Systematic error of lidar profiles caused by a polarization-dependent receiver transmission: quantification and error correction scheme.
Signals of many types of aerosol lidars can be affected with a significant systematic error, if depolarizing scatterers are present in the atmosphere. That error is caused by a polarization-dependent receiver transmission. In this contribution we present an estimation of the magnitude of this systematic error. We show that lidar signals can be biased by more than 20%, if linearly polarized laser light is emitted, if both polarization components of the backscattered light are measured with a single detection channel, and if the receiver transmissions for these two polarization components differ by more than 50%. This signal bias increases with increasing ratio between the two transmission values (transmission ratio) or with the volume depolarization ratio of the scatterers. The resulting error of the particle backscatter coefficient increases with decreasing backscatter ratio. If the particle backscatter coefficients are to have an accuracy better than 5%, the transmission ratio has to be in the range between 0.85 and 1.15. We present a method to correct the measured signals for this bias. We demonstrate an experimental method for the determination of the transmission ratio. We use collocated measurements of a lidar system strongly affected by this signal bias and an unbiased reference system to verify the applicability of the correction scheme. The errors in the case of no correction are illustrated with example measurements of fresh Saharan dust.


Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia.
The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.


Family education for people with schizophrenia in Beijing, China: randomised controlled trial.
Much of China lacks well-developed services for people with schizophrenia and their families, and most of the existing services focus on hospitals. There is a need for culturally sensitive family treatments offered by nurses. To conduct a longitudinal experimental study examining the effect of patient and family education in a sample of Chinese people with schizophrenia. A randomised controlled trial was conducted in a large hospital with a was conducted in a large hospital with a sample of 101 patients with schizophrenia and their families. Data were collected at admission and at discharge, and then at 3 and 9 months after discharge. The intervention group received family education, and data on their knowledge about schizophrenia, symptoms, functioning, psychosocial behaviour, relapse and medication adherence were collected and compared with the control group. There was a significant improvement in knowledge about schizophrenia in the experimental group and a significant difference in symptom scores and functioning at 9 months after discharge. Patients who were nonadherent to medication regimens were more likely to relapse. Family education on schizophrenia by nurses in China was effective in improving knowledge and promoting improvement in patients' symptoms.


Factors affecting catastrophic health expenditure and impoverishment from medical expenses in China: policy implications of universal health insurance.
To assess the degree to which the Chinese people are protected from catastrophic household expenditure and impoverishment from medical expenses and to explore the health system and structural factors influencing the first of these outcomes. Data were derived from the Fourth National Health Service Survey. An analysis of catastrophic health expenditure and impoverishment from medical expenses was undertaken with a sample of 55 556 households of different characteristics and located in rural and urban settings in different parts of the country. Logistic regression was used to identify the determinants of catastrophic health expenditure. The rate of catastrophic health expenditure was 13.0%; that of impoverishment was 7.5%. Rates of catastrophic health expenditure were higher among households having members who were hospitalized, elderly, or chronically ill, as well as in households in rural or poorer regions. A combination of adverse factors increased the risk of catastrophic health expenditure. Families enrolled in the urban employee or resident insurance schemes had lower rates of catastrophic health expenditure than those enrolled in the new rural corporative scheme. The need for and use of health care, demographics, type of benefit package and type of provider payment method were the determinants of catastrophic health expenditure. Although China has greatly expanded health insurance coverage, financial protection remains insufficient. Policy-makers should focus on designing improved insurance plans by expanding the benefit package, redesigning cost sharing arrangements and provider payment methods and developing more effective expenditure control strategies.


Evidence on the Chronic Care Model in the new millennium.
Developed more than a decade ago, the Chronic Care Model (CCM) is a widely adopted approach to improving ambulatory care that has guided clinical quality initiatives in the United States and around the world. We examine the evidence of the CCM's effectiveness by reviewing articles published since 2000 that used one of five key CCM papers as a reference. Accumulated evidence appears to support the CCM as an integrated framework to guide practice redesign. Although work remains to be done in areas such as cost-effectiveness, these studies suggest that redesigning care using the CCM leads to improved patient care and better health outcomes.


School start times for adolescents.
The American Academy of Pediatrics recognizes insufficient sleep in adolescents as an important public health issue that significantly affects the health and safety, as well as the academic success, of our nation's middle and high school students. Although a number of factors, including biological changes in sleep associated with puberty, lifestyle choices, and academic demands, negatively affect middle and high school students' ability to obtain sufficient sleep, the evidence strongly implicates earlier school start times (ie, before 8:30 am) as a key modifiable contributor to insufficient sleep, as well as circadian rhythm disruption, in this population. Furthermore, a substantial body of research has now demonstrated that delaying school start times is an effective countermeasure to chronic sleep loss and has a wide range of potential benefits to students with regard to physical and mental health, safety, and academic achievement. The American Academy of Pediatrics strongly supports the efforts of school districts to optimize sleep in students and urges high schools and middle schools to aim for start times that allow students the opportunity to achieve optimal levels of sleep (8.5-9.5 hours) and to improve physical (eg, reduced obesity risk) and mental (eg, lower rates of depression) health, safety (eg, drowsy driving crashes), academic performance, and quality of life.


Virtue ethics, positive psychology, and a new model of science and engineering ethics education.
This essay develops a new conceptual framework of science and engineering ethics education based on virtue ethics and positive psychology. Virtue ethicists and positive psychologists have argued that current rule-based moral philosophy, psychology, and education cannot effectively promote students' moral motivation for actual moral behavior and may even lead to negative outcomes, such as moral schizophrenia. They have suggested that their own theoretical framework of virtue ethics and positive psychology can contribute to the effective promotion of motivation for self-improvement by connecting the notion of morality and eudaimonic happiness. Thus this essay attempts to apply virtue ethics and positive psychology to science and engineering ethics education and to develop a new conceptual framework for more effective education. In addition to the conceptual-level work, this essay suggests two possible educational methods: moral modeling and involvement in actual moral activity in science and engineering ethics classes, based on the conceptual framework.


Can first-year medical students acquire quality improvement knowledge prior to substantial clinical exposure? A mixed-methods evaluation of a pre-clerkship curriculum that uses education as the context for learning.
Quality Improvement (QI) training for health professionals is essential to strengthen health systems. However, QI training during medical school is constrained by students' lack of contextual understanding of the health system and an already saturated medical curriculum. The Program for Improvement in Medical Education (PRIME), an extracurricular offered at the Michael G. DeGroote School of Medicineat McMaster University (Hamilton, Canada), addresses these obstacles by having first-year medical students engage in QI by identifying opportunities for improvement within their own education. A sequential explanatory mixed-methods approach, which combines insights derived from quantitative instruments and qualitative interview methods, was used to examine the impact of PRIME on first-year medical students and the use of QI in the context of education. The study reveals that participation in PRIME increases both knowledge of, and comfort with, fundamental QI concepts, even when applied to clinical scenarios. Participants felt that education provided a meaningful context to learn QI at this stage of their training, and were motivated to participate in future QI projects to drive real-world improvements in the health system. Early exposure to QI principles that uses medical education as the context may be an effective intervention to foster QI competencies at an early stage and ultimately promote engagement in clinical QI. Moreover, PRIME also provides a mechanism to drive improvements in medical education. Future research is warranted to better understand the impact of education as a context for later engagement in clinical QI applications as well as the potential for QI methods to be translated directly into education.


Radiofrequency ablation for lung tumors: outcomes, effects on survival, and prognostic factors.
We aimed to evaluate the survival benefit achieved with radiofrequency (RF) ablation of primary and metastatic lung tumors and determine significant prognostic factors for recurrence-free survival. Forty-nine patients with lung cancer (10 primary and 39 metastatic) underwent computed tomography-guided percutaneous RF ablation between June 2005 and October 2013. A total of 112 tumors (101 metastatic and 11 primary non-small cell lung cancer) were treated with RF ablation. Tumor diameter ranged from 0.6 to 4 cm (median 1.5 cm). Effectiveness of treatment, complications, and survival were analyzed. Primary success rate was 79.5% and local tumor progression occurred in 23 tumors. Among tumors showing progression, 10 were re-treated with RF ablation and secondary success rate was 87.5%. One-, two-, and three-year overall survival rates of 10 patients with primary lung cancer were 100%, 86%, and 43%, respectively. One-, two-, three-, four-, and five-year overall survival rates for 39 patients with metastatic lung tumors were 90%, 73%, 59%, 55%, and 38%, respectively. One-, two-, three-, and four-year overall survival rates for 16 patients with colorectal pulmonary metastases were 94%, 80%, 68%, and 23%, respectively. Complications occurred in 30 sessions (24.6%). Pneumothorax occurred in 19 sessions with seven requiring image-guided percutaneous chest tube drainage. Tumor status (solitary or multiple) and presence of extrapulmonary metastasis at initial RF ablation were significant prognostic factors in terms of recurrence-free survival. RF ablation is a safe and effective treatment with a survival benefit for selected patients with primary and secondary lung tumors.


