Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.
Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.


Normal variations in personality predict eating behavior, oral health, and partial syndrome bulimia nervosa in adolescent girls.
Eating disorders are among the most prevalent disorders in adolescence and can have negative consequences including poor quality of life, medical complications, and even death. This study addresses whether normal variations in personality relate to eating behavior and eating disorder symptomatology in adolescent girls. Participants were a near-representative sample of Australian adolescent girls (n = 1,676). Three personality traits (neuroticism, extraversion, and conscientiousness) were assessed at age 12 and again at age 14, and self-reported eating and weight management behaviors were assessed at age 14. After controlling for sociodemographic factors, higher levels of conscientiousness at age 12, and increases in conscientiousness between ages 12 and 14, were associated with greater fruit and vegetable consumption, a lower intake of high fat foods and high sugar drinks, less frequent meal skipping, better oral health, and decreased risk of partial syndrome bulimia nervosa at age 14. Higher neuroticism at age 12 was associated with more frequent meal skipping, and increases in neuroticism between ages 12 and 14 were associated with more frequent meal skipping and increased risk of partial syndrome bulimia nervosa at age 14. Extraversion was generally unrelated to eating and weight management behaviors. These findings provide evidence that normal variations in personality are related to eating behavior, oral health, and eating disorder symptoms during midadolescence.


Iron(III)-quantity-dependent aggregation-dispersion conversion of functionalized gold nanoparticles.
Developing gold nanoparticles (AuNPs) with well-designed functionality is highly desirable for boosting the performance and versatility of inorganic-organic hybrid materials. In an attempt to achieve ion recognition with specific signal expressions, we present here 4-piperazinyl-1,8-naphthalimide-functionalized AuNPs for the realization of quantitative recognition of Fe(III) ions with dual (colorimetric and fluorescent) output. The research takes advantage of 1) quantity-controlled chelation-mode transformation of the piperazinyl moiety on the AuNPs towards Fe(III), thereby resulting in an aggregation-dispersion conversion of the AuNPs in solution, and 2) photoinduced electron transfer of a naphthaimide fluorophore on the AuNPs, thus leading to reversible absorption and emission changes. The functional AuNPs are also responsive to pH variations. This strategy for realizing the aggregation-dispersion conversion of AuNPs with returnable signal output might exhibit application potential for advanced nanoscale chemosensors.


Increased Stability and Breakdown of Brain Effective Connectivity During Slow-Wave Sleep: Mechanistic Insights from Whole-Brain Computational Modelling.
Recent research has found that the human sleep cycle is characterised by changes in spatiotemporal patterns of brain activity. Yet, we are still missing a mechanistic explanation of the local neuronal dynamics underlying these changes. We used whole-brain computational modelling to study the differences in global brain functional connectivity and synchrony of fMRI activity in healthy humans during wakefulness and slow-wave sleep. We applied a whole-brain model based on the normal form of a supercritical Hopf bifurcation and studied the dynamical changes when adapting the bifurcation parameter for all brain nodes to best match wakefulness and slow-wave sleep. Furthermore, we analysed differences in effective connectivity between the two states. In addition to significant changes in functional connectivity, synchrony and metastability, this analysis revealed a significant shift of the global dynamic working point of brain dynamics, from the edge of the transition between damped to sustained oscillations during wakefulness, to a stable focus during slow-wave sleep. Moreover, we identified a significant global decrease in effective interactions during slow-wave sleep. These results suggest a mechanism for the empirical functional changes observed during slow-wave sleep, namely a global shift of the brain's dynamic working point leading to increased stability and decreased effective connectivity.


Centipede bite victims: a review of patients presenting to two emergency departments in Hong Kong.
OBJECTIVE. To review the clinical characteristics of patients presenting after centipede bites in Hong Kong. DESIGN. Descriptive case series. SETTING. Emergency departments of two public hospitals in Hong Kong. PATIENTS. Patients presenting after centipede bites between 2006 and 2010. MAIN OUTCOME MEASURES. Demographics, time and locations of bites, symptoms and signs, treatments and outcomes. RESULTS. A total of 46 relevant patient records were retrieved. The bites were frequently at night, indoors, on lower limbs, and consistently resulted in pain. The majority of the victims were treated with analgesia, anti-histamines, and antibiotics. One patient developed necrosis and five re-attended for delayed pruritus and relapsed/recurrent swelling. CONCLUSIONS. Centipede bites are usually uncomplicated, but may lead to necrosis or delayed hypersensitive reactions.


Temperature responses of mutation rate and mutational spectrum in an Escherichia coli strain and the correlation with metabolic rate.
Temperature is a major determinant of spontaneous mutation, but the precise mode, and the underlying mechanisms, of the temperature influences remain less clear. Here we used a mutation accumulation approach combined with whole-genome sequencing to investigate the temperature dependence of spontaneous mutation in an Escherichia coli strain. Experiments were performed under aerobic conditions at 25, 28 and 37 °C, three temperatures that were non-stressful for the bacterium but caused significantly different bacterial growth rates. Mutation rate did not differ between 25 and 28 °C, but was higher at 37 °C. Detailed analyses of the molecular spectrum of mutations were performed; and a particularly interesting finding is that higher temperature led to a bias of mutation to coding, relative to noncoding, DNA. Furthermore, the temperature response of mutation rate was extremely similar to that of metabolic rate, consistent with an idea that metabolic rate predicts mutation rate. Temperature affects mutation rate and the types of mutation supply, both being crucial for the opportunity of natural selection. Our results help understand how temperature drives evolutionary speed of organisms and thus the global patterns of biodiversity. This study also lend support to the metabolic theory of ecology for linking metabolic rate and molecular evolution rate.


Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.
Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).


The efficiency of granulocyte colony-stimulating factor in hemorrhagic mucositis and febrile neutropenia resulted from methotrexate toxicity.
Methotrexate (MTX) remains one of the most frequently used anti-metabolite agents in dermatology. MTX is an analog of folate that competitively and irreversibly inhibits dihydrofolate reductase. Oral mucositis is a common side effect of chemotherapy drugs and is characterized by erythema, pain, poor oral intake, pseudomembranous destruction, open ulceration and hemorrhage of the oral mucosa. In this paper, we report a 32-year-old female with a case of mucositis due to MTX intoxication that resulted from an overdose for rheumatoid arthritis. The patient had abdominal pain, vomiting, and nausea. During follow-up, the patient's white blood cell count was found to be 0.9 × 10(9)/L (4-10 × 10(9)/L). The patient developed fever exceeding 40 °C. The patient was consulted to the hematology service. They suggested using granulocyte colony-stimulating factor for febrile neutropenia. On the fifth day of treatment, the white blood cell count reached 5.3 × 10(9)/L and the patient's fever and mucositis started to resolve. Here, we presented a case of hemorrhagic mucositis and febrile neutropenia resulted from high-dose MTX that responded very well to granulocyte colony-stimulating factor treatment and we reviewed the literature.


B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis.
B cells are increasingly regarded as integral to the pathogenesis of multiple sclerosis, in part as a result of the success of B cell-depletion therapy. Multiple B cell-dependent mechanisms contributing to inflammatory demyelination of the CNS have been explored using experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for multiple sclerosis. Although B cell Ag presentation was suggested to regulate CNS inflammation during EAE, direct evidence that B cells can independently support Ag-specific autoimmune responses by CD4 T cells in EAE is lacking. Using a newly developed murine model of in vivo conditional expression of MHC class II, we reported previously that encephalitogenic CD4 T cells are incapable of inducing EAE when B cells are the sole APC. In this study, we find that B cells cooperate with dendritic cells to enhance EAE severity resulting from myelin oligodendrocyte glycoprotein (MOG) immunization. Further, increasing the precursor frequency of MOG-specific B cells, but not the addition of soluble MOG-specific Ab, is sufficient to drive EAE in mice expressing MHCII by B cells alone. These data support a model in which expansion of Ag-specific B cells during CNS autoimmunity amplifies cognate interactions between B and CD4 T cells and have the capacity to independently drive neuroinflammation at later stages of disease.


