addition of 5 mM Ca2+ transiently reversed the effects of clonidine on both membrane potential and [Ca2+]i. Although the clonidine-induced repolarization should be enough for closing the voltage-activated Ca2+ channels with a resulting decrease in [Ca2+]i, a direct interaction of the agonist with these channels cannot be excluded. The fact that it was possible to increase [Ca2+]i with only a minor effect on insulin release suggests that the inhibitory effect of clonidine not only is due to a reduction in [Ca2+]i, but also involves interference with some more distal step in the insulin secretory machinery.


Automated and rapid identification of multidrug resistant Escherichia coli against the lead drugs of acylureidopenicillins, cephalosporins, and fluoroquinolones using specific Raman marker bands.
A Raman-based, strain-independent, semi-automated method is presented that allows the rapid (<3 hours) determination of antibiotic susceptibility of bacterial pathogens isolated from clinical samples. Applying a priori knowledge about the mode of action of the respective antibiotic, we identified characteristic Raman marker bands in the spectrum and calculated batch-wise weighted sum scores from standardized Raman intensity differences between spectra of antibiotic exposed and nonexposed samples of the same strains. The lead substances for three relevant antibiotic classes (fluoroquinolone ciprofloxacin, third-generation cephalosporin cefotaxime, ureidopenicillin piperacillin) against multidrug-resistant Gram-negative bacteria (MRGN) revealed a high sensitivity and specificity for the susceptibility testing of two Escherichia coli laboratory strains and 12 clinical isolates. The method benefits from the parallel incubation of control and treated samples, which reduces the variance due to alterations in cultivation conditions and the standardization of differences between batches leading to long-term comparability of Raman measurements.


Three-dimensional cancer-bone metastasis model using ex-vivo co-cultures of live calvarial bones and cancer cells.
One of the major limitations of studying cancer-bone metastasis has been the lack of an appropriate ex-vivo model which can be used under defined conditions that simulates closely the in vivo live bone microenvironment in response to cancer-bone interactions. We have developed and utilized a three-dimensional (3D) cancer-bone metastasis model using free-floating live mouse calvarial bone organs in the presence of cancer cells in a roller tube system. In such co-cultures under hypoxia and a specifically defined bone remodeling stage, viz., resorption system, cancer cells showed a remarkable affinity and specificity for the "endosteal side" of the bone where they colonize and proliferate. This was concurrent with differentiation of resident stem/progenitor cells to osteoclasts and bone resorption. In contrast, under bone formation conditions this model revealed different pathophysiology where the breast cancer cells continued to induce osteoclastic bone resorption whereas prostate cancer cells led to osteoblastic bone formation. The current 3D model was used to demonstrate its application to studies involving chemical and biochemical perturbations in the absence and presence of cancer cells and cellular responses. We describe proof-of-principle with examples of the broad versatility and multi-faceted application of this model that adds another dimension to the ongoing studies in the cancer-bone metastasis arena.


Subclinical Vascular Disease and Subsequent Erectile Dysfunction: The Multiethnic Study of Atherosclerosis (MESA).
The association between subclinical cardiovascular disease and subsequent development of erectile dysfunction (ED) remains poorly described. Among multiple subclinical atherosclerosis and vascular dysfunction measurements, coronary artery calcium (CAC) score best predicts ED. After excluding participants taking ED medications at baseline, we studied 1862 men age 45 to 84 years free of known cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA) with comprehensive baseline subclinical vascular disease phenotyping and ED status assessed at MESA visit 5 (9.4 ± 0.5 years after baseline) using a standardized question on ED symptoms. Multivariable logistic regression was used to assess the associations between baseline measures of vascular disease (atherosclerosis domain: CAC, carotid intima-media thickness, carotid plaque, ankle-brachial index; vascular stiffness/function domain: aortic stiffness, carotid stiffness, brachial flow-mediated dilation) and ED symptoms at follow-up. Mean baseline age was 59.5 ± 9 years, and 839 participants (45%) reported ED symptoms at follow-up. Compared with symptom-free individuals, participants with ED had higher baseline prevalence of CAC score >100 (36.4% vs 17.2%), carotid intima-media thickness Z score >75th percentile (35.3% vs 16.6%), carotid plaque score ≥2 (39% vs 21.1%), carotid distensibility <25th percentile (34.6% vs 17.1%), aortic distensibility <25th percentile (34.2% vs 18.7%), and brachial flow-mediated dilation <25th percentile (28.4% vs 21.3%); all P < 0.01. Only CAC >100 (odds ratio: 1.43, 95% confidence interval: 1.09-1.88) and carotid plaque score ≥2 (odds ratio: 1.33, 95% confidence interval: 1.02-1.73) were significantly associated with ED. Subclinical vascular disease is common in men who later self-report ED. Early detection of subclinical atherosclerosis, particularly advanced CAC and carotid plaque, may provide opportunities for predicting the onset of subsequent vascular ED.


The FDA guidance on therapeutic cancer vaccines: the need for revision to include preventive cancer vaccines or for a new guidance dedicated to them.
Cancer vaccines based on antigens derived from self molecules rather than pathogens have been under basic and clinical investigations for many years. Up until very recently, they had been tested primarily in the setting of metastatic disease with the goal to engage the immune system in slowing down disease progression. Many therapeutic vaccine trials, either investigator initiated or led by pharmaceutical companies, have been completed and many are currently ongoing, following the FDA Guidance on therapeutic cancer vaccines published in 2011. In recent years, the target of cancer vaccines is being shifted to early cancer and even premalignant disease with the goal of preventing cancer. Although some issues addressed in the FDA Guidance on therapeutic vaccines apply to preventive vaccines, many do not. Here, we discuss a set of recommendations for revising the current Guidance to also cover preventive vaccines, or to include in a new Guidance dedicated specifically to vaccines for cancer prevention.