Hirschsprung's disease and idiopathic megacolon in adults and adolescents.
The distinction between Hirschsprung's disease and idiopathic megacolon in childhood dates from the classic clinical, radiological, and histological studies of Bodian, Stephens, and Ward. This article describes clinical experience over 15 years of 94 patients in whom megacolon of these two types was recognised for the first time after the age of 10, to illustrate the problems of diagnosis and treatment in later years. Just as it is now recognised that patients with the clinical characteristics of Hirschsprung's disease may have one of several abnormalities of the myenteric plexus, including not only absence of ganglion cells, but also patchy or zonal loss, abnormal neurones or neuronal dysplasia, so idiopathic megacolon may also be a heterogeneous group of cases. This paper suggests on clinical grounds that those patients with idiopathic megacolon whose symptoms start in childhood differ from those whose symptoms develop in later years.


Role of routine chest radiographs in the evaluation of patients with stable blunt chest trauma--a prospective analysis.
The study sought to assess the test performance characteristics of clinical judgement in the evaluation of stable blunt chest trauma patients compared with chest radiography (CXR) in the determination of significant intra-thoracic injury. We prospectively enrolled all adult patients (older than 16years) who were considered to have stable blunt chest trauma over a six-month period (May 1-October 31, 2009). We defined the latter as patients who were unintubated, normotensive (systolic blood pressure > 90 mm Hg) and without hypoxia (oxygen saturation> 95% at room air). Patients eligible for the study were sent for anteroposterior (AP) CXRs which were then interpreted by the same consultant radiologist throughout the study period. Both test (clinical judgement) and disease status (CXR) were assigned and correlated as binary measures. We compared the test performance characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic likelihood ratios of clinical judgement to CXR findings in the determination of significant intra-thoracic injury. During the six-month period, data were collected from 77 eligible stable blunt chest trauma patients (age over 16 years). Fifty-nine patients (76.6%) were male. Nine patients (11.7%) were radiologically confirmed to have significant blunt chest injuries including rib fractures, pneumothorax and an isolated case of pulmonary contusion. All nine (11.7%) patients had a positive (abnormal) radiograph for rib fractures. In addition, three (3.9%) of them also had both rib fracture and pneumothoraces and one (1.3%) had both a rib fracture and pulmonary contusion. Clinical judgementfor the diagnosis of significant blunt chest injuries matched with the CXR finding with 95% confidence intervals (CIs): sensitivity 100% (95% CI 66.4, 100), specificity 32.4% (95% CI 21.5, 44.8), prevalence 11.7%, PPV 16.4% (95% CI 7.77, 28.8), NPV100% (95% CI 84.6, 100), DLR+ 1.48 (95% CI 1.25, 1.74). The majority ofpatients who sustained blunt chest injuries and were assessed as stable patients do not require CXR routinely. This study revealed that physicians in the local Emergency Department may be over-utilizing CXRfor patients who have stable blunt chest trauma.


Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters.
Human chorionic gonadotropin (hCG) is a heterogeneous glycoprotein hormone comprising an alpha-subunit and beta-subunit that can vary in peptide and carbohydrate structure. After conception, hCG produced by early trophoblast cells acts on luteinizing hormone (LH)/hCG receptor corpus luteum cells to promote progesterone production and establish maternal recognition of pregnancy. hCG is not simply 1 molecule, and 2 variants of hCG appear to have independent activities in promoting tumor cell growth, invasion and malignancy. Hyperglycosylated hCG (H-hCG), produced by cytotrophoblast cells, is a marker for cytotrophoblast cells and tumor marker for gestational trophoblastic diseases. H-hCG promotes growth and invasion in these cells during pregnancy implantation, and growth in varying degrees by many nontrophoblastic neoplasms. beta-hCG is a marker of poor prognosis shown to promote growth and invasion in vitro, suggesting autocrine growth factor properties. Vaccines to beta-hCG have been successfully demonstrated, suggesting a potential adjuvant therapy in cancer treatment. Although sufficiently distinct in both structure and occurrence, similarities have been observed between H-hCG and beta-hCG as promoters of cell growth, invasion and malignancy. It is somewhat irregular for 2 structural variants of a molecule to have independent actions, actions very different to the gonadotropic function of the established hormone hCG.


[Alveolar lipoproteinosis, an incidental finding during an unrelated pre-surgical study with inadequate response to complete pulmonary washing].
The alveolar lipoproteinosis (ALP) is a rare pulmonary disease, characterized by an excess of phospholipids in the distal airway, and the most symptom of which is dyspnea. 35 years old patient in whom we observed incidentally pulmonary infiltrations in a chest X-ray during a unrelated pre-surgical study. We could not make a definitive diagnosis after further investigations carried out in the Division of Respiratory Medicine. We, therefore, sent this patient to the Division of Chest Surgery for a complementary video-thoracoscopy. Biopsy showed presence of ALP. The ALP is a rare disease that originates diagnosis difficulties, and that often needs lung biopsies to confirm its diagnosis. Once treated, its prognosis is excellent. The safest and most effective treatment is a complete pulmonary washing, that, in our patient, was required 7 months after diagnosis as this patient presented clinical deterioration and worsening in the lung function studies. This treatment did not achieve the expected goal. In the subsequent 6 months, we repeated the same treatment and failed again. We then started a treatment with granulocyte-macrophage-colony stimulating factor (GM-CSF) and obtain good response.


A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.
The purpose of this study was to evaluate the activity and toxicity of electro-hyperthermia (ET) on relapsed malignant glioma patients. Twelve patients with histologically diagnosed malignant glioma entered the study. Eight patients had glioblastoma multiforme, two had anaplastic astrocytoma grade III and two had anaplastic oligodendroglioma. All patients were pre-treated with temozolamide-based chemotherapy and radiotherapy. Hyperthermia with short radiofrequency waves of 13.56 MHz was applied using a capacitive coupling technique keeping the skin surface at 20 degrees C. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumours was above 40 degrees C for more than 90% of the treatment duration. One complete remission and 2 partial remission were achieved, with a response rate of 25%. The median duration of response was 10 months (range 4-32). The median survival of the entire patient population was 9 months, with 25% survival rate at 1 year. ET appears to have some effectiveness in adults with relapsed malignant glioma.


Teaching forensic psychiatry to psychiatric residents.
This study outlines current trends in the education of psychiatric residents in forensic psychiatry. As general psychiatrists are more frequently confronted with issues pertaining to psychiatry and the law, residency training in these areas becomes increasingly important. In order to study the educational experience of psychiatric residents in forensic psychiatry, a survey was sent to all residency training directors in the United States and Canada. The findings of the study included a description of didactics and experiential rotations in forensic psychiatry, the background of those teaching forensics, inclusion of key topics in the curriculum, and the training directors' opinions of both the importance of forensic education and the inclusion of these specific topics in the curriculum.


Two-dimensional delocalized states in organometallic bis-acetylide networks on Ag(111).
The electronic structure of surface-supported organometallic networks with Ag-bis-acetylide bonds that are intermediate products in the bottom-up synthesis of graphdiyne and graphdiyne-like networks were studied. Scanning tunneling microscopy (STM) and spectroscopy (STS) reveal a frontier, unoccupied electronic state that is delocalized along the entire organometallic network and proves the covalent nature of the Ag-bis-acetylide bonds. Density-functional theory (DFT) calculations corroborate the spatial distribution of the observed delocalized state and attribute it to band mixing of carbon and silver atoms combined with n-doping of the metal surface. The metal-bis-acetylide bonds are typical metal-organic bonds with mixed character containing covalent and strong ionic contributions. Moreover, the organometallic networks exhibit a characteristic graphene-like band structure with linear band dispersion at each K point.


Safe intubation in Morquio-Brailsford syndrome: A challenge for the anesthesiologist.
Morquio-Brailsford syndrome is a type of mucopolysaccharidoses. It is a rare disease with features of short stature, atlantoaxial instability with risk of cord damage, odontoid hypoplasia, pectus carinatum, spine deformities, hepatomegaly, and restrictive lung disease. Neck movements during intubation are associated with the risk of quadriparesis due to cervical instability. This, along with the distortion of the airway anatomy due to deposition of mucopolysaccharides makes airway management arduous. We present our experience in management of difficult airway in a 3-year-old girl with Morquio-Brailsford syndrome posted for magnetic resonance imaging and computerized tomography scan of a suspected unstable cervical spine. As utmost sagacity during intubation is required, the child was intubated inside operation theatre in the presence of experienced anesthesiologists and then shifted to the peripheral location. Intubation was done with an endotracheal tube railroaded over a pediatric fibreoptic bronchoscope passed through the lumen of a classic laryngeal mask airway, keeping head in neutral position.