Optic Nerve Sheath Tethering in Adduction Occurs in Esotropia and Hypertropia, But Not in Exotropia.
Repetitive strain to the optic nerve (ON) due to tethering in adduction has been recently proposed as an intraocular pressure-independent mechanism of optic neuropathy in primary open-angle glaucoma. Since strabismus may alter adduction, we investigated whether gaze-related ON straightening and associated globe translation differ in horizontal and vertical strabismus. High-resolution orbital magnetic resonance imaging was obtained in 2-mm thick quasi-coronal planes using surface coils in 25 subjects (49 orbits) with esotropia (ET, 19 ± 3.6Δ SEM), 11 (15 orbits) with exotropia (XT, 33.7 ± 7.3Δ), 7 (12 orbits) with hypertropia (HT, 14.6 ± 3.2Δ), and 31 normal controls (62 orbits) in target-controlled central gaze, and in maximum attainable abduction and adduction. Area centroids were used to determine ON path sinuosity and globe positions. Adduction angles achieved in ET (30.6° ± 0.9°) and HT (27.2° ± 2.3°) did not significantly differ from normal (28.3° ± 0.7°), but significantly less adduction was achieved in XT (19.0° ± 2.5°, P = 0.005). ON sheath tethering in adduction occurred in ET and HT similarly to normal, but did not in XT. The globe translated significantly less than normal, nasally in adduction in XT and temporally in abduction in ET and HT (P < 0.02, for all). Globe retraction did not occur during abduction or adduction in any group. Similar to normal subjects, the ON and sheath become tethered without globe retraction in ET and HT. In XT, adduction tethering does not occur, possibly due to limited adduction angle. Thus, therapeutic limitation of adduction could be considered as a possible treatment for ON sheath tethering.


Simultaneous right retroperitoneal schwannoma and left renal hydatid cyst.
Retroperitoneal schwannomas are quite rare tumors. Isolated renal hydatid cyst is also rare, and it forms 2-4% of hydatid disease. Because of their infrequent occurrence, nonspecific signs and symptoms, and lack of distinguishing radiologic features, we report herein a case of right retroperitoneal mass in a 26-year-old woman which was found to be benign schwannoma following a percutaneous core needle biopsy and a large cortical cyst in the lower pole of the left kidney which was diagnosed as isolated renal hydatid cyst following exploration.


Unraveling structural dynamics in isoenergetic excited S1 and multi-excitonic 1(TT) states of 9,10-bis(phenylethynyl)anthracene (BPEA) in solution via ultrafast Raman loss spectroscopy.
Polyacenes, such as anthracene, tetracene, pentacene etc., have been identified as potential candidates for singlet fission (SF) and triplet-triplet annihilation (TTA) processes in their crystalline and thin film forms as they possess significant singlet and triplet exciton couplings. Interestingly, phenyl-ethynyl substitution to anthracene at the 9,10 positions (9,10-bis(phenylethynyl)anthracene/BPEA) enhances the transverse π-electron conjugation and retains the planar structure even in the excited state. The excited singlet state S1 and the multi-excitonic state 1(TT) in BPEA are separated by ∼30 meV (∼250 cm-1) making it an ideal system for both SF and TTA applications. BPEA is very effective in photon up-conversion even for low input intensities. Transient absorption measurements of BPEA in n-hexane solution are inadequate for distinguishing the S1 state and the multi-excitonic state 1(TT), since the spectroscopic features are complex (mixed) due to the isoenergetic nature and the existence of an equilibrium between these states. However, ultrafast Raman loss spectroscopy reveals a systematic red shift and a blue shift in the central frequencies of the Raman modes corresponding to C[double bond, length as m-dash]C and C[triple bond, length as m-dash]C vibrational frequencies with time constants of ∼2.0 and ∼20 ps, respectively. Such a shift in the Raman frequencies is direct evidence of the structural changes that take place while changing from excited singlet state S1 to the multi-excitonic state on the potential surface.


The Child PTSD Symptom Scale: an update and replication of its psychometric properties.
The psychometric properties of the child PTSD Symptom Scale (CPSS) were examined in 2 samples. Sample 1 (N = 185, ages 6-17 years) consisted of children recruited from hospitals after accidental injury, assault, and road traffic trauma, and assessed 6 months posttrauma. Sample 2 (N = 68, ages 6-17 years) comprised treatment-seeking children who had experienced diverse traumas. In both samples psychometric properties were generally good to very good (internal reliability for total CPSS scores = .83 and .90, respectively). The point-biserial correlation of the CPSS with posttraumatic stress disorder (PTSD) diagnosis derived from structured clinical interview was .51, and children diagnosed with PTSD reported significantly higher symptoms than non-PTSD children. The CPSS demonstrated applicability to be used as a diagnostic measure, demonstrating sensitivity of 84% and specificity of 72%. The performance of the CPSS Symptom Severity Scale to accurately identify PTSD at varying cutoffs is reported in both samples, with a score of 16 or above suggested as a revised cutoff.


Some ambiguities of the student's role in undergraduate nurse training.
Proposed changes in the way in which nurses are educated and trained will lead to stronger links between the academic and practical worlds of nursing. However, little or no attention has been focused on the potential difficulties associated with such a move for the student in this new and changing role. Important ambiguities of the student's role need to be addressed if the degree nursing student is to make the most of available opportunities for learning. In this paper we draw a distinction between two kinds of ambiguity in the role of nursing degree student during clinical placements. The first type is essential to the very nature of degree education in nursing, since the ambiguities here all entail problems in bridging the gap between the world of practical nursing and that of education. They include whether he or she is to regard the role as one of learner or producer of work; whether to become unreflectively acculturated to the organization or to reflect on its norms and values; and the student function within the organization. A second kind of ambiguity is not essential to nurse education, but is an unintended consequence of placement arrangements. The student is thrust into the clinical field as a short-term member of an organization; their position is anomalous and the motive for their involvement is largely different from that of permanent employees. These ambiguities of the role are also the source of important learning opportunities.


Challenges with colorectal cancer staging: results of an international study.
Challenges exist with standardized colorectal cancer reporting despite adoption of the American Joint Committee on Cancer-Staging Manual 8th edition. We performed this study to gauge current practice patterns among a diverse group of surgical pathologists. A web-based questionnaire depicting problematic issues and images related to colorectal carcinoma staging was circulated among 118 surgical pathologists and their responses were correlated with their geographic location (North America vs. Europe vs. others), nature of practice (academic vs. community), the sign-out model (gastrointestinal subspecialty vs. general surgical pathology), and years of professional experience. We found that a substantial number of practicing pathologists ignore recommended-staging criteria in specific settings, particularly with respect to assessment of advanced T stage. Tumors that communicated with the serosa through inflammatory foci were staged as pT3 (49%) or pT4a (51%) by nearly equal numbers of pathologists regardless of level of experience, the sign-out model, or geographic location. Only 65% assigned T stage and margin status based on extent of viable tumor in the neoadjuvant setting. One-third of pathologists, particularly those in Europe (p = 0.015), classified acellular mucin deposits as N1 disease when detected in treatment-naive cases. Nearly 50% of pathologists classified isolated tumor cells (i.e., deposits <0.2 mm) in lymph nodes as metastatic disease (i.e., pN1, p = 0.02). Our results suggest that pathologists ignore recommendations that are based on insufficient data and apply individualized criteria when faced with situations that are not addressed in the American Joint Committee on Cancer Staging Manual 8th edition. These variations in practice limit the ability to compare outcome data across different institutions and draw attention to areas that require further study.


Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
Suboptimal diet is an important preventable risk factor for non-communicable diseases (NCDs); however, its impact on the burden of NCDs has not been systematically evaluated. This study aimed to evaluate the consumption of major foods and nutrients across 195 countries and to quantify the impact of their suboptimal intake on NCD mortality and morbidity. By use of a comparative risk assessment approach, we estimated the proportion of disease-specific burden attributable to each dietary risk factor (also referred to as population attributable fraction) among adults aged 25 years or older. The main inputs to this analysis included the intake of each dietary factor, the effect size of the dietary factor on disease endpoint, and the level of intake associated with the lowest risk of mortality. Then, by use of disease-specific population attributable fractions, mortality, and disability-adjusted life-years (DALYs), we calculated the number of deaths and DALYs attributable to diet for each disease outcome. In 2017, 11 million (95% uncertainty interval [UI] 10-12) deaths and 255 million (234-274) DALYs were attributable to dietary risk factors. High intake of sodium (3 million [1-5] deaths and 70 million [34-118] DALYs), low intake of whole grains (3 million [2-4] deaths and 82 million [59-109] DALYs), and low intake of fruits (2 million [1-4] deaths and 65 million [41-92] DALYs) were the leading dietary risk factors for deaths and DALYs globally and in many countries. Dietary data were from mixed sources and were not available for all countries, increasing the statistical uncertainty of our estimates. This study provides a comprehensive picture of the potential impact of suboptimal diet on NCD mortality and morbidity, highlighting the need for improving diet across nations. Our findings will inform implementation of evidence-based dietary interventions and provide a platform for evaluation of their impact on human health annually. Bill & Melinda Gates Foundation.