Rebound depolarization in single units of the ventral cochlear nucleus: a contribution to grouping by common onset?
Simultaneous grouping by common onset time is believed to be a powerful cue in auditory perception; components that start or stop roughly at the same time are judged as far more likely to have originated from the same source. Here we report a simple experiment designed to simulate a complex psychophysical paradigm first described by Darwin and Sutherland [(1984) Grouping frequency components of vowels. When is a harmonic not a harmonic? Quarterly J of Experimental Psychology: Hum Exp Psychol 36(A):193-208]. It is possible to change the perception of the vowel /I/ to /epsilon/ by manipulating the harmonics around the first formant (F1). Increasing the amplitude of one harmonic around F1 caused the perception of the vowel to change from /I/ to /epsilon/. Extending the increased component before the vowel could, however, greatly reduce this change. The role of neural adaptation in this effect was questioned by repeating the experiment but this time using a 'captor' tone which was switched on with the asynchronous harmonic and off when the vowel started. This time the vowel percept did change in a fashion analogous to the effect of an increase in the amplitude of the fourth harmonic (which is close to F1). This effect was explained by assuming that the captor had grouped with the leading portion of the asynchronous component enabling the remainder of the asynchronous component to be grouped with the remainder of the components. We propose a relatively low-level neuronal explanation for this grouping effect: the captor reduces the neural response to the leading segment of the asynchronous component by activating across-frequency suppression, either from the cochlea, or acting via a wideband inhibitor in the ventral cochlear nucleus. The reduction in neural response results in a release from adaptation with the offset of the captor terminating the inhibition, such that the response to the continuation of that component is now enhanced. Using a simplified paradigm we show that both primary-like and chopper units in the ventral cochlear nucleus of the anesthetized guinea pig may show a rebound in excitation when a captor is positioned so as to stimulate the suppressive sidebands in its receptive field. The strength of the rebound was positively correlated with the strength of the suppression. These and other results are consistent with the view that low-level mechanisms underlie the psychophysical captor effect.


Assessment of adaptive evolution between wheat and rice as deduced from full-length common wheat cDNA sequence data and expression patterns.
Wheat is an allopolyploid plant that harbors a huge, complex genome. Therefore, accumulation of expressed sequence tags (ESTs) for wheat is becoming particularly important for functional genomics and molecular breeding. We prepared a comprehensive collection of ESTs from the various tissues that develop during the wheat life cycle and from tissues subjected to stress. We also examined their expression profiles in silico. As full-length cDNAs are indispensable to certify the collected ESTs and annotate the genes in the wheat genome, we performed a systematic survey and sequencing of the full-length cDNA clones. This sequence information is a valuable genetic resource for functional genomics and will enable carrying out comparative genomics in cereals. As part of the functional genomics and development of genomic wheat resources, we have generated a collection of full-length cDNAs from common wheat. By grouping the ESTs of recombinant clones randomly selected from the full-length cDNA library, we were able to sequence 6,162 independent clones with high accuracy. About 10% of the clones were wheat-unique genes, without any counterparts within the DNA database. Wheat clones that showed high homology to those of rice were selected in order to investigate their expression patterns in various tissues throughout the wheat life cycle and in response to abiotic-stress treatments. To assess the variability of genes that have evolved differently in wheat and rice, we calculated the substitution rate (Ka/Ks) of the counterparts in wheat and rice. Genes that were preferentially expressed in certain tissues or treatments had higher Ka/Ks values than those in other tissues and treatments, which suggests that the genes with the higher variability expressed in these tissues is under adaptive selection. We have generated a high-quality full-length cDNA resource for common wheat, which is essential for continuation of the ongoing curation and annotation of the wheat genome. The data for each clone's expression in various tissues and stress treatments and its variability in wheat and rice as a result of their diversification are valuable tools for functional genomics in wheat and for comparative genomics in cereals.


Physical activity and energy expenditure in adolescent male sport participants and nonparticipants aged 13 to 16 years.
Sport has high social valence and is a primary context for physical activity for the majority of youth. The aim of this study was to estimate the contribution of participation in organized sport to the total daily energy expenditure and also to its moderate-to-vigorous portion in male adolescents. The sample comprised 165 Portuguese male youth, aged 13 to 16 years. Physical activity was assessed with a multi-method approach (Actigraph GT1M accelerometer plus 3-day diary record). Differences in the intensities of physical activity and sedentary behavior of male sport participants and nonsport participants were compared using independent sample t-test. Male participants in organized sports spent significantly more time in moderate-to-vigorous activities than nonparticipants, although the P-value for the 15 to 16 years age-group was marginal (P = .08) on the weekend days. In addition, male adolescents spent 11% to 13% of total daily energy expenditure in organized sports which corresponded to 35% to 42% of the moderate-to-vigorous portion of daily energy expenditure. Organized sport appears to be a relevant component of daily activity energy expenditure to promote healthy lifestyles among male adolescents.


From chemo-prevention to epigenetic regulation: The role of isothiocyanates in skin cancer prevention.
Skin cancer incidence is rapidly growing over the last decades and is generally divided into malignant melanoma and non-melanoma (NMSC) with the latter being subdivided into squamous (SCC) and basal cell carcinoma (BCC). Among them, melanoma is the most aggressive type with high mortality rates. On the other hand, aberrant gene expression is a critical step towards malignant transformation. To this end, epigenetic modifications like changes in DNA methylation patterns and miRNA expression profile as well as histone modifications are all capable of inducing an altered gene expression profile involved in various cellular cascades including cell cycle, proliferation and apoptosis. In general, there is an interest about the beneficiary effect of various phytochemicals in the prevention and treatment of skin malignancies. Among them, glucosinolates are an important type of compounds, abundant in cruciferous vegetables, which are hydrolysed by an endogenous enzyme called myrosinase to a range of bioactive compounds including isothiocyanates (ITCs). These are the major biologically active products capable of mediating the anti-cancer effect of cruciferous vegetables. Their chemo-preventive action is mainly attributed to a plurality of anti-cancer properties including regulation of the epigenetic machinery. Current evidence supports the view that ITCs are potent compounds in interacting with the epigenome in order to restore the normal epigenetic landscape in malignant cells. This review article summarizes the current state of knowledge on the epigenetic modifications that lead to malignant transformation and the role of ITCs with respect to their ability to restore the epigenetic landscape that contributes to skin carcinogenesis.


CD105 protein depletion enhances human adipose-derived stromal cell osteogenesis through reduction of transforming growth factor β1 (TGF-β1) signaling.
Clinically available sources of bone for repair and reconstruction are limited by the accessibility of autologous grafts, infectious risks of cadaveric materials, and durability of synthetic substitutes. Cell-based approaches for skeletal regeneration can potentially fill this need, and adipose tissue represents a promising source for development of such therapies. Here, we enriched for an osteogenic subpopulation of cells derived from human subcutaneous adipose tissue utilizing microfluidic-based single cell transcriptional analysis and fluorescence-activated cell sorting (FACS). Statistical analysis of single cell transcriptional profiles demonstrated that low expression of endoglin (CD105) correlated with a subgroup of adipose-derived cells with increased osteogenic gene expression. FACS-sorted CD105(low) cells demonstrated significantly enhanced in vitro osteogenic differentiation and in vivo bone regeneration when compared with either CD105(high) or unsorted cells. Evaluation of the endoglin pathway suggested that enhanced osteogenesis among CD105(low) adipose-derived cells is likely due to identification of a subpopulation with lower TGF-β1/Smad2 signaling. These findings thus highlight a potential avenue to promote osteogenesis in adipose-derived mesenchymal cells for skeletal regeneration.