Are surgical trials with negative results being interpreted correctly?
Many published accounts of clinical trials report no differences between the treatment arms, while being underpowered to find differences. This study determined how the authors of these reports interpreted their findings. We examined 54 reports of surgical trials chosen randomly from a database of 110 influential trials conducted in 2008. Seven that reported having adequate statistical power (β ≥ 0.9) were excluded from further analysis, as were the 32 that reported significant differences between the treatment arms. We examined the remaining 15 to see whether the authors interpreted their negative findings appropriately. Appropriate interpretations discussed the lack of power and/or called for larger studies. Three of the 7 trials that did not report an a priori power calculation offered inappropriate interpretations, as did 3 of the 8 trials that reported an a priori power < 0.90. However, we examined only a modest number of trial reports from 1 year. Negative findings in underpowered trials were often interpreted as showing the equivalence of the treatment arms with no discussion of the issue of being underpowered. This may lead clinicians to accept new treatments that have not been validated.


The Impact of Hospital Teaching Status on Colonoscopy Perforation Risk: A National Inpatient Sample Study.
Colonoscopy has been widely used as a diagnostic tool for many conditions, including inflammatory bowel disease and colorectal cancer. Colonoscopy complications include perforation, hemorrhage, abdominal pain, as well as anesthesia risk. Although rare, perforation is the most dangerous complication that occurs in the immediate post-colonoscopy period with an estimated risk of less than 0.1%. Studies on colonoscopy perforation risk between teaching hospitals and non-teaching hospitals are scarce. The National Inpatient Sample database was queried for patients who underwent inpatient colonoscopy between January 2010 and December 2014 in teaching versus non-teaching facilities in order to study their perforation rates. Our study population included 257,006 patients. Univariate regression was performed, and the positive results were analyzed using a multivariate regression module. Teaching hospitals had a higher risk of perforation (odds ratio 1.23, confidence interval 1.07 - 1.42, P = 0.004). Perforation rates were higher in females, patients with inflammatory bowel disease and dilatation of strictures. Polypectomy did not yield any statistical difference between the study groups. Other factors such as African-American ethnicity appeared to have a lower risk. Perforation rates are higher in teaching hospitals. More studies are needed to examine the difference and how to mitigate the risks.


Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.
An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes. Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface. CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.


Myelodysplastic syndromes: who and when in the course of disease to transplant.
The myelodysplastic syndromes are clonal hematopoietic disorders for which hematopoietic stem cell transplantation remains the only curative therapy. The timing of transplantation, methods of disease risk stratification, patient selection, pretransplantation therapies, and preparative regimens have evolved over the years, resulting in increasing disease-free survival. In recent years, alternative donor sources have been demonstrated to be a viable alternative to traditional sibling and matched unrelated donor stem cell sources. Efforts at transplantation regimen development continue with the aim of maximizing the chances of cure with minimal toxicity and improved quality of life. Integrating new knowledge regarding disease biology will be critical to continue to improve the success of hematopoietic stem cell transplantation. Exciting areas of ongoing research that may lead to reductions in posttransplantation relapse rate include posttransplantation therapies such as DNA methyltransferase inhibitors, vaccine strategies, and donor lymphocyte infusions to enhance the GVL effect.


Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator.
Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH-, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases.


The 'light touch' of the Black Death in the Southern Netherlands: an urban trick?
Although the fanciful notion that the Black Death bypassed the Low Countries has long been rejected, nevertheless a persistent view remains that the Low Countries experienced only a 'light touch' of the plague when placed in a broader European perspective, and recovered quickly and fully. However, in this article an array of dispersed sources for the Southern Netherlands together with a new mortmain accounts database for Hainaut show that the Black Death was severe, perhaps no less severe than other parts of western Europe; that serious plagues continued throughout the fourteenth and fifteenth centuries; and that the Black Death and recurring plagues spread over vast territories-including the countryside. The previous conception of a 'light touch' of plague in the Low Countries was created by the overprivileging of particular urban sources, and a failure to account for the rapid replenishment of cities via inward migration, which obscured demographic decimation. We suggest that the population of the Low Countries may not have recovered faster than other parts of western Europe but instead experienced a greater degree of post-plague rural-urban migration.


D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells.
Purpose: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of-function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2-hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment. D 2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH-mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied.Experimental Design: Complement activation and CD4+, CD8+, or FOXP3+ T-cell infiltration into primary tumor tissue were determined by immunohistochemistry using sections from 72 gliomas of World Health Organization (WHO) grade III and IV with or without IDH mutations. Ex vivo experiments with D 2-HG identified immune inhibitory mechanisms.Results: IDH mutation associated with significantly reduced complement activation and decreased numbers of tumor-infiltrating CD4+ and CD8+ T cells with comparable FOXP3+/CD4+ ratios. D 2-HG potently inhibited activation of complement by the classical and alternative pathways, attenuated complement-mediated glioma cell damage, decreased cellular C3b(iC3b) opsonization, and impaired complement-mediated phagocytosis. Although D 2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion.Conclusions: D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors. Clin Cancer Res; 24(21); 5381-91. ©2018 AACR.


Enhanced virus resistance of transgenic mice expressing the human MxA protein.
MxA is a GTPase that accumulates to high levels in the cytoplasm of interferon-treated human cells. Expression of MxA cDNA confers to transfected cell lines a high degree of resistance against several RNA viruses, including influenza, measles, vesicular stomatitis, and Thogoto viruses. We have now generated transgenic mice that express MxA cDNA in the brain and other organs under the control of a constitutive promoter. Embryonic fibroblasts derived from the transgenic mice were nonpermissive for Thogoto virus and showed reduced susceptibility for influenza A and vesicular stomatitis viruses. The transgenic animals survived challenges with high doses of Thogoto virus by the intracerebral or intraperitoneal route. Furthermore, the transgenic mice were more resistant than their nontransgenic littermates to intracerebral infections with influenza A and vesicular stomatitis viruses. These results demonstrate that MxA is a powerful antiviral agent in vivo, indicating that it may protect humans from the deleterious effects of infections with certain viral pathogens.


Multiple refocusing in NMR spectroscopy: compensation of pulse imperfections by scalar couplings.
When applying multiple refocusing pulses to characterize the cross-correlated relaxation of heteronuclear multiple quantum coherence 2NxHx in biomolecules, the unavoidable effects of pulse imperfections are compensated by the scalar couplings between nitrogen atoms and protons. The experiment, which is useful as a tool for studying slow internal dynamics of biomolecules, greatly benefits from this compensation. The underlying effect is a manifestation of an interchange between three noncommuting components of the density operator. One perturbing Hamiltonian is counteracted by another, which leads to a nearly complete suppression of the perturbation. The effect proves to be an example of a hitherto unknown phenomenon in NMR spectroscopy.


The morphology of cervical deformities: a two-step cluster analysis to identify cervical deformity patterns.
Cervical deformity (CD) is difficult to define due to the high variability in normal cervical alignment based on postural- and thoracolumbar-driven changes to cervical alignment. The purpose of this study was to identify whether patterns of sagittal deformity could be established based on neutral and dynamic alignment, as shown on radiographs. This study is a retrospective review of a prospective, multicenter database of CD patients who underwent surgery from 2013 to 2015. Their radiographs were reviewed by 12 individuals using a consensus-based method to identify severe sagittal CD. Radiographic parameters correlating with health-related quality of life were introduced in a two-step cluster analysis (a combination of hierarchical cluster and k-means cluster) to identify patterns of sagittal deformity. A comparison of lateral and lateral extension radiographs between clusters was performed using an ANOVA in a post hoc analysis. Overall, 75 patients were identified as having severe CD due to sagittal malalignment, and they formed the basis of this study. Their mean age was 64 years, their body mass index was 29 kg/m2, and 66% were female. There were significant correlations between focal alignment/flexibility of maximum kyphosis, cervical lordosis, and thoracic slope minus cervical lordosis (TS-CL) flexibility (r = 0.27, 0.31, and -0.36, respectively). Cluster analysis revealed 3 distinct groups based on alignment and flexibility. Group 1 (a pattern involving a flat neck with lack of compensation) had a large TS-CL mismatch despite flexibility in cervical lordosis; group 2 (a pattern involving focal deformity) had focal kyphosis between 2 adjacent levels but no large regional cervical kyphosis under the setting of a low T1 slope (T1S); and group 3 (a pattern involving a cervicothoracic deformity) had a very large T1S with a compensatory hyperlordosis of the cervical spine. Three distinct patterns of CD were identified in this cohort: flat neck, focal deformity, and cervicothoracic deformity. One key element to understanding the difference between these groups was the alignment seen on extension radiographs. This information is a first step in developing a classification system that can guide the surgical treatment for CD and the choice of fusion level.