Kinetic models of migration of melamine and formaldehyde from melamine kitchenware with data of liquid chromatography.
European legislation has established a specific migration limit (SML) of 15 mg kg-1 for formaldehyde and 2.5 mg kg-1 for melamine. Formaldehyde resins are used in the manufacture of melamine kitchenware. Formaldehyde is listed in group 1 of the IARC list of carcinogenic compounds. To determine the quantity of formaldehyde and melamine as potential migrants from different types of melamine kitchenware (glass, mug, cutlery, big cup and bowl), a HPLC-DAD method has been implemented. This method is an alternative to the ones proposed in technical guidelines to determine formaldehyde by UV-vis spectrophotometry and melamine by HPLC. The final objective was to fit the migration kinetic curves of these two analytes in melamine kitchenware. After the method was validated, decision limit (CCα) and detection capability (CCβ) were calculated for both analytes, when the probabilities of false positive (α) and false negative (β) were fixed at 0.05; being CCβ 0.269 mg L-1 and 0.311 mg L-1 for melamine and formaldehyde respectively. CCα and CCβ were also calculated at the SML of both analytes. The migration testing were conducted with simulant B (3% acetic acid (w/v) in aqueous solution), the conditions of each exposure being 70 °C for 2 h. The quantities of melamine and formaldehyde found in the third exposure of the total kitchenware analysed were between 0.21 and 1.09 mg L-1 and between 0.55 and 3.86 mg L-1, respectively. Migration kinetic curves were built for each type of kitchenware with the data of sixteen consecutive migration cycles (70 °C each 30 min). The SML for melamine was surpassed in the mug, in the big cup and in the bowl after eleven, thirteen and one cycles, respectively. When more cycles were carried out in the mug, the values of the accumulated quantity of formaldehyde and melamine were 15.30 and 6.79 mg L-1, respectively, after thirty-two cycles. Both concentrations exceeded the corresponding SML.


Advance Care Planning in Norwegian nursing homes-Who is it for?
Advance care planning (ACP) is an international concept for improving patient autonomy and communication in the context of anticipated deterioration and end-of-life care. In a preparatory conversation, health care professionals facilitate one or more conversations where nursing home residents are invited to reflect on, and articulate wishes and preferences concerning future medical treatment and end-of-life care. Our aim with this study was to increase knowledge of existing ACP practices in Norwegian nursing homes. We wanted to know how nursing home residents, relatives and nursing home staff take part in the conversations, and to what extent these conversations can be regarded as promoting autonomy, legal rights and individual needs for the residents. We conducted participant observation of seven preparatory conversations, followed by interviews with health care staff (together) and resident and relative (together). In the result section, we present an informative case example of an ACP conversation where common and important characteristics running through our data are present. These are further elaborated under the following headings: Life critical questions, Residents' quiet participation in the conversations, the Dying phase - a clinical issue, Nurses and physicians; different domains and Timing. We find that nursing home staff in our study wants to contribute to open awareness, autonomy and a good death, but there are little reflections about the purpose and content of the conversations, how they should be carried out and when, and what frail nursing home residents are able to understand and express in ACP conversations.


Reduction in regional cerebral metabolic rate of oxygen during human aging.
To investigate changes in cerebral circulation and oxygen metabolism during aging, regional cerebral blood flow (rCBF), regional oxygen extraction fraction (rOEF), regional cerebral metabolic rate of oxygen (rCMRO2) and regional cerebral blood volume (rCBV) were measured using the 15O labelled gas inhalation technique and a multi-slice positron emission tomograph (PET) in 22 healthy volunteers, aged from 26 to 64 years old. The measurements were performed with subjects at rest, without sensory deprivation. The values of rCBF, rOEF, rCMRO2 and rCBV in more than 40 anatomical structures of the brain were evaluated by studying a large series of scans in each region of interest after the functional PET image had been anatomically identified using x-ray computed tomographic images corresponding to the PET. In mean gray values, only CMRO2 showed significant reduction with age. rCMRO2 significantly decreased with age only in the supratentrium, and much more in the left hemisphere. Especially remarkable was rCMRO2 reduction in the left caudate region. Both CBF and OEF were variable and less age-dependent. It was concluded that CMRO2 could be reflecting healthy brain aging most properly.


Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits.
Rho kinase plays an important role in vascular smooth muscle cell (VSMC) contraction and other cellular functions, such as proliferation, migration, and apoptosis. Recent studies have demonstrated that long-term inhibition of Rho kinase suppresses coronary artery spasm and vascular lesion formation after arterial injury. In the cardiovascular surgery field, intimal thickening in vein grafts is the major cause of late graft failure, for which no effective treatment has yet been developed. In this study, we examined whether long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits. Male rabbits were randomly divided into two groups and received normal chow (control group) or a special chow containing 0.09% fasudil (fasudil group). After oral administration, fasudil is metabolized to a specific Rho kinase inhibitor, hydroxyfasudil. Each group underwent reversed autologous vein graft surgery with the internal jugular vein into the left common carotid artery. At 1, 2, and 4 weeks after the operation, we examined the extent of intimal thickening of the graft and VSMC proliferation and apoptosis. The intimal thickening was significantly suppressed in the fasudil group compared with the control group at 2 and 4 weeks after the operation. In the fasudil group, VSMC proliferation was suppressed at 1 and 2 weeks after the operation, whereas VSMC apoptosis was enhanced at 2 weeks after the procedure. These results indicate that Rho kinase is substantially involved in the pathogenesis of intimal thickening of vein grafts and that it is an important therapeutic target for the prevention of graft failure.


Land-based climate solutions for the United States.
Meeting end-of-century global warming targets requires aggressive action on multiple fronts. Recent reports note the futility of addressing mitigation goals without fully engaging the agricultural sector, yet no available assessments combine both nature-based solutions (reforestation, grassland and wetland protection, and agricultural practice change) and cellulosic bioenergy for a single geographic region. Collectively, these solutions might offer a suite of climate, biodiversity, and other benefits greater than either alone. Nature-based solutions are largely constrained by the duration of carbon accrual in soils and forest biomass; each of these carbon pools will eventually saturate. Bioenergy solutions can last indefinitely but carry significant environmental risk if carelessly deployed. We detail a simplified scenario for the United States that illustrates the benefits of combining approaches. We assign a portion of non-forested former cropland to bioenergy sufficient to meet projected mid-century transportation needs, with the remainder assigned to nature-based solutions such as reforestation. Bottom-up mitigation potentials for the aggregate contributions of crop, grazing, forest, and bioenergy lands are assessed by including in a Monte Carlo model conservative ranges for cost-effective local mitigation capacities, together with ranges for (a) areal extents that avoid double counting and include realistic adoption rates and (b) the projected duration of different carbon sinks. The projected duration illustrates the net effect of eventually saturating soil carbon pools in the case of most strategies, and additionally saturating biomass carbon pools in the case of forest management. Results show a conservative end-of-century mitigation capacity of 110 (57-178) Gt CO2 e for the U.S., ~50% higher than existing estimates that prioritize nature-based or bioenergy solutions separately. Further research is needed to shrink uncertainties, but there is sufficient confidence in the general magnitude and direction of a combined approach to plan for deployment now.


Effect of scheduled monitoring of liver function during anti-Tuberculosis treatment in a retrospective cohort in China.
Data on effect of regular liver function monitoring during anti-TB treatment is limited in China. This study aimed to evaluate the effects of scheduled liver function monitoring on identification of asymptomatic liver damage and anti-TB treatment outcomes during anti-TB treatment. A retrospective analysis was performed based on a national-level cohort study. A total of 273 patients developing liver dysfunction were divided into two groups, 111 patients who were diagnosed through scheduled liver function test within two months after initiation of anti-TB treatment formed scheduled monitoring group, others who were diagnosed due to developing symptoms formed passive detection group (n = 162). The two groups were compared through clinical features, prognosis of liver dysfunction and impact on anti-TB treatment using propensity score weighting analysis. 33.3% of 273 patients did not have any clinical symptoms, including 8 with severe hepatotoxicity. 1.8% in scheduled monitoring group and 11.1% in passive detection group required hospitalization (P = 0.004). Regarding the prognosis of liver dysfunction, most patients recovered, no death happened in scheduled monitoring group while 3 died in passive detection group. In terms of impact on anti-TB treatment, 35.1% in scheduled monitoring group and 56.8% in passive detection group changed their anti-TB treatment (P = 0.001). Scheduled monitoring is effective in identifying asymptomatic liver damage, reducing hospitalization rate and improving compliance of anti-TB treatment.