LC-HRMS-Database Screening Metrics for Rapid Prioritization of Samples to Accelerate the Discovery of Structurally New Natural Products.
In order to accelerate the isolation and characterization of structurally new or novel secondary metabolites, it is crucial to develop efficient strategies that prioritize samples with greatest promise early in the workflow so that resources can be utilized in a more efficient and cost-effective manner. We have developed a metrics-based prioritization approach using exact LC-HRMS, which uses data for 24 618 marine natural products held in the PharmaSea database. Each sample was evaluated and allocated a metric score by a software algorithm based on the ratio of new masses over the total (sample novelty), ratio of known masses over the total (chemical novelty), number of peaks above a defined peak area threshold (sample complexity), and peak area (sample diversity). Samples were then ranked and prioritized based on these metric scores. To validate the approach, eight marine sponges and six tunicate samples collected from the Fiji Islands were analyzed, metric scores calculated, and samples targeted for isolation and characterization of new compounds. Structures of new compounds were elucidated by spectroscopic techniques, including 1D and 2D NMR, MS, and MS/MS. Structures were confirmed by computer-assisted structure elucidation methods (CASE) using the ACD/Structure Elucidator Suite.


A targeted siRNA screen identifies regulators of Cdc42 activity at the natural killer cell immunological synapse.
Natural killer (NK) cells kill tumor cells and virally infected cells, and an effective NK cell response requires processes, such as motility, recognition, and directional secretion, that rely on cytoskeletal rearrangement. The Rho guanosine triphosphatase (GTPase) Cdc42 coordinates cytoskeletal reorganization downstream of many receptors. The Rho-related GTPase from plants 1 (ROP1) exhibits oscillatory activation behavior at the apical plasma membrane of growing pollen tubes; however, a similar oscillation in Rho GTPase activity has so far not been demonstrated in mammalian cells. We hypothesized that oscillations in Cdc42 activity might occur within NK cells as they interact with target cells. Through fluorescence lifetime imaging of a Cdc42 biosensor, we observed that in live NK cells forming immunological synapses with target cells, Cdc42 activity oscillated after exhibiting an initial increase. We used protein-protein interaction networks and structural databases to identify candidate proteins that controlled Cdc42 activity, leading to the design of a targeted short interfering RNA screen. The guanine nucleotide exchange factors RhoGEF6 and RhoGEF7 were necessary for Cdc42 activation within the NK cell immunological synapse. In addition, the kinase Akt and the p85α subunit of phosphoinositide 3-kinase (PI3K) were required for Cdc42 activation, the periodicity of the oscillation in Cdc42 activity, and the subsequent polarization of cytotoxic vesicles toward target cells. Given that PI3Ks are targets of tumor therapies, our findings suggest the need to monitor innate immune function during the course of targeted therapy against these enzymes.


Magnetic Fluctuations, Precursor Phenomena, and Phase Transition in MnSi under a Magnetic Field.
The reference chiral helimagnet MnSi is the first system where Skyrmion lattice correlations have been reported. At a zero magnetic field the transition at T_{C} to the helimagnetic state is of first order. Above T_{C}, in a region dominated by precursor phenomena, neutron scattering shows the buildup of strong chiral fluctuating correlations over the surface of a sphere with radius 2π/ℓ, where ℓ is the pitch of the helix. It has been suggested that these fluctuating correlations drive the helical transition to first order following a scenario proposed by Brazovskii for liquid crystals. We present a comprehensive neutron scattering study under magnetic fields, which provides evidence that this is not the case. The sharp first order transition persists for magnetic fields up to 0.4 T whereas the fluctuating correlations weaken and start to concentrate along the field direction already above 0.2 T. Our results thus disconnect the first order nature of the transition from the precursor fluctuating correlations. They also show no indication for a tricritical point, where the first order transition crosses over to second order with increasing magnetic field. In this light, the nature of the first order helical transition and the precursor phenomena above T_{C}, both of general relevance to chiral magnetism, remain an open question.


Smoking and alcohol intake as risk factors for myelodysplastic syndromes (MDS).
The term myelodysplastic syndromes (MDS) include a diverse group of diseases in which the bone marrow production of blood cells is disrupted. In spite of the wealth of information on therapeutic options, little is known about the epidemiology of MDS, including population variations and risk factors. A narrative review of published literature and meta-analyses were conducted, identifying and summarizing key reports that describe the association between smoking, alcohol and MDS. There were 10 case-control studies that looked at the association between smoking and MDS, for a total of 1839 cases and 2831 controls. The meta-estimate for the association between ever smoking and MDS was 1.45 (95% CI: 1.21-1.74), with heterogeneity among studies (p=0.05), but no evidence of publication bias. The relationship between alcohol consumption and MDS has been examined in five studies, including 745 cases and 1642 controls. The overall association was 1.31 (95% CI: 0.79-2.18), with significant heterogeneity (p=0.003) and no evidence of publication bias. This re-analysis of published data strongly suggests that smoking is significantly associated with MDS, while alcohol does not seem to play a major role in MDS etiology. Large epidemiological studies incorporating biomarkers of exposure, along with pooled analysis are needed to better address the contribution of lifestyle factors to the development of MDS.


Age and height dependence of lung clearance index and functional residual capacity.
The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.