Influence of implant design on blood metal ion concentrations in metal-on-metal total hip replacement patients.
Most factors considered to affect blood metal ions following metal-on-metal hip replacement are based on hip resurfacing patients. The study aims were to determine which factors affect blood metal ion concentrations following metal-on-metal total hip replacement (MoM THR). All unilateral MoM THR patients at one centre with whole-blood cobalt (Co) and chromium (Cr) concentrations measured up to May 2013 were included. Blood sampling was at a mean of 4.5 years (range 1.1-11.8 years) postoperatively. Of 496 patients (mean age 59.1 years; 52.8% male), blood metal ions >7 μg/l were observed in 9.7% (n = 48). Large femoral head sizes (≥38 mm) had significantly higher (p < 0.0001) blood metal ions than smaller sizes (28/36 mm). Corail-Pinnacle implants produced significantly lower blood metal ions compared to other implant designs (p < 0.01 Co and Cr). Univariate linear regression demonstrated the only significant predictors of both blood Co and Cr concentrations were femoral head size (R(2) = 8.6% Co and R(2) = 3.3% Cr, both p < 0.0001) and implant design (R(2) = 8.8%, p = 0.005 Co and R(2) = 5.1%, p = 0.003 Cr). When the three THR implant design groups (Corail-Pinnacle, Synergy, Other) were analysed separately, femoral head size no longer significantly affected blood metal ions in any of the three implant design groups. Implant design was the most important factor affecting blood metal ion concentrations. We recommend the regularity of follow-up be tailored to survival rates of various MoM THR designs rather than according to femoral head size.


Fungal development and induction of defense response genes during early infection of wheat spikes by Fusarium graminearum.
Fusarium head blight (FHB) of wheat is a crippling disease that causes severe economic losses in many of the wheat-growing regions of the world. Temporal patterns of fungus development and transcript accumulation of defense response genes were studied in Fusarium graminearum-inoculated wheat spikes within the first 48 to 76 h after inoculation (hai). Microscopy of inoculated glumes revealed that the fungus appeared to penetrate through stomata, exhibited subcuticular growth along stomatal rows, colonized glume parenchyma cells, and sporulated within 48 to 76 hai. No major differences in the timing of these events were found between Sumai 3 (resistant) and Wheaton (susceptible) genotypes. In complementary experiments, RNA was extracted from spikes at several time intervals up to 48 hai and temporal expression patterns were determined for defense response genes encoding peroxidase, PR-1, PR-2 (beta-1,3-glucanase), PR-3 (chitinase), PR-4, and PR-5 (thaumatin-like protein). In both genotypes, transcripts for the six defense response genes accumulated as early as 6 to 12 hai during F. graminearum infection and peaked at 36 to 48 hai. Greater and earlier PR-4 and PR-5 transcript accumulation was observed in Sumai 3, compared with Wheaton. Our results show that the timing of defense response gene induction is correlated with F. graminearum infection.


[Results after radical prostatectomy for prostate carcinoma].
35 of 54 patients undergoing radical prostatectomy for localized cancer were asymptomatic and the tumor had been found during a routine check-up by the family physician. In 53 of 54 patients the indication for surgery was based on a positive cytological finding in fine-needle aspiration biopsy of the suspected tumor. In all patients the carcinoma was confirmed by histological work-up of the radical prostatectomy specimen. Cytological and histological grading was identical in three quarters of all patients. However, the preoperative tumor stage (T) was confirmed histologically (pT) only in half of all the patients. The extension of the carcinoma was often underestimated at the preoperative clinical staging. After a mean observation time of close to 4 years, the survival rate in patients undergoing radical prostatectomy for localized cancer is comparable to an age and sex matched control group. Our data suggest that fine-needle aspiration biopsy of the prostate is a very reliable procedure in the diagnosis of prostatic carcinoma, provided the aspiration technique is correct and the smears are interpreted by a well-trained cytologist. Moreover, patients with localized prostate cancer seem to have an excellent chance of survival with low morbidity, provided the indication for surgery is restricted to carefully selected patients.


Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype.
Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety-like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HTT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.


The interplay between macrophages and angiogenesis in development, tissue injury and regeneration.
During organ development and remodeling, macrophages support angiogenesis, not only by secreting proangiogenic growth factors and matrix-remodeling proteases, but also by physically interacting with the sprouting vasculature to assist the formation of complex vascular networks. Recent data further indicate that embryonic and tumor-associated macrophages express similar genetic programs, possibly suggesting convergent functions in organogenesis and tumorigenesis. In this article, we review the role of macrophages in development, tissue injury and regeneration, by focusing on the mechanisms used by subsets of these cells, such as the TIE2-expressing macrophages, to regulate angiogenesis and lymphangiogenesis in both fetal and post-natal life.


The ongoing violence against women: Female Genital Mutilation/Cutting.
Female Genital Mutilation/Cutting (FGM/C) comprises different practices involving cutting, pricking, removing and sometimes sewing up external female genitalia for non-medical reasons. The practice of FGM/C is highly concentrated in a band of African countries from the Atlantic coast to the Horn of Africa, in areas of the Middle East such as Iraq and Yemen, and in some countries in Asia like Indonesia. Girls exposed to FGM/C are at risk of immediate physical consequences such as severe pain, bleeding, and shock, difficulty in passing urine and faeces, and sepsis. Long-term consequences can include chronic pain and infections. FGM/C is a deeply entrenched social norm, perpetrated by families for a variety of reasons, but the results are harmful. FGM/C is a human rights issue that affects girls and women worldwide. The practice is decreasing, due to intensive advocacy activities of international, national, and grassroots agencies. An adolescent girl today is about a third less likely to be cut than 30 years ago. However, the rates of abandonment are not high enough, and change is not happening as rapidly as necessary. Multiple interventions have been implemented, but the evidence base on what works is lacking. We in reproductive health must work harder to find strategies to help communities and families abandon these harmful practices.


Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review.
Cognitive impairment frequently accompanies major depressive disorder (MDD) and can persist during remission. This review examined pharmacotherapy effects on cognitive function in MDD. PubMed and EMBASE searches were conducted on July 30, 2013, for English language reports of cognitive assessments following pharmacologic monotherapy or augmentation therapy in MDD. A total of 43 research reports were identified (31 monotherapy [8 placebo-controlled, 11 active-comparator, 12 open-label], 12 augmentation therapy [7 placebo-controlled, 5 open-label]). Results reported in each publication were examined for open-label and placebo- or active comparator-controlled studies. Studies varied widely in terms of size (median, 50 participants; interquartile range, 21-143 participants), populations examined, duration (median, 8 weeks; interquartile range, 6-12 weeks), and neurocognitive assessments used. Most individual studies reported some benefit to cognition with pharmacotherapy, but there was no pattern of response in specific domains and only 12% of individually analyzed changes favored active treatment over placebo or untreated healthy controls. Sample weighted mean effect sizes revealed that verbal memory improved with monotherapy, while the largest treatment effect with augmentation therapy was for visual memory. Pharmacotherapy may have benefit in reducing cognitive impairment in MDD, with augmentation therapy being a potential approach for addressing cognitive deficits that persist after monotherapy has brought about clinical response or remission. However, given the wide variability in study design and treatment duration across studies, these findings should be interpreted cautiously. More definitive research is required before firm conclusions can be reached.


Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities.
There are numerous hurdles hindering the clinical translation of nanomedicines. The major challenges are: reproducible manufacturing and scale-up, availability of appropriate characterization methods, instability under in vivo environments, safety issues, poor understanding of the disease heterogeneity and patient preselection strategies, regulatory barriers and inadequate understanding of the biophysical and chemical interactions of nanoformulations. Thus, a better understanding of key physicochemical attributes and their characterization methods, in vivo behavior and the in-vitro-in-vivo characterization cascade of stability, safety and efficacy testing is needed to accelerate nanomedicine translation. Technologies such as quality-by-design, process analytical techniques and microfluidics could significantly accelerate the translation of nanomedicines. However, these approaches require further learning and an adequate regulatory background. Overall, to achieve an efficient clinical translation, collaboration among academia, industry and regulatory bodies is required to ensure safe and effective nanomedicine products. This review discusses the challenges and opportunities to facilitate the translation of nanomedicines to a commercial product.


Antagonistic but complementary actions of phytochromes A and B allow seedling de-etiolation.
Using dichromatic radiation, we show that the actions of phytochromes A and B (phyA and phyB) in Arabidopsis thaliana are antagonistic in mediating red and far-red radiation effects on seedling de-etiolation and yet act in a complementary manner to regulate de-etiolation, irrespective of spectral composition. At low phytochrome photoequilibria inhibition of hypocotyl extension was strong, because of the action of a far-red high-irradiance response mediated by phyA. At high phytochrome photoequilibria inhibition of hypocotyl extension was also strong, because of the action of phyB. At intermediate photoequilibria hypocotyl inhibition was less strong. In their natural environment, this dual action will strongly retard hypocotyl growth and promote cotyledon opening and expansion both in open daylight and under dense vegetation. Overlapping action by phyA and phyB will substantially promote de-etiolation in sparse vegetation. The antagonistic and complementary actions of phyA and phyB, therefore, allow the optimum regulation of seedling growth after emergence from the soil.