Expression of human Mn SOD in Chinese hamster ovary cells confers protection from oxidant injury.
Manganese superoxide dismutase (Mn SOD) is an important component of antioxidant defense in aerobic cells because of its location in the mitochondria, a significant source of oxygen radicals and an important target of oxidant injury. To test the hypothesis that increased mitochondrial Mn SOD protects from oxidant injury, Chinese hamster ovary (CHO) cells were transfected with a eukaryotic expression vector containing the human Mn SOD cDNA. In recombinant CHO cells, Mn SOD activity was increased threefold over wild-type controls. Acute survival during paraquat exposure (0-500 microM) was significantly improved in CHO cells expressing human Mn SOD, with 71% of recombinant CHO cells surviving at the 50% lethal dose (LD50) for wild-type CHO controls. Cell growth following exposure to paraquat (100 microM) was also significantly improved in recombinant CHO cells. CHO cells expressing human Mn SOD continued to grow and divide after paraquat exposure, whereas growth of wild-type CHO cells was negligible. Protection against oxidant-induced injury was directly related to increased Mn SOD, occurring in the absence of changes in other antioxidant enzymes including catalase, Cu,Zn SOD, and glutathione associated cellular antioxidant mechanisms. We conclude that increased expression of human Mn SOD in vitro directly confers protection against oxidant injury.


Post circumcision meatal stenosis: 12 years' experience.
To study the presentation of meatal stenosis as a complication of circumcision done in boys of neonatal or nappy age. A total of 50 patients were studied. These patients had meatotomy performed to treat meatal stenosis. All the patients had circumcision during the neonatal period or in the nappy age. Meatal stenosis was defined as change in the appearance of the delicate lips of the urinary meatus, with loss of elliptical shape to a circular shape because of fibrosis or scarring, with visually apparent narrowing. Patients with this appearance and no symptoms, but who had presented with a hernia, undescended testes or some other unassociated condition and had meatotomy were for the purpose of this study classed as the incidental group. Patients who were symptomatic and had the meatal stenosis as defined above were classed as the symptomatic group. Sixteen patients (total n = 50) had the diagnosis of meatal stenosis made incidentally. Thirty four patients, (68% of the total treated by meatotomy) presented to the clinic, being symptomatic due to meatal stenosis. The median age at presentation of the symptomatic group was 48 months (range 3 months-13 years) following circumcision. In all the symptomatic patients meatotomy alleviated the symptoms. All the operated patients were seen between one to three months following the operation and discharged. There were no late presentations with recurrence of meatal stenosis or complications of the treatment. Meatal stenosis is an under recognised complication of circumcision done in neonatal and nappy aged boys. Symptomatic presentation from meatal stenosis can be very late.


β-Glucan supplementation, allergy symptoms, and quality of life in self-described ragweed allergy sufferers.
This randomized, placebo-controlled, double-blind study compared the effects of daily supplementation for 4 week with 250 mg Wellmune WGP® β-1,3/1,6-Glucan (WGP) with placebo 250 mg/day (rice flour) on physical and psychological health attributes of self-described "moderate" ragweed allergy sufferers. Study participants (mean age = 36 ± 9 year; range 18-53 year) were recruited before the beginning of ragweed season (September) in Northeastern Ohio. Serum IgE concentration, allergy symptoms [via self-report, Visual Analog Scale (VAS), and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)], psychological well-being [Profile of Mood States (POMS)], and physical function (RAND SF-36 Medical Outcomes Study) were measured immediately prior to and after supplementation with WGP (n = 24) or placebo (n = 24) for 4 weeks. Data were analyzed using repeated measures analyses of variance (ANOVA). Compared with placebo, WGP reduced total allergy symptoms (28%), symptom severity (52%), and symptom rating on the VAS (37%) (P < 0.05), but had no effect on serum IgE levels. As measured by the POMS, WGP increased participants' rating of vigor (10%), but reduced tension (34%), depression (45%), anger (41%), fatigue (38%), and confusion (34%) (P < 0.05). Study participants given WGP reported increased physical health (11%), energy (19%), and emotional well-being (7%) compared with study participants given the placebo (RAND SF-36 Medical Outcomes Study). The WGP group also reported decreased sleep problems (53%), reduced nasal symptoms (59%), eye symptoms (57%), non-nasal symptoms (50%), activities (53%), emotions (57%), and improved quality of life (QOL) (56%), as well as improved global mood state (13%). Supplementation with WGP for 4 weeks improved allergy symptoms, overall physical health, and emotional well-being compared with placebo in self-described "moderate" ragweed allergy sufferers during ragweed allergy season.


Metabolic Control of Smoldering Neuroinflammation.
Compelling evidence exists that patients with chronic neurological conditions, which includes progressive multiple sclerosis, display pathological changes in neural metabolism and mitochondrial function. However, it is unknown if a similar degree of metabolic dysfunction occurs also in non-neural cells in the central nervous system. Specifically, it remains to be clarified (i) the full extent of metabolic changes in tissue-resident microglia and infiltrating macrophages after prolonged neuroinflammation (e.g., at the level of chronic active lesions), and (ii) whether these alterations underlie a unique pathogenic phenotype that is amenable for therapeutic targeting. Herein, we discuss how cell metabolism and mitochondrial function govern the function of chronic active microglia and macrophages brain infiltrates and identify new metabolic targets for therapeutic approaches aimed at reducing smoldering neuroinflammation.


Stalking: false claims of victimisation.
False allegations of victimisation although uncommon are important to recognise. This paper examines those who falsely claim to have been the victims of stalking. To highlight the phenomenon of false victims of stalking. Twelve individuals who falsely claimed to be victims of stalking were compared with a group of 100 true stalking victims. False stalking victims presented for help earlier than real victims and were less likely to claim harassment via letters. They reported equivalent levels of violence directed at themselves but seldom claimed others were attacked. Five types of false claimants were recognisable. False victims consumed more medical services than genuine stalking victims and they were more likely to be embroiled in legal action. They reported similar levels of distress with suicidal ruminations in over 40%. The current interest in stalking is promoting false claims of being stalked. Early identification of these cases and appropriate intervention are essential to both minimising abuses of resources available to true victims and equally to ensure appropriate care for those who express their own disordered state in false claims of victimisation.


Effect of drought and rewatering on the cellular status and antioxidant response of Medicago truncatula plants.
Effects of water stress on plants have been well-documented. However, the combined responses to drought and rewatering and their underlying mechanisms are relatively unknown. The present study attempts to describe spatiotemporal alterations in the physiology and cellular status of Medicago truncatula tissues that result from and subsequently follow a period of moderate water deficit. Physiological processes and cellular damage levels were monitored in roots and leaves by determining lipid peroxidation levels, as well as nitric oxide and hydrogen peroxide content, further supported by stomatal conductance and chlorophyll fluorescence measurements in leaves. During water stress, cells in both organs displayed increased damage levels and reactive oxygen and nitrogen species content, while leaves showed reduced stomatal conductance. Furthermore, both tissues demonstrated increased proline content. Upon rewatering, plants recovered displaying readings similar to pre-stress control conditions. Furthermore, molecular analysis of antioxidant gene expression by quantitative real-time RT-PCR revealed differential spatiotemporal regulation in a number of genes examined (including catalase, cytosolic ascorbate peroxidase, copper/zinc and iron superoxide dismutase and alternative oxidase). Overall, M. truncatula plants demonstrated increased sensitivity to drought-induced oxidative damage; however, this was reversed following rewatering indicating a great elasticity in the plant's capacity to cope with free oxygen radicals.


Engineering the exchange bias and bias temperature by modulating the spin glassy state in single phase Bi9Fe5Ti3O27.
Exchange anisotropy is normally observed at ferromagnetic (FM)/anti-ferromagnetic (AFM) interfaces and also usually at low temperatures. An effective way to find new single-phase materials with strong exchange bias (EB) and high operation temperatures is required for making them useful in practical applications of future spintronic devices. In this work, the exchange bias behaviors of single phase Bi9Fe5Ti3O27 (BFT) were found able to be manipulated by altering its spin glassy state, when the material was intentionally prepared in the nanobelt format. A core-shell model has been proposed to explain the controllable behavior of both exchange bias and bias temperature, in which the AFM domain could be effectively reduced within the nanobelts when changing their particle sizes. A direct observation of two spin glassy behaviors corresponding to two distinct peaks in the zero field cooling (ZFC) curves manifests the validity of the proposed core-shell model.