Recovery of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) from Ralstonia eutropha cultures with non-halogenated solvents.
Reduced downstream costs, together with high purity recovery of polyhydroxyalkanoate (PHA), will accelerate the commercialization of high quality PHA-based products. In this work, a process was designed for effective recovery of the copolymer poly(hydroxybutyrate-co-hydroxyhexanoate) (P(HB-co-HHx)) containing high levels of HHx (>15 mol%) from Ralstonia eutropha biomass using non-halogenated solvents. Several non-halogenated solvents (methyl isobutyl ketone, methyl ethyl ketone, and butyl acetate and ethyl acetate) were found to effectively dissolve the polymer. Isoamyl alcohol was found to be not suitable for extraction of polymer. All PHA extractions were performed from both dry and wet cells at volumes ranging from 2 mL to 3 L using a PHA to solvent ratio of 2% (w/v). Ethyl acetate showed both high recovery levels and high product purities (up to 99%) when using dry cells as starting material. Recovery from wet cells, however, eliminates a biomass drying step during the downstream process, potentially saving time and cost. When wet cells were used, methyl isobutyl ketone (MIBK) was shown to be the most favorable solvent for PHA recovery. Purities of up to 99% and total recovery yields of up to 84% from wet cells were reached. During polymer recovery with either MIBK or butyl acetate, fractionation of the extracted PHA occurred, based on the HHx content of the polymer. PHA with higher HHx content (17-30 mol%) remained completely in solution, while polymer with a lower HHx content (11-16 mol%) formed a gel-like phase. All PHA in solution could be precipitated by addition of threefold volumes of n-hexane or n-heptane to unfiltered PHA solutions. Effective recycling of the solvents in this system is predicted due to the large differences in the boiling points between solvent and precipitant. Our findings show that two non-halogenated solvents are good candidates to replace halogenated solvents like chloroform for recovery of high quality PHA.


Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin.
Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function. Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin.


[Marshmallow Root Extract for the Treatment of Irritative Cough: Two Surveys on Users' View on Effectiveness and Tolerability].
Cough preparations containing aqueous marshmallow root extracts (Althaea officinalis) have a long history as medicinal products in Germany. The aim of the 2 prospective, non-interventional surveys reported here was to create a better documentation of the users' impression of the effectiveness and tolerability, and user satisfaction. Consumers (n = 822) buying either lozenges or syrup of the aqueous marshmallow root extract STW42 to treat their dry cough were recruited in pharmacies in 2 independently performed surveys. They were asked to fill in a questionnaire covering a treatment duration of 7 days so that the course of symptoms could be documented, and the overall effectiveness, tolerability and satisfaction assessed. This consumer-reported outcome shows that both preparations showed a good effect with respect to the symptomatic treatment of oral or pharyngeal irritation and associated dry cough with a very rapid onset of effects, in the majority of cases within 10 min. The tolerability was very good (with only 3 minor adverse events for the syrup). The results of the surveys justify the long-established use of both marshmallow preparations for symptomatic treatment of dry cough.


Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial.
We conducted a phase 1 trial of direct injection of an E1, E3-deleted adenovirus encoding interleukin-2 (AdCAIL-2) into subcutaneous deposits of melanoma or breast cancer. Twenty-three patients were injected at seven dose levels (10(7)-10(10) p.f.u). Local inflammation was observed at the site of injection in 60% of patients, but side-effects were otherwise minor. Incomplete local tumor regression occurred at the site of injection in 24% of patients, but no conventional clinical responses were seen. Circulating CD4 and CD8 counts fell significantly 24 h after injection. Post-injection biopsies demonstrated tumor necrosis and lymphocytic infiltration with the predominant tumor-infiltrating cells both CD3- and CD8-positive. Vector-derived sequences were detected in 14 of 18 biopsies examined 7 days after injection and vector-derived hIL-2 mRNA was detected in 80% of 7-day biopsies processed after injection of 10(8) p.f.u. of AdCAIL-2 or higher. While IL-2 was detectable by ELISA in tumor biopsies at 48 h, no protein was detectable in injected tumors after 7 days and no circulating IL-2 was detectable at any time-point. No Ad5E1 sequences were detected either before or after injection indicating absence of replication-competent virus or endogenous E1-like sequence; furthermore, only rare vector shedding was detected. Anti-adenovirus and neutralizing antibody titers were elevated 1 month after injection in all patients. This trial therefore confirms the safety of use of adenoviral vectors for gene delivery in humans and demonstrates successful transgene expression even in the face of pre-existing immunity to adenovirus.


Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series.
Although tumor necrosis factor-alpha (TNF-alpha) antagonists are effective in the treatment of refractory psoriasis, some cases have suggested that psoriasis might be induced as a result of treatment prescribed mainly for rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. To investigate anti-TNF-alpha induced psoriasis, we conducted a systematic analysis of the 6 cases we observed among our inflammatory patient cohort treated with anti-TNF-alpha (infliximab or etanercept). We report 6 cases of psoriasis with onset during TNF-alpha antagonist therapy (infliximab and etanercept); characteristics and skin lesions are described. No patient had a personal or family history of psoriasis. The development of psoriasis was seen in all the types of inflammatory diseases we treated with TNF-alpha antagonists. There was great variation in the age of affected patients and in the onset of psoriasis after initiation of TNF-alpha antagonists. Both TNF-alpha antagonists studied were associated with development of psoriasis. In 2 cases psoriasis was associated with 2 different TNF-alpha antagonists in the same patient. In half our patients, skin lesions started in the inguinal and pubic regions, but palmoplantar pustulosis was also common. In half the cases, skin lesions responded favorably with topical agents despite continuation of TNF-alpha antagonist therapy. In light of previously published cases describing psoriasis or psoriasiform lesions after TNF-alpha antagonist therapy, our series strongly confirms that TNF-alpha antagonists may induce psoriasis in some patients. Further studies are needed to identify risk factors for TNF-alpha antagonist induced psoriasis.


Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB.
Members of the nuclear factor (NF)-kappaB/Rel family transcription factors are induced during thymic selection and in mature T lymphocytes after ligation of the T cell antigen receptor (TCR). Despite these findings, disruption of individual NF-kappaB/Rel genes has revealed no intrinsic defect in the development of mature T cells, perhaps reflecting functional redundancy. To circumvent this possibility, the T cell lineage was targeted to express a trans-dominant form of IkappaBalpha that constitutively represses the activity of multiple NF-kappaB/Rel proteins. Transgenic cells expressing this inhibitor exhibit a significant proliferative defect, which is not reversed by the addition of exogenous interleukin-2. Moreover, mitogenic stimulation of splenocytes leads to increased apoptosis of transgenic T cells as compared with controls. In addition to deregulated T cell growth and survival, transgene expression impairs the development of normal T cell populations as evidenced by diminished numbers of TCRhi CD8 single-positive thymocytes. This defect was significantly amplified in the periphery and was accompanied by a decrease in CD4(+) T cells. Taken together, these in vivo findings indicate that the NF-kappaB/Rel signaling pathway contains compensatory components that are essential for the establishment of normal T cell subsets.