Inference for the Case Probability in High-dimensional Logistic Regression.
Labeling patients in electronic health records with respect to their statuses of having a disease or condition, i.e. case or control statuses, has increasingly relied on prediction models using high-dimensional variables derived from structured and unstructured electronic health record data. A major hurdle currently is a lack of valid statistical inference methods for the case probability. In this paper, considering high-dimensional sparse logistic regression models for prediction, we propose a novel bias-corrected estimator for the case probability through the development of linearization and variance enhancement techniques. We establish asymptotic normality of the proposed estimator for any loading vector in high dimensions. We construct a confidence interval for the case probability and propose a hypothesis testing procedure for patient case-control labelling. We demonstrate the proposed method via extensive simulation studies and application to real-world electronic health record data.


Hybrid lightwave subcarrier CATV/16-QAM/16-QAM OFDM transmission system.
A hybrid lightwave subcarrier CATV/16-QAM/16-QAM orthogonal frequency-division multiplexing (OFDM) transmission system employing light injection/optoelectronic feedback techniques and photonic crystal fiber (PCF) is proposed and demonstrated. Good performance of carrier-to-noise ratio (CNR), composite second order, and composite triple beat were obtained for the CATV band, and high CNR and low bit error rate values were achieved for the 16-QAM and 16-QAM OFDM bands over a combination of 80 km single-mode fiber (SMF) and 2.86 km PCF transport.


NuMA is required for the organization of microtubules into aster-like mitotic arrays.
NuMA (Nuclear protein that associates with the Mitotic Apparatus) is a 235-kD intranuclear protein that accumulates at the pericentrosomal region of the mitotic spindle in vertebrate cells. To determine if NuMA plays an active role in organizing the microtubules at the polar region of the mitotic spindle, we have developed a cell free system for the assembly of mitotic asters derived from synchronized cultured cells. Mitotic asters assembled in this extract are composed of microtubules arranged in a radial array that contain NuMA concentrated at the central core. The organization of microtubules into asters in this cell free system is dependent on NuMA because immunodepletion of NuMA from the extract results in randomly dispersed microtubules instead of organized mitotic asters, and addition of the purified recombinant NuMA protein to the NuMA-depleted extract fully reconstitutes the organization of the microtubules into mitotic asters. Furthermore, we show that NuMA is phosphorylated upon mitotic aster assembly and that NuMA is only required in the late stages of aster assembly in this cell free system consistent with the temporal accumulation of NuMA at the polar ends of the mitotic spindle in vivo. These results, in combination with the phenotype observed in vivo after the prevention of NuMA from targeting onto the mitotic spindle by antibody microinjection, suggest that NuMA plays a functional role in the organization of the microtubules of the mitotic spindle.


Specialty versus community hospitals: what role for the law?
U.S. health care has long featured a struggle between regulation and markets as vehicles of reform, and the community hospital is at the center of this struggle. The key to its financial viability is cross-subsidization, whereby revenues from insured patients subsidize the care of the uninsured and underinsured, and profits from well-compensated services support those operating at a loss. Cross-subsidization has been challenged by efforts to move highly compensated services and well-insured patients to ambulatory surgical centers and specialty hospitals. We review the ongoing battle between through a legal lens and offer conjectures about the outcome. Refined certificate-of-need regulation may be the preferable policy choice.


[Antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus strains from outpatient individuals].
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged worldwide as a cause of infections among patients without risk factors. This CA-MRSA is different from nosocomial strains in terms of epidemiology, microbiology and clinical manifestations. We report the epidemiologic characteristics and resistance to antimicrobial agents of CA-MRSA strains isolated in the last three years in the Microbiology Lab of Hospital General La Mancha-Centro (Alcázar de San Juan, Ciudad Real). We performed a retrospective analysis of microbiological cultures in patients with S. aureus diagnosed from 2007 to 2009 in La Mancha-Centro Health-Care Area, within Castilla-La Mancha Community. The distribution of CA-MRSA in the studied period was 26 out of a total of 97 S. aureus isolates in 2007 (26.8%), 40/113 in 2008 (35.4%) and 57/157 in 2009 (36.3%). The percentage from purulent skin and soft tissue infections was 63.4%. All strains were susceptible to linezolid, quinupristin/dalfopristin, and glycopeptides. The resistance was high to fluoroquinolones (94.3%), erythromycin (87.0%), tobramycin (82.9%), and clindamycin (65.3%). CA-MRSA isolates percentage increased along the period of the study. The majority were obtained from skin and soft tissue specimens. The most commonly associated antimicrobial resistance was to fluoroquinolones, erythromycin, tobramycin and clindamycin. An understanding of the CAMRSA epidemiology is important to prevent these organisms from becoming endemic in the world.


[Histopathological diagnosis of pneumoconiosis].
Asbestos-related diseases constitute a major health problem due to the great number of workers exposed to asbestos over the past 50 years. Personal injury lawsuits against industries that deal with asbestos number in the hundreds, and new cases continue to be filed. The scientific issues related to asbestos are complex, and, although the broad outlines of asbestos-related diseases have been well-established, many significant aspects (such as the pathology involved) are poorly understood. In Brazil, asbestos has been mined commercially since 1940, with production levels recently approaching 200,000 tons/year, resulting in the asbestos exposure of approximately 10,000 workers in the mining activity, and an unknown number of workers in asbestos-cement industry, primarily roofers and concrete rooftop water tank installers. One study, using appropriate methods of scientific investigation to evaluate the effects of such exposure on the health of asbestos mine workers in Brazil was conducted as part of a multicenter study and entitled "Morbidity and Mortality Among Workers Exposed to Asbestos in Mining Activities, 1940-1996". Drawing upon the experience acquired during the course of that study, the objective of the current report was to give an overview of asbestos-related diseases, with a special focus on the difficulties involved in establishing the histopathological diagnosis.


Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro.
Human peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and exposed in vitro to phenytoin or carbamazepine, two widely used antiepileptic drugs (AED). This study investigated the effects of these drugs on natural killer (NK) cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC), which are both thought to protect against developing neoplasms. Also, the genotoxicity of phenytoin on human PBMC was investigated by gravity-flow alkaline elution. Concentrations of phenytoin considered therapeutic (10 and 20 micrograms/ml) and a dose considered acutely toxic (40 micrograms/ml) were used while carbamazepine levels of 8 micrograms/ml (therapeutic) and 10 and 16 micrograms/ml (acutely toxic) were tested. Phenytoin at all three concentrations significantly suppressed NK cell activity in a dose-dependent manner. Carbamazepine had no significant effect on NK cell activity at the dose levels studied. Incubation in propylene glycol, the diluent for carbamazepine, significantly decreased NK cell activity compared to saline. Phenytoin also significantly depressed interferon augmentation of NK cell cytotoxicity in a dose dependent manner. ADCC activity was significantly depressed with 20 and 40 micrograms/ml phenytoin. Alkaline elution showed a slight but significant increase in DNA single-strand breaks of PBMC exposed to 40 micrograms/ml phenytoin for 18 or 72 hr. These results show phenytoin may induce pronounced immunosuppression of NK cell and ADCC activity in patients receiving antiepileptic therapy and that this agent has a potential for genotoxic side effects. Phenytoin may also increase the potential for neoplasm development by a direct interaction with cellular DNA and/or an indirect mechanism by immunosuppression.


Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells.
In this report, we show that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron transport chain activates the three major pathways of hyperglycemic damage found in aortic endothelial cells by inhibiting GAPDH activity. In bovine aortic endothelial cells, GAPDH antisense oligonucleotides activated each of the pathways of hyperglycemic vascular damage in cells cultured in 5 mM glucose to the same extent as that induced by culturing cells in 30 mM glucose. Hyperglycemia-induced GAPDH inhibition was found to be a consequence of poly(ADP-ribosyl)ation of GAPDH by poly(ADP-ribose) polymerase (PARP), which was activated by DNA strand breaks produced by mitochondrial superoxide overproduction. Both the hyperglycemia-induced decrease in activity of GAPDH and its poly(ADP-ribosyl)ation were prevented by overexpression of either uncoupling protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD), which decrease hyperglycemia-induced superoxide. Overexpression of UCP-1 or MnSOD also prevented hyperglycemia-induced DNA strand breaks and activation of PARP. Hyperglycemia-induced activation of each of the pathways of vascular damage was abolished by blocking PARP activity with the competitive PARP inhibitors PJ34 or INO-1001. Elevated glucose increased poly(ADP-ribosyl)ation of GAPDH in WT aortae, but not in the aortae from PARP-1-deficient mice. Thus, inhibition of PARP blocks hyperglycemia-induced activation of multiple pathways of vascular damage.