Drug-induced immune-complex disease.
A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.


Hexose permeation pathways in Plasmodium falciparum-infected erythrocytes.
Plasmodium falciparum requires glucose as its energy source to multiply within erythrocytes but is separated from plasma by multiple membrane systems. The mechanism of delivery of substrates such as glucose to intraerythrocytic parasites is unclear. We have developed a system for robust functional expression in Xenopus oocytes of the P. falciparum asexual stage hexose permease, PfHT1, and have analyzed substrate specificities of PfHT1. We show that PfHT1 (a high-affinity glucose transporter, K(m) approximately 1.0 mM) also transports fructose (K(m) approximately 11.5 mM). Fructose can replace glucose as an energy source for intraerythrocytic parasites. PfHT1 binds fructose in a furanose conformation and glucose in a pyranose form. Fructose transport by PfHT1 is ablated by mutation of a single glutamine residue, Q169, which is predicted to lie within helix 5 of the hexose permeation pathway. Glucose transport in the Q169N mutant is preserved. Comparison in oocytes of transport properties of PfHT1 and human facilitative glucose transporter (GLUT)1, an archetypal mammalian hexose transporter, combined with studies on cultured P. falciparum, has clarified hexose permeation pathways in infected erythrocytes. Glucose and fructose enter erythrocytes through separate permeation pathways. Our studies suggest that both substrates enter parasites via PfHT1.


Plasma creatine kinase B correlates with injury severity and symptoms in professional boxers.
Each year in the United States, approximately 1.7 million people sustain a traumatic brain injury (TBI). Of these TBI events, about 75 percent are characterized as being mild brain injuries. Immediately following TBI, a secondary brain damage persists for hours, days, and even months. Previously, detection of neuronal and glial biomarkers have proven to be useful to predict neurological outcomes. Here, we hypothesized that creatine kinase, brain (CKBB) is a sensitive biomarker for acute secondary brain injury in professional boxers. Blood (8cc) was collected from the boxing athletes (n=18) prior to and after competition (∼30min). The plasma levels of CKBB were measured using the Meso Scale Diagnostic (MSD) electrochemiluminescence (ECL) array-based multiplex format. Additional data such as number of blows to the head and symptom score (Rivermead Post Concussion Symptoms Questionnaire) were collected. At approximately 30min after the competition, the plasma levels of CKBB were significantly elevated in concussed professional boxers and correlated with the number of blows to the head and symptom scores. Additionally, receiver operating curve (ROC) analysis yielded a 77.8% sensitivity and a specificity of 82.4% with an area under the curve (AUC) of 90% for CKBB as an identifier of secondary brain injury within this population. This study describes the detection of CKBB as a brain biomarker to detect secondary brain injury in professional athletes that have experienced multiple high impact blows to the head. This acute biomarker may prove useful in monitoring secondary brain injury after injury.


Game Profile-Based Training in Soccer: A New Field Approach.
Dello Iacono, A, Martone, D, Cular, D, Milic, M, and Padulo, J. Game profile-based training in soccer: a new field approach. J Strength Cond Res 31(12): 3333-3342, 2017-The aim of the study was to profile and compare the time-motion, physiological, and neuromuscular responses of both National Youth League (NYL) and UEFA Youth League (UYL) matches with those of an experimental game profile-based training (GPBT) protocol. Time-motion traits and physiological, perceptual, and neuromuscular responses were investigated in 24 male soccer players across 14 matches and 6 GPBT training sessions, for a total of 420 samples. The GPBT had a greater influence on time-motion traits and perceptual responses than the NYL and UYL matches (all p < 0.001). No significant GPBT vs. match differences were found for mean heart rate or blood lactate (F = 1.228, p = 0.304, and F = 0.978, p = 0.385, respectively). Finally, the GPBT protocol led to greater impairment of the neuromuscular explosive performances when compared with those of the postmatch scores (squat jump: F = 19.991, p < 0.001; countermovement jump: F = 61.703, p < 0.001). Results identified the GPBT protocol as characterized by relatively greater high-intensity workloads than official NYL and UYL matches, requiring increased demanding efforts. In light of these outcomes, the GPBT protocol can be considered an advantageous training method for elite soccer players, capable of stimulating the physical effort and physiological capabilities required during a match. This approach is favorable when designing a training intervention according to the principle of sport specificity, as it is based on the specific metabolic demands.


Health and Care Related Risk Factors for Suicide Among Nursing Home Residents: A Data Linkage Study.
This study aimed to examine associations between health status and care needs of nursing home residents and risk of death from suicide compared to other causes through a retrospective data linkage cohort study examining nursing home resident deaths in Australia between 2000 and 2013. Data linkage was performed between aged care assessment tools-Resident Classification System and Aged Care Funding Instrument-and the National Coronial Information System. A competing risks survival analysis was performed to determine the association between care assessment variables (activities of daily living (ADL), behavior, and complex health care) and the risk of death from suicide and any other cause. Of the 146 nursing home residents who died from suicide, 130 (89%) were matched to their assessment data, with comparable information available for 95 residents (65%). Residents who required high levels of care with ADL, physical health care, and cognitive and behavioral issues had a higher risk of dying from all other causes, yet lower risk of dying from suicide. The study findings demonstrate the feasibility and value of linking these two data sets; highlight a need for improved data collection processes; and support a person-centered care approach for prevention of suicide among nursing home residents.


[Living with responsibility: Max Born and Carl Friedrich von Weizsäcker as philosophers with distance].
Both Carl Friedrich von Weizsäcker und Max Born belong to the most active scientists, which have raised their voice for peace in the 1950s. While Born, senior to Weizsäcker by one generation, engaged in peace movements at an early stage, which was also due to his emigration, and was a driving force for the Einstein-Russell memorandum, Weizsäcker entered the stage essentially with the Göttingen declaration but quickly dominated the discourse. The comparison of their different engagements for peace sheds new light on Weizsäcker. Unlike the German emigrant with a British passport, who was mainly influenced by EInstein and Russell as well as some socialist thoughts he had encountered at an early age, the son of a noble diplomat and the physicist, who was saved from military duties because of his work in the German wartime nuclear project, had quite a different perspective on the postwar atomic threat. The relation of Born and Weizsäcker remained marked by a certain distance even when both took up very similar roles of 'public scientists' active for peace, be it as delegates at Pugwash conferences, on the air, or as speakers in the Frankfurt Paulskirche.


Value of amniotic fluid interleukin-8 for the prediction of histological chorioamnionitis in preterm premature rupture of membranes.
To determine whether amniotic fluid levels of interleukin-8 (IL-8) are of value in the antenatal diagnosis of acute histological chorioamnionitis (HCA) in preterm premature rupture of membranes (PPROM). Department of Obstetrics and Gynaecology, Charles University, Medical School and University Hradec Kralove, Czech Republic. We compared amniotic fluid IL-8 levels in twenty-nine pregnant women with preterm premature rupture of membranes between 24th and 36th gestational weeks with presence and absence acute histological chorioamnionitis or/and microbial invasion in the amniotic cavity using nonparametric tests (Mann-Whitney test), given the non-normal distribution of analyte. Comparisons of proportions were performed with Shapiro-Wilk normality test. Patients with HCA had a significantly higher median amniotic fluid IL-8 concentration than patients without the histological signs of chorioamnionitis (1867 pg/mL, 826-5577 versus 1045 pg/mL, 60-4133, p=0.013). Patients with MIAC had a significantly higher median amniotic fluid level than patients without invasion (1888 pg/mL, 519-5577 versus 1225 pg/mL, 60-2766, p= 0.017). Women with HCA and MIAC had a significantly higher median amniotic fluid IL-8 level than women without histological signs of chorioamnionitis and microbial invasion (3117 pg/mL, 826-5577 versus 1468 pg/mL, 394-2766, p=0.034). HCA or/and MIAC are associated with a significant increase of amniotic fluid interleukin-8 levels. Amniotic fluid IL-8 seems to be a marker of intraamniotic inflammation.