From projected species distribution to food-web structure under climate change.
Climate change is inducing deep modifications in species geographic ranges worldwide. However, the consequences of such changes on community structure are still poorly understood, particularly the impacts on food-web properties. Here, we propose a new framework, coupling species distribution and trophic models, to predict climate change impacts on food-web structure across the Mediterranean Sea. Sea surface temperature was used to determine the fish climate niches and their future distributions. Body size was used to infer trophic interactions between fish species. Our projections reveal that 54 fish species of 256 endemic and native species included in our analysis would disappear by 2080-2099 from the Mediterranean continental shelf. The number of feeding links between fish species would decrease on 73.4% of the continental shelf. However, the connectance of the overall fish web would increase on average, from 0.26 to 0.29, mainly due to a differential loss rate of feeding links and species richness. This result masks a systematic decrease in predator generality, estimated here as the number of prey species, from 30.0 to 25.4. Therefore, our study highlights large-scale impacts of climate change on marine food-web structure with potential deep consequences on ecosystem functioning. However, these impacts will likely be highly heterogeneous in space, challenging our current understanding of climate change impact on local marine ecosystems.


Serotonin hypothesis of autism: implications for selective serotonin reuptake inhibitor use during pregnancy.
Serotonin, a neurotransmitter found throughout the brain and body, has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led some to believe that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure to substances that manipulate serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs). This review examines evidence regarding the serotonin system and autism spectrum disorders (ASD), as well as what the literature has reported thus far on developmental effects of prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus during pregnancy and clinical implications are also discussed. Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes. The only published study that focused on prenatal SSRI exposure and ASD found an increased risk with exposure to SSRIs, especially during the first trimester. Obstacles that will be faced in future research are isolating medication effects from maternal depression and, given the infrequent occurrence of exposure and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic factor in ASD, and what it points to as a marker for subgrouping, remains unclear. Understanding how the development of ASD might be affected by prenatal factors that influence serotonin levels, such as SSRIs, could identify modifiable targets for prevention.


Prevalence of serum antibodies to human papilloma virus in patients with genital ulcer disease in an urban population of Tanzania.
The epidemiology of human papillomavirus (HPV) in Tanzania is largely unknown both in risk groups and in the general population. To determine the cumulative seroprevalence of selected HPV types in order to evaluate exposure to HPV in urban Tanzania. In a cross-sectional study, sera of 200 patients of both sexes with genital ulcer disease (GUD) and sera of 60 male blood donors and 60 pregnant women were tested for antibodies to the oncogenic HPV types 16, 18, 31, 33, 35, 51 and 52 using an ELISA based on virus-like particles (VLP). The overall seroprevalence of HPV types for all patients with GUD was 83% and 77% for women and men, respectively. For pregnant women and male blood donors, the corresponding percentages were 55% and 15%, respectively. The most common HPV types were 16, 18 and 52. Infection with multiple types was more than 10 and 5 times more frequent than infection with a single type 16 in patients with GUD and in pregnant women, respectively. The seroprevalence to HPV types 16, 18, 51 and 52 was considerably higher in HIV-positive patients with GUD than in HIV-negative patients. Infections with the oncogenic HPV types 16, 18 and 52 are common among patients with GUD and pregnant women in urban Tanzania, emphasising the need for control, treatment and implementation of appropriate HPV vaccine programmes.


Attitudes toward suicide bombing in Pakistan.
Although suicide bombing is a historical phenomenon, there has been a recent upsurge in such incidents. In Pakistan, over the last year, more than 1,000 people have been killed in suicide bombing incidents. Assessing the attitudes and perceptions of people toward suicide bombing can help understand some of the root causes of this phenomenon. In this pilot study, we conducted a cross-sectional survey of people (N = 215) in Karachi, Pakistan, to assess their attitudes and perceptions toward suicide bombing. The majority of the respondents condemned suicide bombing and disagreed with the notion that Islam or any other religion supports it. Belonging to the Sunni Muslim sect and strong adherence to religion predicted support for suicide bombing. The majority believed suicide bombing to be a result of religious fundamentalism. Opinion was divided as to whether suicide bombers have an underlying psychiatric illness. Further studies with larger sample sizes are needed to determine the attitudes and perceptions of the Pakistani population regarding this important issue.


First Report of Soybean Cyst Nematode (Heterodera glycines) on Soybean in North Dakota.
During August 2003, soybean (Glycine max) plants from Richland County, North Dakota with white-to-yellow, lemon-shaped structures on the roots were brought to the North Dakota State University Plant Diagnostic Laboratory. To confirm that the structures were females of a cyst nematode, they were crushed and observed microscopically to determine if nematode eggs and second-stage juveniles were present. Morphology of the second-stage juveniles was consistent with Heterodera glycines, the soybean cyst nematode (SCN). A survey was conducted in soybean fields in 34 km2 around the field in which the samples originated. Ten of twenty fields surveyed had visible females on the roots of plants. Symptoms observed in those fields included patches of stunted, chlorotic, and dead plants. Soil samples were collected from selected areas within eight fields, eggs were extracted using standard soil sieving techniques, and egg numbers were determined. Egg numbers ranged from 550 to 20,000 eggs per 100 cm3 of soil. SCN collected from two different fields, designated as Dwight and LaMars, were used to determine their HG Type. Standardized procedures (1) were used in a growth chamber set at 27°C with 16-h days. Pots in the test were organized in a completely randomized design with three replicates; the test was repeated over time. After 30 days, females were extracted from roots and counted, and a female index (FI) was calculated for each indicator line (1). The mean number of females on susceptible standard cv. Lee 74, was 110. The Dwight SCN population had an FI of 5.3 on plant introduction (PI) 88788, 1.5 on PI 209332, 5.8 on PI 548316 (Cloud), and 0 on all other indicator lines. The LaMars population had an FI of 1.0 on PI 88788, 3.1 on PI 548316 (Cloud), and 0 on all other indicator lines. These results indicate that both SCN populations tested are HG Type 0. To our knowledge, this is the first report of SCN on soybean in North Dakota. Because other hosts of SCN, as well as soybean, are economically important in North Dakota, such as dry edible bean (Phaseolus vulgaris) and dry pea (Pisum sativum), this disease could adversely impact several commodities throughout the state. Reference: (1) T. L. Niblack et al. J. Nematol. 34:279, 2002.