Relationships Between Lateral Limb Bias, Turnout, and Lower Limb Injury in a Female Pre-Professional Ballet Dancer Population.
Dancers are known to have specific limb preferences when they dance and commonly experience lower limb injury, especially early in their training. The primary aim of this study was to determine and examine the relationships between lateral limb bias, perceived turnout profile, and lower limb injury history in female pre-professional ballet dancers using current definitions of lateral bias, leg dominance, and the concept of "working" and "supporting" legs in dance. A cross-sectional survey design with retrospective recall of 12-month injury history was employed. An online questionnaire was distributed to female dancers between the ages of 16 and 21 years who were training in classical ballet at the pre-professional level in Australia. The questionnaire gathered information regarding laterality, perceived turnout asymmetry, and self-reported 12-month injury profile. Descriptive and correlation analyses were employed to describe dancer profiles and determine relationships between the three variables. Thirty-two dancers participated. The majority of participants (67%) had right-side dominance and most indicated the right leg as their preferred supporting leg (86.7%) and working leg (60%). A total of 17 participants (53.1%) reported at least one injury in the preceding 12-month period and the side injured was significantly correlated with leg dominance (rS = 0.595, p = 0.012), with the majority of injuries also affecting the preferred supporting and working leg. Dancer perceptions regarding turnout range were correlated with their perceptions of leg dominance (rS = 0.556, p = 0.001), but no statistically significant associations were found between perceptions of turnout range and injury side. In pre-professional dancers, the dominant and the preferred supporting or working leg tend to be the same leg, and the results suggest that the dominant and preferred supporting and working leg of dancers are at greatest risk of injury.


Citrullination of autoantigens: upstream of TNFα in the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by synovial inflammation and destruction of joints. Over 20 years ago, tumour necrosis factor alpha (TNFα) was identified as a key player in a cytokine network, whose multifunctional effects could account for both the inflammation and destruction in RA. The remarkable efficacy of TNF inhibitors in the treatment of RA has resulted in extensive research addressing the regulation of TNFα production responsible for this excessive production. The discovery of autoimmunity to citrullinated protein/peptide antigens (ACPA) has led the concept that ACPA may be the essential link between disease susceptibility factors and the production of TNFα, which ultimately accounts for the disease phenotype. In this review we will consider (1) the mechanisms of citrullination, both physiological and pathological, (2) how known genetic and environmental factors could drive this peculiar form of autoimmunity and (3) how the immune response could lead to excessive production of TNFα by the synovial cells and ultimately to the disease phenotype (Fig. 1).


Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus.
Aspergillus fumigatus is the most prevalent airborne fungal pathogen, causing invasive fungal infections mainly in immunosuppressed individuals. Death rates from invasive aspergillosis remain high because of limited treatment options and increasing antifungal resistance. The aim of this study was to identify key fungal-specific genes participating in vitamin B biosynthesis in A. fumigatus. Because these genes are absent in humans they can serve as possible novel targets for antifungal drug development. By sequence homology we identified, deleted and analysed four key A. fumigatus genes (riboB, panA, pyroA, thiB) involved respectively in the biosynthesis of riboflavin (vitamin B2), pantothenic acid (vitamin B5), pyridoxine (vitamin B6) and thiamine (vitamin B1). Deletion of riboB, panA, pyroA or thiB resulted in respective vitamin auxotrophy. Lack of riboflavin and pantothenic acid biosynthesis perturbed many cellular processes including iron homeostasis. Virulence in murine pulmonary and systemic models of infection was severely attenuated following deletion of riboB and panA, strongly reduced after pyroA deletion and weakly attenuated after thiB deletion. This study reveals the biosynthetic pathways of the vitamins riboflavin and pantothenic acid as attractive targets for novel antifungal therapy. Moreover, the virulence studies with auxotrophic mutants serve to identify the availability of nutrients to pathogens in host niches. BPS: bathophenanthrolinedisulfonate; BSA: bovine serum albumin; CFU: colony forming unit; -Fe: iron starvation; +Fe: iron sufficiency; hFe: high iron; NRPSs: nonribosomal peptide synthetases; PKSs: polyketide synthaseses; wt: wild type.


Hemi-dystonia secondary to localised basal ganglia tumour.
An 8-year-old boy with an 18 month history of left limb hemi-dystonia due to a right lenticular nucleus astrocytoma originating in the putamen is reported. Subsequent neuropathological study demonstrated that the tumour was mainly localised to the right lenticular nucleus, with cystic necrosis in the infero-lateral putamen. Solid tumour also infiltrated the right hypothalamus, the anterior commisure and the optic chiasm, and there was perivascular spread into the globus pallidus, internal capsule and roof of the right lateral ventricle. This case, and the few other published reports of symptomatic dystonia due to focal brain lesions verified pathologically, indicate that damage to the lenticular nucleus, and to the putamen in particular, can cause limb dystonia in man.


Effects of Transcranial Alternating Current Stimulation on Repetitive Finger Movements in Healthy Humans.
Transcranial alternating current stimulation (tACS) is a noninvasive neurophysiological technique that can entrain brain oscillations. Only few studies have investigated the effects of tACS on voluntary movements. We aimed to verify whether tACS, delivered over M1 at beta and gamma frequencies, has any effect on repetitive finger tapping as assessed by means of kinematic analysis. Eighteen healthy subjects were enrolled. Objective measurements of repetitive finger tapping were obtained by using a motion analysis system. M1 excitability was assessed by using single-pulse TMS and measuring the amplitude of motor-evoked potentials (MEPs). Movement kinematic measures and MEPs were collected during beta, gamma, and sham tACS and when the stimulation was off. Beta tACS led to an amplitude decrement (i.e., progressive reduction in amplitude) across the first ten movements of the motor sequence while gamma tACS had the opposite effect. The results did not reveal any significant effect of tACS on other movement parameters, nor any changes in MEPs. These findings demonstrate that tACS modulates finger tapping in a frequency-dependent manner with no concurrent changes in corticospinal excitability. The results suggest that cortical beta and gamma oscillations are involved in the motor control of repetitive finger movements.


Ring-opening copolymerization (ROCOP): synthesis and properties of polyesters and polycarbonates.
Controlled routes to prepare polyesters and polycarbonates are of interest due to the widespread application of these materials and the opportunities provided to prepare new copolymers. Furthermore, ring-opening copolymerization may enable new poly(ester-carbonate) materials to be prepared which are inaccessible using alternative polymerizations. This review highlights recent advances in the ring-opening copolymerization catalysis, using epoxides coupled with anhydrides or CO2, to produce polyesters and polycarbonates. In particular, the structures and performances of various homogeneous catalysts are presented for the epoxide-anhydride copolymerization. The properties of the resultant polyesters and polycarbonates are presented and future opportunities highlighted for developments of both the materials and catalysts.


Identifying and Prioritizing Diseases Important for Detection in Adult Hearing Health Care.
The purpose of this research note is to identify and prioritize diseases important for detection in adult hearing health care delivery systems. Through literature review and expert consultation, the authors identified 195 diseases likely to occur in adults complaining of hearing loss. Five neurotologists rated the importance of disease on 3 dimensions related to the necessity of detection prior to adult hearing aid fitting. Ratings of adverse health consequences, diagnostic difficulty, and presence of nonotologic symptoms associated with these diseases resulted in the identification of 104 diseases potentially important for detection prior to adult hearing aid fitting. Current and evolving health care delivery systems, including direct-to-consumer sales, involve inconsistent means of disease detection vigilance prior to device fitting. The first steps in determining the safety of these different delivery methods are to identify and prioritize which diseases present the greatest risk for poor health outcomes and, thus, should be detected in hearing health care delivery systems. Here the authors have developed a novel multidimensional rating system to rank disease importance. The rankings can be used to evaluate the effectiveness of alternative detection methods and to inform public health policy. The authors are currently using this information to validate a consumer questionnaire designed to accurately identify when pre- fitting medical evaluations should be required for hearing aid patients.


Focus issue: plant communication.
This week's issues of Science and Science's STKE focus on plant signaling with an emphasis on volatile organic compounds. Science emphasizes the chemistry of and information encoded by plant volatiles and how plants, plant pathogens, or humans utilize this aromatic information. Articles and resources at STKE highlight the evolution of olfactory signal transduction, describe the biosynthetic and signaling pathways of the plant hormone jasmonate, and provide an animated overview of how the plant hormone auxin regulates gene expression.