Different polyamine pathways from bacteria have replaced eukaryotic spermidine biosynthesis in ciliates Tetrahymena thermophila and Paramecium tetaurelia.
The polyamine spermidine is absolutely required for growth and cell proliferation in eukaryotes, due to its role in post-translational modification of essential translation elongation factor eIF5A, mediated by deoxyhypusine synthase. We have found that free-living ciliates Tetrahymena and Paramecium lost the eukaryotic genes encoding spermidine biosynthesis: S-adenosylmethionine decarboxylase (AdoMetDC) and spermidine synthase (SpdSyn). In Tetrahymena, they were replaced by a gene encoding a fusion protein of bacterial AdoMetDC and SpdSyn, present as three copies. In Paramecium, a bacterial homospermidine synthase replaced the eukaryotic genes. Individual AdoMetDC-SpdSyn fusion protein paralogues from Tetrahymena exhibit undetectable AdoMetDC activity; however, when two paralogous fusion proteins are mixed, AdoMetDC activity is restored and spermidine is synthesized. Structural modelling indicates a functional active site is reconstituted by sharing critical residues from two defective protomers across the heteromer interface. Paramecium was found to accumulate homospermidine, suggesting it replaces spermidine for growth. To test this concept, a budding yeast spermidine auxotrophic strain was found to grow almost normally with homospermidine instead of spermidine. Biosynthesis of spermidine analogue aminopropylcadaverine, but not exogenously provided norspermidine, correlated with some growth. Finally, we found that diverse single-celled eukaryotic parasites and multicellular metazoan Schistosoma worms have lost the spermidine biosynthetic pathway but retain deoxyhypusine synthase.


Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1.
To clarify the mechanism of cartilage degradation induced by mechanical stress, we investigated the influence of cyclic tension force (CTF) on the metabolism of cultured chondrocytes. The chondrocytes were exposed to CTF using a Flexercell strain unit. Five or 15 kPa of high frequency CTF significantly inhibited the syntheses of DNA, proteoglycan, collagen, and protein. Fifteen kPa of high frequency CTF induced the expression of interleukin-1 (IL-1), matrix metalloproteinase (MMP)-2 and -9 mRNA, and increased the production of pro- and active-MMP-9. The degradation of proteoglycan was inhibited by and MMP inhibitor, indicating that MMPs are involved in the degradation of proteoglycans induced by high frequency CTF. Moreover, reducing the frequency of CTF from high to low decreased the inhibition of proteoglycan synthesis. These findings suggest that the CTF frequency is one of the key determinants of chondrocyte metabolism. Low magnitude CTF, whether high or low frequency, did not cause the gene expression of cartilage degradation factors, suggesting that this CTF magnitude causes only minor changes in the cartilage matrix. High magnitude and frequency CTF caused the gene expression of IL-1 and MMP-9, followed by increases in the production of MMP-2 and -9 proteins, suggesting that excessive and continuous cyclic mechanical stress induces the production of IL-1 and MMP-9, resulting in cartilage degradation.


How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?
Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease. Several studies have documented that long-acting bronchodilators can reduce exacerbation rate and/or severity, and others have shown that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroid combinations in patients at low and high risk for these events. In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single long-acting bronchodilators or LABA/inhaled corticosteroids in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary clearance, and symptom severity may all contribute to decreasing exacerbations. Although preclinical studies suggest LABAs and LAMAs have antiinflammatory effects, such effects have not been demonstrated yet in patients with chronic obstructive pulmonary disease.


Extended sequence typing of Campylobacter spp., United Kingdom.
Supplementing Campylobacter spp. multilocus sequence typing with nucleotide sequence typing of 3 antigen genes increased the discriminatory index achieved from 0.975 to 0.992 among 620 clinical isolates from Oxfordshire, United Kingdom. This enhanced typing scheme enabled identification of clusters and retained data required for long-range epidemiologic comparisons of isolates.


COVID-19: Initial experience of an international group of hand surgeons.
The emergence of the COVID-19 pandemic has severely affected medical treatment protocols throughout the world. While the pandemic does not affect hand surgeons at first glance, they have a role to play. The purpose of this study was to describe the different measures that have been put in place in response to the COVID-19 pandemic by hand surgeons throughout the world. The survey comprised 47 surgeons working in 34 countries who responded to an online questionnaire. We found that the protocols varied in terms of visitors, health professionals in the operating room, patient waiting areas, wards and emergency rooms. Based on these preliminary findings, an international consensus on hand surgery practices for the current viral pandemic, and future ones, needs to be built rapidly.


Morphologic and ultrastructural examination of I-A+ cells in the murine iris.
The surface membrane expression of major histocompatibility (MHC) class II antigens is an important prerequisite for presentation of foreign antigens to the immune system. Because particular antigens that are placed within the anterior chamber of the eye elicit a deviant form of immunity in which effector delayed-type hypersensitivity responses are suppressed, it has been proposed that novel MHC class II antigen-bearing cells exist in the tissues that line the anterior chamber. Class II MHC antigen expression has been identified within the iris, but the detailed morphologic description of these cells is incomplete. With the use of in situ immunoperoxidase and immunoelectron microscopic techniques, we examined the morphologic and ultrastructural characteristics of resident MHC-positive class II (I-A+) cells in murine irises. A significant number of these cells was found in the connective tissue of BALB/c irises. The majority showed extensive dendritic morphologic characteristics and formed a network throughout the iris that did not overlap. Ultrastructurally, I-A+ cells had an indented nucleus, some vacuoles, lysosomes, mitochondria, and an occasional phagosome within their cytoplasm and an absence of desmosomes or other intercellular junctions. Based on these features, it is unlikely that these cells are epithelial or endothelial in origin, but rather are similar to cells of the monocyte/macrophage/dendritic cell lineage. These results show the presence of an I-A+ dendritic cell population, within the murine iris, distributed in a pattern that is similar to that of Langerhans cells in the skin. Due to their compartmentalization within the eye, this cell population may represent a novel antigen-presenting cell that contributes to the immunologic privilege of the anterior chamber.


White matter integrity as a marker for cognitive plasticity in aging.
Age-related differences in white matter (WM) integrity are substantial, but it is unknown whether between-subject variability in WM integrity influences the capacity for cognitive improvement. We investigated the effects of memory training related to active and passive control conditions in older adults and tested whether WM integrity at baseline was predictive of training benefits. We hypothesized that (1) memory improvement would be restricted to the training group, (2) widespread areas would show greater mean diffusivity (MD) and lower fractional anisotropy in older adults relative to young adults, and (3) within these areas, variability in WM microstructure in the older group would be predictive of training gains. The results showed that only the group receiving training improved their memory. Significant age differences in MD and fractional anisotropy were found in widespread areas. Within these areas, voxelwise analyses showed a negative relationship between MD and memory improvement in 3 clusters, indicating that WM integrity could serve as a marker for the ability to adapt in response to cognitive challenges in aging.


Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study.
We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS.


Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients.
The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.


Protein-DNA cross-linking reveals dramatic variation in RNA polymerase II density on different histone repeats of Drosophila melanogaster.
In Drosophila melanogaster the five histone genes are within a 5-kilobase region which is repeated 100 times at a single chromosomal site. These 5-kilobase repeats are of two distinct classes, short and long, that differ by approximately 200 base pairs of DNA in the spacer region between the H1 and H3 genes. Since the mRNA-homologous regions of the repeats are highly conserved, one cannot examine differential expression of the repeats by classical hybridization methods. In this study, we assessed their transcriptional activity by measuring in vivo the relative amounts of RNA polymerase II that were cross-linked by UV irradiation to the two different histone repeats. The RNA polymerase II density on the long repeat in Schneider line 2 cells was strikingly lower (10-fold) than the density on the short repeat. The magnitude of this difference cannot be accounted for by reduced transcription of only one or two genes of the repeat. The density of topoisomerase I, an indicator of transcriptional activity, was also much higher on the short repeat than on the long repeat of line 2 cells. In contrast, the RNA polymerase II density was slightly higher on the long repeat than on the short repeat in a second cell line, KcH. The major difference between active (KcH) and inactive (S2) long repeats resides in the H1-H3 nontranscribed spacer. This portion of the spacer may contain a component necessary for expression that can act over a moderate distance and affect multiple genes of the repeat.


Laser-diode wavelength tuning based on butt coupling into an optical fiber.
An extremely short external cavity that is realized when a Fabry-Perot laser diode is butt coupled to a waveguide or a fiber produces feedback that is effective for controlled wavelength tuning. We used butt coupling to tune a high-output-power laser diode over a wide range (as great as 15 nm) while maintaining constant driving current and temperature. Single-mode or multimode operation repeatedly occurred at specific points throughout the tuning range. An analytical model that includes the effect of multiple reflections from the external cavity, each attenuated by a modal overlap integral, and which is based on phenomenological principles, shows good agreement with the experimental results.