Effect of quinine-loaded polysorbate-coated nanocapsules on male and female reproductive systems of rats.
Quinine is an antimalarial drug; however, its use is limited by its narrow therapeutic index and elevated side effects. The nanosystems are promising delivery vehicles of antimalarial drugs, enhancing their therapeutic potential. This study aimed to compare the toxicity of quinine and quinine loaded nanocapsules (Q-NC) on the reproductive system of male and female rats. The animals received quinine or Q-NC orally at the same dose of 25 mg kg-1 for 7 days (real period of quinine therapy in humans). 24 hours after the last administration, the rats were euthanized and the ovarian and testicular tissues were removed for histological and biochemical analyses. The groups treated with quinine presented ovarian and testicular damage, evidenced by the increase of reactive species and malondialdehyde levels, the decrease of 17β-hydroxysteroid dehydrogenase activity and alterations on total antioxidant capacity. The females presented a decrease of follicular viability and the males presented a decrease of spermatozoa membrane integrity, as well as moderated histological alterations on testis after the exposure to quinine. After the treatment with Q-NC, the males presented decreased reactive species levels and total antioxidant capacity at control levels, as well as spermatozoa with 100% of membrane integrity. The females treated with Q-NC presented reactive species levels, total antioxidant capacity, 17β-hydroxysteroid dehydrogenase activity and follicular viability at control levels, and decreased malondialdehyde levels when compared to quinine, but not at control levels. This study demonstrated that loading polymeric nanocapsules with quinine decreased the deleterious effects induced by quinine on ovaries and partially on testicles.


Assessing the Association between Participation in Extracurricular Activities and Delinquent Behavior among Justice-Involved Young Men.
Extracurricular activities (ECAs) have been found to promote positive youth development and protect against misconduct and minor delinquency. However, little research has examined whether ECA participation predicts delinquency among at-risk young men or considered how delinquent behavior, in turn, impacts ECA participation. This study examined extracurricular participation over three years in a sample of 1,216 justice-involved young men (Mage = 15.29). Approximately half of the sample participated in ECA each year. A cross-lagged panel model was used to examine the bidirectional association between ECA participation and two types of delinquency, school misconduct and criminal offending. The results suggest that ECA participation did not consistently predict subsequent delinquency. Rather, justice-involved young men who engaged in more delinquency were less likely to participate in ECAs.


Clinical performance of direct composite restorations for treatment of severe tooth wear.
The aim of this retrospective clinical study was to evaluate the performance of direct composite restorations that were placed in patients with severe tooth wear requiring an increase of the occlusal vertical dimension. Eighteen patients with severe tooth wear, who had been treated in a private practice between April 1996 and July 2007, were selected. All subjects had been treated with direct composite resin restorations in increased vertical dimension using a three-step etch-and-rinse adhesive system and a hybrid composite resin. From the dental records, information about re-intervention and replacement of restorations was obtained. Patients were then clinically examined to evaluate the status of the restorations and interviewed about their satisfaction with the restorative treatment using a Visual Analogue Scale (VAS). Eighteen patients (16 male, 2 female with an average age of 44.8 years) with severe tooth wear were included in the study. Time since treatment ranged from 6 months to 12 years and the mean observation time was 3.98 years. Of the 332 restored teeth, 23 restorations showed failures (6.9%). Eight restorations (2.4%) showed major fractures, 11 restorations (3.3%) showed minor fractures, and four restorations (1.2%) failed due to secondary caries. VAS data on a scale of 0 to 10 revealed high patient satisfaction with this type of restoration (mean 9.0). Treatments with direct hybrid composite restorations placed in an increased occlusal vertical dimension showed good clinical performance in patients with severe tooth wear.


A Bayesian approach to the evolution of metabolic networks on a phylogeny.
The availability of genomes of many closely related bacteria with diverse metabolic capabilities offers the possibility of tracing metabolic evolution on a phylogeny relating the genomes to understand the evolutionary processes and constraints that affect the evolution of metabolic networks. Using simple (independent loss/gain of reactions) or complex (incorporating dependencies among reactions) stochastic models of metabolic evolution, it is possible to study how metabolic networks evolve over time. Here, we describe a model that takes the reaction neighborhood into account when modeling metabolic evolution. The model also allows estimation of the strength of the neighborhood effect during the course of evolution. We present Gibbs samplers for sampling networks at the internal node of a phylogeny and for estimating the parameters of evolution over a phylogeny without exploring the whole search space by iteratively sampling from the conditional distributions of the internal networks and parameters. The samplers are used to estimate the parameters of evolution of metabolic networks of bacteria in the genus Pseudomonas and to infer the metabolic networks of the ancestral pseudomonads. The results suggest that pathway maps that are conserved across the Pseudomonas phylogeny have a stronger neighborhood structure than those which have a variable distribution of reactions across the phylogeny, and that some Pseudomonas lineages are going through genome reduction resulting in the loss of a number of reactions from their metabolic networks.


Penile rehabilitation after radical prostatectomy: what the evidence really says.
The pathophysiology of erectile dysfunction after radical prostatectomy (RP) is believed to include neuropraxia, which leads to temporarily reduced oxygenation and subsequent structural changes in penile tissue. This results in veno-occlusive dysfunction, therefore, penile rehabilitation programmes focus on tissue oxygenation. Animal studies support the use of phosphodiesterase type 5 inhibitors (PDE5Is) after cavernous nerve damage but results from human studies are contradictory. The largest study to date found no long-term effect of either daily or on-demand PDE5I administration after RP compared with placebo. The effects of prostaglandin and vacuum erection devices are questionable and high-quality studies are lacking. Better documentation for current penile rehabilitation and/or better rehabilitation protocols are needed. One must be careful not to repeat the statement that penile rehabilitation improves erectile function after RP so many times that it becomes a truth even without the proper scientific backing.


Population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe Falciparum malaria.
Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).


SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects.
Inherited thrombocytopenias are a group of disorders that are characterized by a low platelet count and are sometimes associated with excessive bleeding that ranges from mild to severe. We evaluated 36 unrelated patients and 17 family members displaying thrombocytopenia that were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study. All patients had a history of excessive bleeding of unknown etiology. We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families. Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern. Three heterozygous missense mutations were identified in affected family members and predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4, GTP/ATP-binding region of SLFN14. Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant SLFN14 expression was markedly decreased compared with that of WT SLFN14 when overexpressed in transfected cells. Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies. These results identify SLFN14 mutations as cause for an inherited thrombocytopenia with excessive bleeding, outlining a fundamental role for SLFN14 in platelet formation and function.