Anti-nociceptive and anti-inflammatory actions of sulforaphane in chronic constriction injury-induced neuropathic pain mice.
Neuropathic pain is still considered as incurable disease as current therapies are not ideal in terms of efficacy and tolerability. It is imperative to search for novel drugs to obtain better treatments. Sulforaphane (SFN), a derivative of glucoraphanin present in cruciferous vegetables, exhibits therapeutic effects on inflammation-related diseases. Since inflammation plays an important role in regulating chronic pain, in the present study, we investigated anti-nociceptive effects of SFN and its underlying mechanisms in a neuropathic pain mouse model, sciatic nerve chronic constriction injury (CCI). SFN (0.1-100 mg/kg) was injected intraperitoneally for 7 days when pain behaviors, including mechanical allodynia and thermal hyperalgesia, reached to the maximum in CCI mice. We observed that SFN dose-dependently attenuated CCI-induced pain behavioral hypersensitivity, accompanied by reduction in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and upregulation of an anti-inflammatory cytokine (IL-10). Moreover, SFN counteracted CCI enhancement of COX2 and iNOS in injured nerves, two key enzymes implicated in inflammation and neuropathic pain. Furthermore, pretreatment of naloxone, an antagonist of opioid receptors, significantly blocked SFN attenuation of behavioral hypersensitivity without affecting SFN modulation of inflammatory cytokines in CCI mice. Interestingly, CCI-induced increase in µ-opioid receptors in injured sciatic nerves was further increased by SFN treatment. Taken together, SFN has both anti-nociceptive and anti-inflammatory actions.


Reconciling DNA replication and transcription in a hyphal organism: visualizing transcription complexes in live Streptomyces coelicolor.
Reconciling transcription and DNA replication in the growing hyphae of the filamentous bacterium Streptomyces presents several physical constraints on growth due to their apically extending and branching, multigenomic cells and chromosome replication being independent of cell division. Using a GFP translational fusion to the β'-subunit of RNA polymerase (rpoC-egfp), in its native chromosomal location, we observed growing Streptomyces hyphae using time-lapse microscopy throughout the lifecycle and under different growth conditions. The RpoC-eGFP fusion co-localized with DNA around 1.8 µm behind the extending tip, whereas replisomes localize around 4-5 µm behind the tip, indicating that at the growing tip, transcription and chromosome replication are to some degree spatially separated. Dual-labelled RpoC-egfp/DnaN-mCherry strains also indicate that there is limited co-localization of transcription and chromosome replication at the extending hyphal tip. This likely facilitates the use of the same DNA molecule for active transcription and chromosome replication in growing cells, independent of cell division. This represents a novel, but hitherto unknown mechanism for reconciling two fundamental processes that utilize the same macromolecular template that allows for rapid growth without compromising chromosome replication in filamentous bacteria and may have implications for evolution of filamentous growth in micro-organisms, where uncoupling of DNA replication from cell division is required.


GLK transcription factors coordinate expression of the photosynthetic apparatus in Arabidopsis.
Chloroplasts of photosynthetic organisms harness light energy and convert it into chemical energy. In several land plants, GOLDEN2-LIKE (GLK) transcription factors are required for chloroplast development, as glk1 glk2 double mutants are pale green and deficient in the formation of the photosynthetic apparatus. We show here that glk1 glk2 double mutants of Arabidopsis thaliana accumulate abnormal levels of chlorophyll precursors and that constitutive GLK gene expression leads to increased accumulation of transcripts for antenna proteins and chlorophyll biosynthetic enzymes. To establish the primary targets of GLK gene action, an inducible expression system was used in combination with transcriptome analysis. Following induction, transcript pools were substantially enriched in genes involved in chlorophyll biosynthesis, light harvesting, and electron transport. Chromatin immunoprecipitation experiments confirmed the direct association of GLK1 protein with target gene promoters, revealing a putative regulatory cis-element. We show that GLK proteins influence photosynthetic gene expression independently of the phyB signaling pathway and that the two GLK genes are differentially responsive to plastid retrograde signals. These results suggest that GLK genes help to coregulate and synchronize the expression of a suite of nuclear photosynthetic genes and thus act to optimize photosynthetic capacity in varying environmental and developmental conditions.


Involvement of the small GTPases XRhoA and XRnd1 in cell adhesion and head formation in early Xenopus development.
The Rho family of small GTPases regulates a variety of cellular functions, including the dynamics of the actin cytoskeleton, cell adhesion, transcription, cell growth and membrane trafficking. We have isolated the first Xenopus homologs of the Rho-like GTPases RhoA and Rnd1 and examined their potential roles in early Xenopus development. We found that Xenopus Rnd1 (XRnd1) is expressed in tissues undergoing extensive morphogenetic changes, such as marginal zone cells involuting through the blastopore, somitogenic mesoderm during somite formation and neural crest cells. XRnd1 also causes a severe loss of cell adhesion in overexpression experiments. These data and the expression pattern suggest that XRnd1 regulates morphogenetic movements by modulating cell adhesion in early embryos. Xenopus RhoA (XRhoA) is a potential XRnd1 antagonist, since overexpression of XRhoA increases cell adhesion in the embryo and reverses the disruption of cell adhesion caused by XRnd1. In addition to the potential roles of XRnd1 and XRhoA in the regulation of cell adhesion, we find a role for XRhoA in axis formation. When coinjected with dominant-negative BMP receptor (tBR) in the ventral side of the embryo, XRhoA causes the formation of head structures resembling the phenotype seen after coinjection of wnt inhibitors with dominant-negative BMP receptor. Since dominant-negative XRhoA is able to reduce the formation of head structures, we propose that XRhoA activity is essential for head formation. Thus, XRhoA may have a dual role in the embryo by regulating cell adhesion properties and pattern formation.


Risk and timing of recurrent ischemic events among patients with stable ischemic heart disease, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction.
We aimed to compare differences in risk and timing of recurrent ischemic events among patients with stable ischemic heart disease (SIHD), non-ST-segment elevation acute coronary syndrome (NSTE-ACS), and ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). We performed an individual data pooled analysis of 5 randomized controlled all-comer trials including a total of 8,859 patients and investigated the risk and timing of recurrent ischemic events among patients with SIHD (n = 3,543), NSTE-ACS (n = 3,364), and STEMI (n = 1,952) throughout 2 years of follow-up. At 2 years, all-cause mortality was higher among patients with STEMI (6.4%) and NSTE-ACS (6.1%) compared with those with SIHD (4.2%) (STEMI vs SIHD: hazard ratio [HR] 1.40, 95% CI 1.09-1.78, P = .007; NSTE-ACS vs SIHD: 1.40, 95% CI 1.13-1.73, P = .002). In a landmark analysis, the risk of mortality among patients with STEMI compared with those with SIHD was confined to the first 30 days after PCI (HR 6.19, 95% CI 3.15-12.16, P < .001) but was similar between 30 days and 2 years (HR 1.00, 95% CI 0.76-1.33, P = .974) (Pinteraction < .001). Conversely, patients with NSTE-ACS had a higher risk of mortality compared with those with SIHD both within the first 30 days (HR 2.19, 95% CI 1.08-4.47, P = .031) and beyond (HR 1.34, 95% CI 1.07-1.67, P = .012) (Pinteraction < .001). A similar pattern in the differential timing of events was observed for cardiac death. Beyond 30 days, the risk of myocardial infarction was comparable in patients with STEMI and SIHD, whereas the risk in patients with NSTE-ACS was increased (HR 1.65, 95% CI 1.23-2.21, P = .001). Whereas patients with NSTE-ACS are at increased risk for death at any time after PCI, the mortality of STEMI patients is higher during the first 30 days after PCI but not thereafter compared with patients with SIHD.


Correlation matrices of completely unpolarized beams.
The simplest form for the correlation matrix of a completely unpolarized electromagnetic beam is the product of a scalar correlation function times a unit matrix. We show, however, that classes of unpolarized beams exist for which the diagonal elements of the correlation matrix are not equal to each other and the off-diagonal elements do not vanish identically. This gives rise to a distinction between pure and impure unpolarized beams. The two types of beams can be distinguished at the experimental level by their behavior in a Young's interferometer.