Life-style changes in a cardiac rehabilitation program: the client perspective.
Major life-style changes are required after an acute coronary event, although the vast majority of patients are unsuccessful in maintaining these changes. This study examines factors clients view as enabling or disabling their life-style changes for health promotion. Ten patients in a cardiac rehabilitation program were interviewed using grounded theory methodology. Both health protection and health promotion stimulated life-style change, as did instructions from the physician and life enjoyment. Enabling and disabling factors affecting the process of repatterning were individually defined, but changes in beliefs, attitudes, and plans facilitated repatterning. Specific precipitants to change, forces influencing change, and methods of repatterning life style are discussed, as are nursing implications.


Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria.
Mitochondria must adjust both their intracellular location and their metabolism in order to balance their output to the needs of the cell. Here we show by the proteomic technique of time series difference gel electrophoresis that a major result of neuroendocrine stimulation of the Drosophila renal tubule is an extensive remodeling of the mitochondrial matrix. By generating Drosophila that were transgenic for both luminescent and fluorescent mitochondrial calcium reporters, it was shown that mitochondrial calcium tracked the slow (minutes) but not the rapid (<1 s) changes in cytoplasmic calcium and that this resulted in both increased mitochondrial membrane polarization and elevated cellular ATP levels. The selective V-ATPase inhibitor, bafilomycin, further enhanced ATP levels, suggesting that the apical plasma membrane V-ATPase is a major consumer of ATP. Both the mitochondrial calcium signal and the increase in ATP were abolished by the mitochondrial calcium uniporter blocker Ru360. By using both mitochondrial calcium imaging and the potential sensing dye JC-1, the apical mitochondria of principal cells were found to be selectively responsive to neuropeptide signaling. As the ultimate target is the V-ATPase in the apical plasma membrane, this selective activation of mitochondria is clearly adaptive. The results highlight the dynamic nature and both spatial and temporal heterogeneity of calcium signaling possible in differentiated, organotypic cells and provide a new model for neuroendocrine control of V-ATPase.


New developments: chloroquine-resistance in Plasmodium falciparum.
Chloroquine-resistance is associated with higher malaria mortality in children in Africa where the drug is still widely used. In sensitive strains the drug attacks hemoglobin digestion in the lysosome and prevents detoxification of hemin to hemozoin. Reduced drug uptake is responsible for resistance, which is incompletely associated with changes in lysosome membrane protein PGH1. The report discussed here gives evidence for the role of another lysosome membrane protein, PfCRT, where a change from lysine to threonine in a transmembrane domain determines the change to resistance. Other changes in PfCRT, and to some extent change(s) in PGH1, are believed to compensate for loss of fitness of the modified PfCRT.


SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer.
We describe a protocol for disclosing unfavorable information-"breaking bad news"-to cancer patients about their illness. Straightforward and practical, the protocol meets the requirements defined by published research on this topic. The protocol (SPIKES) consists of six steps. The goal is to enable the clinician to fulfill the four most important objectives of the interview disclosing bad news: gathering information from the patient, transmitting the medical information, providing support to the patient, and eliciting the patient's collaboration in developing a strategy or treatment plan for the future. Oncologists, oncology trainees, and medical students who have been taught the protocol have reported increased confidence in their ability to disclose unfavorable medical information to patients. Directions for continuing assessment of the protocol are suggested.


Benefit-risk analysis for foods (BRAFO): Evaluation of exposure to dietary nitrates.
Dietary nitrate has been associated with health benefits as well as potential risks, thus presenting a paradox for consumers and health professionals. To address the issue, we applied the Benefit-Risk Analysis for Foods (BRAFO) framework to evaluate dietary exposure to nitrate by considering how the risks and benefits might vary under the reference scenario of the acceptable daily intake (ADI) set forth by JECFA (3.7 mg/kg-day), or under an alternative scenario of a higher ADI (independently developed herein). Results demonstrated that risk, as conservatively characterized by various toxicological benchmarks, was present at levels ranging from the current ADI value of 3.7 mg/kg-day (lowest end of the range) to >15 mg/kg-day. When these ADI values, both established by regulatory bodies as well as independently herein were compared to intakes associated with benefits (decreased blood pressure observed following repeated exposure to nitrates ∼4-18 mg/kg-day), along with considerations of current dietary exposures associated with healthy diets, the alternative scenario allowed for benefits without incurring additional risk. For consumers aged 12 weeks and older, ADI values ∼12-17 mg/kg-day-based on more reliable data than used to derive the current ADI-allow benefits to be realized while still protecting public health. The assessment serves as a case study in how benefits can be considered in a risk assessment paradigm for foods, thus providing useful information to decision makers.


Improving the education of children living in poverty.
Richard Murnane observes that the American ideal of equality of educational opportunity has for years been more the rhetoric than the reality of the nation's political life. Children living in poverty, he notes, tend to be concentrated in low-performing schools staffed by ill-equipped teachers. They are likely to leave school without the skills needed to earn a decent living in a rapidly changing economy. Murnane describes three initiatives that the federal government could take to improve the education of these children and increase their chances of escaping poverty. All would strengthen the standards-based reforms at the heart of the No Child Left Behind Act of 2001 (NCLB) by bracing the three legs on which the reforms rest: accountability, incentives, and capacity. Congress, says Murnane, should improve accountability by amending NCLB to make performance goals more attainable. The goals should emphasize growth in children's skills rather than whether children meet specific test score targets. Congress should also amend NCLB to develop meaningful goals for high school graduation rates. Congress should strengthen states' incentives to improve the education of low-income students. It should also encourage states to develop effective voluntary school choice programs to enable students who attend failing public schools to move to more successful schools in other districts. Finally, Congress should use competitive matching grants to build the capacity of schools to educate low-income children and the capacity of state departments of education to boost the performance of failing schools and districts. The grants would help develop effective programs to improve teaching and to serve students who do not fare well in conventional high school programs. Murnane estimates the annual cost of these three initiatives to be approximately $2.5 billion.


The SpikerBox: a low cost, open-source bioamplifier for increasing public participation in neuroscience inquiry.
Although people are generally interested in how the brain functions, neuroscience education for the public is hampered by a lack of low cost and engaging teaching materials. To address this, we developed an open-source tool, the SpikerBox, which is appropriate for use in middle/high school educational programs and by amateurs. This device can be used in easy experiments in which students insert sewing pins into the leg of a cockroach, or other invertebrate, to amplify and listen to the electrical activity of neurons. With the cockroach leg preparation, students can hear and see (using a smartphone oscilloscope app we have developed) the dramatic changes in activity caused by touching the mechanosensitive barbs. Students can also experiment with other manipulations such as temperature, drugs, and microstimulation that affect the neural activity. We include teaching guides and other resources in the supplemental materials. These hands-on lessons with the SpikerBox have proven to be effective in teaching basic neuroscience.


Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion.
Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, "experience-expectant," and "experience-dependent." Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.


Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells.
Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis. However, limited information is available about autophagy in aristolochic acid (AA) nephropathy. In this study, we investigated the role of autophagy and related signaling pathway during progression of AAI-induced injury to renal tubular epithelial cells (NRK52E cells). The results showed that autophagy in NRK52E cells was detected as early as 3-6 hrs after low dose of AAI (10 µM) exposure as indicated by an up-regulated expression of LC3-II and Beclin 1 proteins. The appearance of AAI-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in NRK52E cells provided further evidence for autophagy. However, cell apoptosis was not detected until 12 hrs after AAI treatment. Blockade of autophagy with Wortmannin or 3-Methyladenine (two inhibitors of phosphoinositede 3-kinases) or small-interfering RNA knockdown of Beclin 1 or Atg7 sensitized the tubular cells to apoptosis. Treatment of NRK52E cells with AAI caused a time-dependent increase in extracellular signal-regulated kinase 1 and 2 (ERK1/2) activity, but not c-Jun N-terminal kinase (JNK) and p38. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 resulted in a decreased AAI-induced autophagy that was accompanied by an increased apoptosis. Taken together, our study demonstrated for the first time that autophagy occurred earlier than apoptosis during AAI-induced tubular epithelial cell injury. Autophagy induced by AAI via ERK1/2 pathway might attenuate apoptosis, which may provide a protective mechanism for cell survival under AAI-induced pathological condition.