Evaluating psychiatric disability: differences by forensic expertise.
The task of evaluating psychiatric disability poses several ethics-related and practical challenges for psychiatrists, especially when they are responding to a request from a third party for a disability evaluation on their own patient. This study sought to evaluate the differences in how forensic and nonforensic psychiatrists approach and view evaluations for Social Security disability benefits. Thirty-two forensic and 75 nonforensic psychiatrists were surveyed on their practice patterns and perceptions of role, objectivity, and dual agency in the disability evaluation process. Significant differences were found between forensic and nonforensic psychiatrists' perceptions of the dual-agency conflict, beliefs about who should perform evaluations, and beliefs about the weight given to different opinions when decisions of whether to award disability benefits are made. A minority of respondents in both groups reported having identified a patient as disabled, despite believing otherwise. The implications of these findings are discussed.


Non-collinear magnetism with analytic Bond-Order Potentials.
The theory of analytic Bond-Order Potentials as applied to non-collinear magnetic structures of transition metals is extended to take into account explicit rotations of Hamiltonian and local moment matrix elements between locally and globally defined spin-coordinate systems. Expressions for the gradients of the energy with respect to the Hamiltonian matrix elements, the interatomic forces and the magnetic torques are derived. The method is applied to simulations of the rotation of magnetic moments in α iron, as well as α and β manganese, based on d-valent orthogonal tight-binding parametrizations of the electronic structure. A new weighted-average terminator is introduced to improve the convergence of the Bond-Order Potential energies and torques with respect to tight-binding reference values, although the general behavior is qualitatively correct for low-moment expansions.


A Comparative Study of the Quality of Apical Seal in Resilon/Epiphany SE Following Intra canal Irrigation With 17% EDTA, 10% Citric Acid, And MTAD as Final Irrigants - A Dye Leakage Study Under Vacuum.
Adequate apical sealing ability of the root canal filling material is an essential requisite for a successful endodontic therapy. Various endodontic irrigants are used for the removal of smear layer before obturating with a solid core material, thereby, reducing microleakage and improving apical seal. Resilon, a synthetic material was developed as an alternative to replace the conventional gutta-percha (standard root canal filling material) and traditional sealers for the obturation of endodontically treated teeth. To evaluate and compare in-vitro, the post obturation apical seal obtained with Resilon /Epiphany SE (Self Etch) sealer following irrigation with 17% Ethylenediamine Tetra-Acetic Acid (EDTA), 10% citric acid, and MTAD (a mixture of doxycycline, citric acid, and a detergent, Tween 80), as final irrigants in combination with Sodium hypochlorite (NaOCl) using dye leakage under vacuum method. Fifty five single rooted human maxillary central incisors were subjected to root canal instrumentation. Based on the final irrigation solution, samples were divided into three experimental groups (n=15); (I) 17% EDTA + 1.3% NaOCl, (II) 10% citric acid + 1.3% NaOCl, (III) MTAD + 1.3% NaOCl and two control groups (positive and negative) with 0.9% normal saline as a final irrigant. The samples were obturated with resilon/epiphany SE sealer according to manufacturer instructions and placed in 2% rhodamine B dye solution under vacuum pressure for 30 minutes and allowed to remain in the dye for seven days. All samples were then longitudinally split and examined for dye leakage under stereomicroscope and the data were statistically analysed using one-way ANOVA and post hoc tukey test. Statistically significant difference (p=0.001) was observed in the mean apical leakage between the experimental and the control groups. However, there was no significant difference (p>0.05) observed in the mean apical leakage amongst the three experimental groups. 17% EDTA, 10% citric acid, and MTAD were equally effective in achieving the post-obturation apical seal with resilon/epiphany SE sealer when used as a final irrigant in combination with NaOCl.


Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway.
Influenza viruses can modulate and hijack several cellular signalling pathways to efficiently support their replication. We recently investigated and compared the cellular gene expression profiles of human lung A549 cells infected by five different subtypes of human and avian influenza viruses (Josset et al. Plos One 2010). Using these transcriptomic data, we have focused our analysis on the modulation of the p53 pathway in response to influenza infection. Our results were supported by both RT-qPCR and western blot analyses and reveal multiple alterations of the p53 pathway during infection. A down-regulation of mRNA expression was observed for the main regulators of p53 protein stability during infection by the complete set of viruses tested, and a significant decrease in p53 mRNA expression was also observed in H5N1 infected cells. In addition, several p53 target genes were also down-regulated by these influenza viruses and the expression of their product reduced. Our data reveal that influenza viruses cause an overall down-regulation of the host p53 pathway and highlight this pathway and p53 protein itself as important viral targets in the altering of apoptotic processes and in cell-cycle regulation.


Transplant tourism in China: a tale of two transplants.
The use of organs obtained from executed prisoners in China has recently been condemned by every major transplant organization. The government of the People's Republic of China has also recently made it illegal to provide transplant organs from executed prisoners to foreigners transplant tourists. Nevertheless, the extreme shortage of transplant organs in the U.S. continues to make organ transplantation in China an appealing option for some patients with end-stage disease. Their choice of traveling to China for an organ leaves U.S. transplant programs with decisions about how to respond to the needs of patients who return after transplantation. By discussing two cases that raised this dilemma, we argue for upholding medicine's commitments to traditional principles of beneficence and nonjudgmental regard in sorting out the policies that a transplant program should adopt. We also explain how position statements that aim for the high ground of moral purity fail to give appropriate weight to the needs and suffering of present and future patients in the U.S. and in China.


Clioquinol: To harm or heal.
Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.


[Pulmonary adenocarcinoma in myasthenia gravis--autoimmunity and late development of malignancy].
We report a 75-year-old man with myasthenia gravis for many years, who was hospitalized because of cough, fever, and dyspnea. Chest x-ray revealed a bilateral pleural effusion. Adenocarcinomatous cells were found in the pleural fluid. Computerized tomography of the chest showed widespread pulmonary dissemination of the tumor. The relationship between myasthenia gravis, an autoimmune disease involving the motor end-plate, and malignancy (thymoma) has been widely recognized. Current literature documents few reports of lung malignancies with concurrent development of myasthenia gravis. A tentative explanation, based on current research, is provided for the possible role of myasthenia gravis and the late development of lung cancer. Moreover, a model for the autoimmune phenomenon and the development of late malignancies is provided with explicit explanations. It is important to search for occult, developing malignancies in newly diagnosed autoimmune diseases.


Multiple FadD acyl-CoA synthetases contribute to differential fatty acid degradation and virulence in Pseudomonas aeruginosa.
A close interconnection between nutrient metabolism and virulence factor expression contributes to the pathophysiology of Pseudomonas aeruginosa as a successful pathogen. P. aeruginosa fatty acid (FA) degradation is complicated with multiple acyl-CoA synthetase homologs (FadDs) expressed in vivo in lung tissue during cystic fibrosis infections. The promoters of two genetically linked P. aeruginosa fadD genes (fadD1 and fadD2) were mapped and northern blot analysis indicated they could exist on two different transcripts. These FadDs contain ATP/AMP signature and FA-binding motifs highly homologous to those of the Escherichia coli FadD. Upon introduction into an E. coli fadD(-)/fadR(-) double mutant, both P. aeruginosa fadDs functionally complemented the E. coli fadD(-)/fadR(-) mutant, allowing degradation of different chain-length FAs. Chromosomal mutagenesis, growth analysis, induction studies, and determination of kinetic parameters suggested that FadD1 has a substrate preference for long-chain FAs while FadD2 prefers shorter-chain FAs. When compared to the wild type strain, the fadD2 mutant exhibited decreased production of lipase, protease, rhamnolipid and phospholipase, and retardation of both swimming and swarming motilities. Interestingly, fadD1 mutant showed only increased swarming motility. Growth analysis of the fadD mutants showed noticeable deficiencies in utilizing FAs and phosphatidylcholine (major components of lung surfactant) as the sole carbon source. This defect translated into decreased in vivo fitness of P. aeruginosa in a BALB/c mouse lung infection model, supporting the role of lipids as a significant nutrient source for this bacterium in vivo.


Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women.
Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.


100 kHz, 100 ms, 400 J burst-mode laser with dual-wavelength diode-pumped amplifiers.
The burst duration of an all-diode-pumped burst-mode laser is extended to 100 ms and 100 kHz (10,000 pulses) by utilizing dual-wavelength diode pumping. Total energies of 225 J at 10 kHz and 400 J at 100 kHz are achieved during the 100 ms burst period at 1064 nm. This represents an order-of-magnitude increase in the number of pulses compared with prior work, while maintaining similar or higher pulse energies. Amplitude tailoring of each pulse is used to flatten the burst profile, reducing the standard deviation in pulse energy over the 100 ms burst from 3.7% to 2.1% with a burst-to-burst standard deviation of 0.8%.


Genetic damage induced by accidental environmental pollutants.
Petroleum is one of the main energy sources worldwide. Its transport is performed by big tankers following some established marine routes. In the last 50 years a total amount of 37 oil tankers have given rise to great spills in different parts of the world, Prestige being the last one. After the accident, a big human mobilisation took place in order to clean beaches, rocks and fauna, trying to reduce the environmental consequences of this serious catastrophe. These people were exposed to the complex mixture of compounds contained in the oil. This study aimed at determine the level of environmental exposure to volatile organic compounds (VOC), and the possible damage induced on the population involved in the different cleaning tasks by applying the genotoxicity tests sister chromatid exchanges (SCE), micronucleus (MN) test, and comet assay. Four groups of individuals were included: volunteers (V), hired manual workers (MW), hired high-pressure cleaner workers (HPW) and controls. The higher VOC levels were associated with V environment, followed by MW and lastly by HPW, probably due to the use of high-pressure cleaners. Oil exposure during the cleaning tasks has caused an increase in the genotoxic damage in individuals, the comet assay being the most sensitive biomarker to detect it. Sex, age and tobacco consumption have shown to influence the level of genetic damage, while the effect of using protective devices was less noticeable than expected, perhaps because the kind used was not the most adequate.


Phenomenological analysis of patient experiences of medical student teaching encounters.
It is important to know how patients are affected by becoming opportunistically involved in medical student education. In previous studies, researchers rather than patients set the research agenda and expert patients or people well known to teachers were more often involved than ordinary people. This study aimed to explore how ordinary patients experience undergraduate medical teaching when they become involved in it opportunistically and to derive practical insights from the lived experiences of these patients. The research was conducted in line with a conceptual orientation towards communities of practice theory and used phenomenology as a way of exploring patients' lived experiences in depth. Minimally structured interviews were carried out with 10 patients following ordinary out-patient or general practice appointments in which students were being taught. Template analysis was used to generate provisional themes and a process of phenomenological reduction was used to distil individual respondents' lived experiences to their essence. The presence of students in ambulatory consultations was normal. Nine respondents described transactional relationships in which they remained outside the community of practice of which the doctor and student were members. Only an intimate problem would engage them deeply enough for a student's presence to 'bother' them. One patient's personal and professional background led her to regard doctors' handling of consultation dynamics as factors contributing to whether teaching consultations were negative or positive experiences. When doctors' sensitive and inclusive behaviour drew her into a triadic relationship with the student and doctor, she experienced mutual benefits with students. When it did not, she felt objectified and alienated. Provided they receive the clinical care for which they are attending a consultation and are treated respectfully, patients may sometimes willingly become 'objects' from which students learn. They may, however, become more deeply engaged in teaching consultations in which they participate actively in a triadic relationship of mutual benefit with a doctor and student. Teaching consultations call for doctors to be sensitive and adaptable.


Single-particle structure determination by correlations of snapshot X-ray diffraction patterns.
Diffractive imaging with free-electron lasers allows structure determination from ensembles of weakly scattering identical nanoparticles. The ultra-short, ultra-bright X-ray pulses provide snapshots of the randomly oriented particles frozen in time, and terminate before the onset of structural damage. As signal strength diminishes for small particles, the synthesis of a three-dimensional diffraction volume requires simultaneous involvement of all data. Here we report the first application of a three-dimensional spatial frequency correlation analysis to carry out this synthesis from noisy single-particle femtosecond X-ray diffraction patterns of nearly identical samples in random and unknown orientations, collected at the Linac Coherent Light Source. Our demonstration uses unsupported test particles created via aerosol self-assembly, and composed of two polystyrene spheres of equal diameter. The correlation analysis avoids the need for orientation determination entirely. This method may be applied to the structural determination of biological macromolecules in solution.