Health promotion and cardiovascular risk reduction in people with spinal cord injury: physical activity, healthy diet and maintenance after discharge- protocol for a prospective national cohort study and a preintervention- postintervention study.
Spinal cord injury (SCI) predisposes those who suffer from it to physical inactivity and weight gain; consequently, death due to cardiovascular diseases is more frequent among people with SCI than in the general population. The literature documents a consensus about an interdisciplinary multimodal approach for the prevention and treatment of cardiovascular risk factors including overweight and obesity in people with SCI, focusing on diet, physical activity (PA) and behavioural interventions. This study will investigate implementation of recommendations from a recent clinical practice guideline for identification and management of cardiometabolic risk after SCI through multimodal patient education in a subacute clinical setting. All patients who are aged 18 years or older with an SCI within the previous 12 months and admitted to highly specialised rehabilitation are included, regardless of SCI aetiology or neurological level. A primary study designed as a controlled, pragmatic, preintervention- postintervention study with 6-month follow-up evaluates the effect of the clinical intervention; a prospective national cohort study on body mass index (BMI) serves as a historical control. The intervention consists of a standardised approach to patient education about cardiovascular risk factors, PA and a healthy diet that begins at the outset of primary SCI rehabilitation and is integrated into existing settings and workflows. Outcome measures are collected at admission, discharge and 6 months after discharge and include peak oxygen uptake (VO2peak) (primary outcome), BMI, body composition, metabolic profile, neurological status, level of functioning, depression, quality of life, objective PA (accelerometry), self-reported PA, self-assessed PA ability, shared decision making, and dietary habits. Test-retest reliability of four VO2peak test protocols are investigated, as is test-retest reliability of a multisensor accelerometer in a rehabilitation setting. The project is approved by the Committees on Health Research Ethics in the Capital Region of Denmark on 10 July 2018 (Journal-nr.: H-18018325). The principal investigator obtains informed consent from all participants. The interventions in the project are closely related to existing rehabilitation care, and the risk of pain and discomfort is considered modest. Any unintended events related to the elements of the intervention are reported, according to existing regional procedures. Data are stored in a secure web-based database (Redcap). The primary study and prospective cohort study are registered at Clinicaltrials.gov. Positive and negative results will be submitted to relevant scientific journals related to SCI for publication. Important protocol modifications are reported to the Committees on Health Research Ethics in the Capital Region of Denmark. NCT03689023 and NCT03369080.


A graph-theory method for pattern identification in geographical epidemiology--a preliminary application to deprivation and mortality.
Graph theoretical methods are extensively used in the field of computational chemistry to search datasets of compounds to see if they contain particular molecular sub-structures or patterns. We describe a preliminary application of a graph theoretical method, developed in computational chemistry, to geographical epidemiology in relation to testing a prior hypothesis. We tested the methodology on the hypothesis that if a socioeconomically deprived neighbourhood is situated in a wider deprived area, then that neighbourhood would experience greater adverse effects on mortality compared with a similarly deprived neighbourhood which is situated in a wider area with generally less deprivation. We used the Trent Region Health Authority area for this study, which contained 10,665 census enumeration districts (CED). Graphs are mathematical representations of objects and their relationships and within the context of this study, nodes represented CEDs and edges were determined by whether or not CEDs were neighbours (shared a common boundary). The overall area in this study was represented by one large graph comprising all CEDs in the region, along with their adjacency information. We used mortality data from 1988-1998, CED level population estimates and the Townsend Material Deprivation Index as an indicator of neighbourhood level deprivation. We defined deprived CEDs as those in the top 20% most deprived in the Region. We then set out to classify these deprived CEDs into seven groups defined by increasing deprivation levels in the neighbouring CEDs. 506 (24.2%) of the deprived CEDs had five adjacent CEDs and we limited pattern development and searching to these CEDs. We developed seven query patterns and used the RASCAL (Rapid Similarity Calculator) program to carry out the search for each of the query patterns. This program used a maximum common subgraph isomorphism method which was modified to handle geographical data. Of the 506 deprived CEDs, 10 were not identified as belonging to any of the seven groups because they were adjacent to a CED with a missing deprivation category quintile, and none fell within query Group 1 (a deprived CED for which all five adjacent CEDs were affluent). Only four CEDs fell within Group 2, which was defined as having four affluent adjacent CEDs and one non-affluent adjacent CED. The numbers of CEDs in Groups 3-7 were 17, 214, 95, 81 and 85 respectively. Age and sex adjusted mortality rate ratios showed a non-significant trend towards increasing mortality risk across Groups (Chi-square = 3.26, df = 1, p = 0.07). Graph theoretical methods developed in computational chemistry may be a useful addition to the current GIS based methods available for geographical epidemiology but further developmental work is required. An important requirement will be the development of methods for specifying multiple complex search patterns. Further work is also required to examine the utility of using distance, as opposed to adjacency, to describe edges in graphs, and to examine methods for pattern specification when the nodes have multiple attributes attached to them.


Efficient photoinduced energy transfer in a newly developed hybrid SBA-15 photonic antenna.
A new hybrid photostable donor-acceptor mesoporous SBA-15 silica system was designed and prepared. It consists of an encapsulated donor, the Super Yellow (SY) polymer, which transfers the photoexcitation energy directly to an acceptor dye that is linked outside the framework. The obtained composite material was characterized by X-ray diffraction, nitrogen-physisorption porosimetry, diffuse-reflectance (DR)-UV/Vis spectroscopy and photoluminescence, space- and time-resolved confocal microscopy. The physico-chemical analyses showed that the system behaves as an efficient Förster resonance energy transfer (FRET) pair, and high photoluminescence was observed from the acceptor. The presented photonic antenna is the first example of dye sensitization by polymer-loaded mesoporous silica and represents a step forward in the search for new efficient and stable materials with opto-electronic applications.


RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter.
The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses.


Physical Activity, Sedentary Behavior, and Symptoms of Major Depression in Middle Childhood.
The prospective relation between physical activity and Diagnostic and Statistical Manual of Mental Disorders-defined major depression in middle childhood is unknown, as is the stability of depression. We therefore aimed to (1) determine whether there are reciprocal relations between moderate-to-vigorous physical activity (MVPA) and sedentary behavior, on one hand, and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition defined symptoms of major depressive disorder, on the other and (2) assess the extent of stability in depressive symptoms from age 6 to 10 years. A community sample of children living in Trondheim, Norway, comprising a total of 795 6-year-old children was followed up at 8 (n = 699) and 10 (n = 702) years of age. Physical activity was recorded by accelerometry and symptoms of major depression were measured through semistructured clinical interviews of parents and children. Bidirectional relationships between MVPA, sedentary activity, and symptoms of depression were analyzed through autoregressive cross-lagged models, and adjusted for symptoms of comorbid psychiatric disorders and BMI. At both age 6 and 8 years, higher MVPA predicted fewer symptoms of major depressive disorders 2 years later. Sedentary behavior did not predict depression, and depression predicted neither MVPA nor sedentary activity. The number of symptoms of major depression declined from ages 6 to 8 years and evidenced modest continuity. MVPA predicts fewer symptoms of major depression in middle childhood, and increasing MVPA may serve as a complementary method to prevent and treat childhood depression.


Maraviroc: in vitro assessment of drug-drug interaction potential.
To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs). Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyptrade mark population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic. Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a K(m) of 21 microM and V(max) of 0.45 pmol pmol(-1) min(-1) in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a K(m) of 13 microM and a V(max) of 3 pmol pmol(-1) CYP min(-1). Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI. Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyptrade mark has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.


Heterogeneous Multilayer Generalized Operational Perceptron.
The traditional multilayer perceptron (MLP) using a McCulloch-Pitts neuron model is inherently limited to a set of neuronal activities, i.e., linear weighted sum followed by nonlinear thresholding step. Previously, generalized operational perceptron (GOP) was proposed to extend the conventional perceptron model by defining a diverse set of neuronal activities to imitate a generalized model of biological neurons. Together with GOP, a progressive operational perceptron (POP) algorithm was proposed to optimize a predefined template of multiple homogeneous layers in a layerwise manner. In this paper, we propose an efficient algorithm to learn a compact, fully heterogeneous multilayer network that allows each individual neuron, regardless of the layer, to have distinct characteristics. Based on the complexity of the problem, the proposed algorithm operates in a progressive manner on a neuronal level, searching for a compact topology, not only in terms of depth but also width, i.e., the number of neurons in each layer. The proposed algorithm is shown to outperform other related learning methods in extensive experiments on several classification problems.


A mortality study of lead workers 1925-76.
The principal causes of mortality of 754 individuals from a population of 1898 pensioners from four lead acid battery factories during the period 1 January 1925 to 31 December 1976 were studied. In addition the causes of 553 deaths occurring before retirement was also studied. All subjects were placed into one of three groups according to their history of lead exposure. Group 1 had no occupational lead exposure, group 2 low, and group 3 the highest. Mortality was studied in 16 principal disease groups as well as all causes combined. A significant excess of deaths from cerebrovascular accidents was found among pensioners dying between 1925 and 1976 in group 3 but not among men in the same exposure group dying in employment. There was also a significant excess of deaths from renal disease among this group. After 1958, however, the causes of most of the deaths from renal disease were not those likely to be associated with exposure to lead. There was no significant excess of deaths from all causes, nor was there a significant excess of deaths in any of the exposure groups from cancer, hypertensive disease, nor any other circulatory disease. There was no excess of observed to expected deaths among any of the three groups of women in any of the cause groups examined. After the introduction of regular blood lead analysis in 1964 the blood lead distribution in men in group 3 had by 1976 come down to roughly the same level as group 2 in 1965-7. Since there was no excess of deaths in any of the 16 categories studied among group 2 subjects present conditions are probably now adequate to prevent any excess of mortality in any of the three groups.