Modulation of Spontaneous Brain Activity during Mental Imagery.
Magnetic measurements of average power of human alpha and beta activity over the occipital and parietal areas of the scalp reveal spatially selective suppression of the activity of the occipital cortex when abstract figures are briefly presented visually and subjects simply indicate that they saw the figure. However, the duration of the suppression increases markedly when subjects must indicate whether or not they had previously seen the figure. The reaction time is similarly prolonged during the search of visual memory, and is commensurate with the duration of selective suppression of brain activity. It is also demonstrated that alpha activity is not replaced by beta activity during this suppression, but that power in the beta band is also diminished during memory search. Low correlations between the scalp distributions of power in the beta and alpha bands indicate that partly different neuronal populations give rise to activity of these different frequency bands. Since magnetic fields are negligibly affected by intervening bone tissues, dramatic asymmetries in the distribution of alpha activity across the scalps of individuals and the differences in distribution between individuals cannot be ascribed to differences in skull thickness but are due instead to differences in underlying brain anatomy or function. Nevertheless, a common pattern of suppression of alpha activity is observed across subjects during well-controlled cognitive tasks. This implies that the visual system is involved in mental imagery.


Comparison of flanged intrascleral intraocular lens fixation versus iris claw intraocular lens fixation: A retrospective study.
To compare the visual outcome and complications of retropupillary fixated iris claw intraocular lens (IOL) and sutureless intrascleral IOL fixation using the flanged fixation technique at 1 year. In this retrospective study, eyes that underwent either iris claw or flanged SFIOL from January 2016 to July 2017 with a minimum of 1-year follow-up were enrolled. Improvement in visual acuity, intraocular pressure measurements, endothelial cell count, central macular thickness, and complications were compared between and within groups at 6 weeks, 3 months, and 1 year postoperatively. Data from 150 eyes were analyzed (n = 90 in the iris claw group and n = 60 in the flanged SFIOL group). Posterior capsular rent was the most common indication for IOL implantation (n = 51, 34%). The iris claw and SFIOL groups were comparable in terms of demographics and baseline characteristics. There was significant improvement in uncorrected distance visual acuity (UCDVA) at 6 weeks in both groups (P = 0.77), and at 1 year, the UCDVA was comparable between groups (0.36 ± 0.32 in the iris claw group and 0.30 ± 0.28 in the SFIOL, P= 0.75). Transient elevation of intraocular pressure was seen slightly more in eyes with SFIOL (17%), while ovalization of the pupil was the main sequelae seen in the iris claw group (20%). Both iris claw IOL fixation and SFIOL using flange are viable options for surgical correction of aphakia. Visual outcomes are excellent at 6 weeks and are maintained till 1-year follow-up, and complication rates are acceptably low, although ovalization of pupil is common with iris claw IOLs.


In vivo two-photon microscopy of the human eye.
Two-photon (2P) microscopy is a powerful tool for imaging and exploring label-free biological tissues at high resolution. Although this type of microscopy has been demonstrated in ex vivo ocular tissues of both humans and animal models, imaging the human eye in vivo has always been challenging. This work presents a novel compact 2P microscope for non-contact imaging of the anterior part of the living human eye. The performance of the instrument was tested and the maximum permissible exposure to protect ocular tissues established. To the best of our knowledge, 2P images of the in vivo human cornea, the sclera and the trabecular meshwork are shown for the very first time. Acquired images are of enough quality to visualize collagen arrangement and morphological features of clinical interest. Future implementations of this technique may constitute a potential tool for early diagnosis of ocular diseases at submicron scale.


The incidence of emboli during cardiac surgery: a histopathologic analysis of 2297 patients.
Manipulation of the atherosclerotic aorta during cardiac surgery is assumed to cause embolization, which can contribute to adverse outcomes. Recently, as a result of worldwide trials deploying the Embol-X intraaortic filter during cardiac surgery, such emboli were captured and processed for histopathologic analysis. Filters with a pore size of 120 microns were placed in 2297 patients who underwent the following operations: coronary artery bypass grafting (CABG) (70%), valve (17%), combination CABG/valve (11%), and other (2%). The filters captured at least one embolus in 98% of the patients. An average of 8.3 particles was captured per filter (range of 0-74). The surface area of the emboli was on an average 5.8 mm2 (range of 0-188 mm2). Histologic analysis of the captured particles indicated that in 79% of the filters fibrous atheromata were noted, in 44% there were platelets and fibrin, 8% had red blood cell thrombus, 3% had fibro-fatty/adventitial tissue, 2% had other material including cartilage, myocardium, lung, suture, and a teflon pledget. Of the patients enrolled, 1569 were high-risk. The average number of particles captured in the high-risk patients was 8.5 versus 5.8 for the low- to moderate-risk patients (P < .0001). Concomitantly,there was an increase in the embolic burden between the higher- and lower-risk patients (surface area 6.6 vs. 4.0 mm2, P < .0001). These data show the ubiquitous incidence of emboli during cardiac procedures. Intraaortic filtration should reduce adverse outcomes as was demonstrated for the high-risk patients in this study. Aortic manipulation during cardiac surgery can cause embolization and increase morbidity. The use of an intraaortic filter can decrease the embolic burden. We now report the histopathologic analysis of these emboli.


Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study.
22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis.


Cytoskeletal actin patterns shape mast cell activation.
Activation of immune cells relies on a dynamic actin cytoskeleton. Despite detailed knowledge of molecular actin assembly, the exact processes governing actin organization during activation remain elusive. Using advanced microscopy, we here show that Rat Basophilic Leukemia (RBL) cells, a model mast cell line, employ an orchestrated series of reorganization events within the cortical actin network during activation. In response to IgE antigen-stimulation of FCε receptors (FCεR) at the RBL cell surface, we observed symmetry breaking of the F-actin network and subsequent rapid disassembly of the actin cortex. This was followed by a reassembly process that may be driven by the coordinated transformation of distinct nanoscale F-actin architectures, reminiscent of self-organizing actin patterns. Actin patterns co-localized with zones of Arp2/3 nucleation, while network reassembly was accompanied by myosin-II activity. Strikingly, cortical actin disassembly coincided with zones of granule secretion, suggesting that cytoskeletal actin patterns contribute to orchestrate RBL cell activation.


"Evita Una Muerte, Esta en Tus Manos" Program: Bystander First Aid Training for Terrorist Attacks.
The latest terrorist attacks in Europe and in the rest of the world, and the military experience in the most recent conflicts leave us with several lessons learned. The most important is that the fate of the wounded rests in the hands of the one who applies the first dressing, because the victims usually die within the first 10 minutes, before professional care providers or police personnel arrive at the scene. A second lesson is that the primary cause of preventable death in these types of incidents involving explosives and firearms is massive hemorraghe. There is a need to develop a training oriented to citizens so they can identify and use available resources to avoid preventable deaths that occur in this kind of incidents, especially massive hemorrhage. A 7-hour training intervention program was developed and conducted between January and May 2017. Data were collected from participants' answers on a multiple-choice test before and after undertaking the training. Improved mean score for at least 75% of a group's members on the posttraining test was considered reflective of adequate knowledge. A total of 173 participants (n = 74 men [42.8%]; n = 99 women [57.2%]) attended the training. They were classified into three groups: a group of citizens/ first responders with no prior health training, a group of health professionals, and a group of nursing students. Significant differences (ρ < .05) between mean pre- and post-training test scores occurred in each of the three groups. There was a clear improvement in the knowledge of the students after the training when pre- and post-training test scores were compared within the three groups. The greatest improvement was seen in the citizens/first responders group.


Three-dimensional imaging with simultaneous reproduction of two image elements in one display pixel by linearization of intensity ratio of two images formed by any physical gear.
Full spatial resolution in stereo image is reached if each (left and right) view of a three-dimensional scene is reproduced by all pixels of the display matrix. It is attractive for this purpose to simultaneously reproduce two image resolvable elements (corresponding to image elements of left and right views) in one display pixel. This paper shows how information-dependent linearization of the optical intensity ratio of left and right image elements (whose sum is submitted in the form of common optical intensity on the input of the display pixel) can be used to present corresponding elements separately in left and right observation windows. Such a linearization principle is valid regardless of the concrete physical gear of optical separation and demonstrated on the examples of optical separators on the basis of polarization, spectral, diffractive, and real amplitude modulation of light.


Cross-presenting CD103+ dendritic cells are protected from influenza virus infection.
CD8+ cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial. Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103+ DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103+ DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8+ T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103+ DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway.