Prison Suicide in Comparison to Suicide Events in Forensic Psychiatric Hospitals in Germany.
Background: There is limited international as well as national research on suicide events in prisons and in forensic psychiatric hospitals. This retrospective study compares completed suicide events within these two high-risk populations in state institutions over a time period of 5 years from 2000 to 2004. Material and Methods: Data was collected through a nationwide survey: all forensic psychiatric hospitals within Germany were contacted via postal mail and received a questionnaire concerning the suicide events from 2000 to 2004. All federal lands of Germany were similarly assessed by a survey endorsed by the respective federal ministries of justice. All prison institutions (100%) participated in the survey, while 84% (53 units) of the forensic psychiatric hospitals nationwide contributed. A comparative statistical analysis was conducted using Fisher's exact test or the Mann-Whitney U-test (age). A multivariate logistic regression analysis was done to assess adjusted effects. For the Kaplan-Meier analysis, the months until suicide were analyzed followed by a Cox-regression analysis. Results: There was no statistically significant difference between the mean suicide rate in forensic psychiatric hospitals (123/100.000, 95% confidence interval: [0.00103, 0.00147]) and in the prison system (130/100.000, 95% confidence interval: [0.00109, 0.00154]). Patients who committed suicide in the forensic hospitals were, in comparison to the prison system, more likely to have committed a violent offense and have had a prior history of suicide attempts. The duration from admission into the institution to the suicide event was significantly shorter in the prison group. Also, younger people commited suicide earlier during their stay in a forensic psychiatric hospital or prison. Conclusions: While the results suggest a necessity to optimize data collection in the prison system (prior suicide events and history of mental disorder), it is important to discuss the current discharge arrangements within the forensic hospitals.


Band selection procedure for multispectral scanners.
Advances in high spectral resolution sensors and in data handling capabilities are enabling development of greatly improved remote-sensing devices for resource monitoring, so that design trade-offs are required. A methodology for optimizing selection of spectral bands for multispectral instruments such as those on the LANDSAT series of satellites is described. The method is applied to a collection of laboratory and outdoor spectra of natural and artificial materials. These reflectance spectra represent the visible and near-infrared spectral ranges at high (0.01-μm) spectral resolution. For most natural materials 15-25 spectral bands appear to be sufficient to describe spectral variability, whereas description of minerals and some artificial substances may require double this number of bands.


Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging.
To investigate whether the variable forms of putative iron deposition seen with susceptibility weighted imaging (SWI) will lead to a set of multiple sclerosis (MS) lesion characteristics different than that seen in conventional MR imaging. Twenty-seven clinically definite MS patients underwent brain scans using magnetic resonance imaging including: pre- and postcontrast T1-weighted imaging, T2-weighted imaging, FLAIR, and SWI at 1.5 T, 3 T, and 4 T. MS lesions were identified separately in each imaging sequence. Lesions identified in SWI were reevaluated for their iron content using the SWI filtered phase images. There were a variety of new lesion characteristics identified by SWI, and these were classified into six types. A total of 75 lesions were seen only with conventional imaging, 143 only with SWI, and 204 by both. From the iron quantification measurements, a moderate linear correlation between signal intensity and iron content (phase) was established. The amount of iron deposition in the brain may serve as a surrogate biomarker for different MS lesion characteristics. SWI showed many lesions missed by conventional methods and six different lesion characteristics. SWI was particularly effective at recognizing the presence of iron in MS lesions and in the basal ganglia and pulvinar thalamus.


Inhibition of metastases by a serum factor associated to concomitant resistance induced by unrelated murine tumors.
Murine lung metatases growing undisturbed by the primary tumor were significantly inhibited by the concomitant resistance induced by a secondary subcutaneous implant of two unrelated tumors. Such inhibition was T-independent since it was also observed in nude mice; its full expression was dependent on the presence of the secondary tumor implant and it was exerted on both macroscopic and microscopic established metastases and not on the process of tumor cell dissemination from the primary tumor. Direct and indirect mechanisms seemed to be involved, the former affecting the metastatic cells per se by causing a decrease in proliferation and an increase in apoptosis while the latter affected neo-vascularization. These antitumor and antiangiogenic effects could be attributed to a serum factor induced by the unrelated tumors generating concomitant resistance. This factor proved to be heat, acid and alkaline resistant and dialysable; it was recovered in an HPLC column with maximum absorption at 215 and 266 nm; it was anionic at neutral pH, exhibiting free carboxil groups and one or more molecules of tyrosine, with a molecular weight between 870 and 1300 Dalton. Intravenous administration of this factor significantly inhibited lung metastases, decreasing mitosis and increasing apoptosis similar to that observed in the presence of the unrelated tumors.


Effect of potassium depletion on renal tubular function in the rat.
1. In order to investigate the effects of K+ depletion on renal function, micropuncture studies were performed on anaesthetized rats which had been kept on a K+-deficient diet for 2 weeks; results were compared with those from control animals. 2. In the K+-depleted animals, values for total glomerular filtration rate and single-nephron filtration rate were significantly lower than in controls. Urine osmolality was also reduced; this was associated with reductions in the osmolality, Na+ concentration and K+ concentration of papillary interstitial fluid. No significant difference between urine and papillary osmolality was observed. 3. Fractional reabsorption by the proximal convoluted tubule was enhanced in the K+-depleted animals; end-proximal fluid delivery was markedly reduced. 4. Absolute, but not fractional, delivery of K+ to the beginning of the distal tubule was reduced in the K+-depleted animals. In contrast to observations in control rats, no net secretion of K+ into the distal tubule occurred and there was indirect evidence of K+ reabsorption in the collecting duct. 5. K+ depletion was associated with reductions in the delivery of Na+ and water to early and late regions of the distal tubule, whereas excretion rates of Na+ and water were unaffected. 6. It is suggested that the reduction in Na+ delivery to the loop of Henle (arising from the changes in filtration rate and proximal tubular reabsorption) might contribute to the reduced medullary osmotic concentration observed during K+ depletion. Reductions in fractional reabsorption of Na+ and water in the collecting duct might result from lowered plasma aldosterone levels and the reduced medullary osmolality.


Global database of matched Plasmodium falciparum and P. vivax incidence and prevalence records from 1985-2013.
Measures of clinical incidence are necessary to help estimate the burden of a disease. Incidence is a metric not commonly measured in malariology because the longitudinal surveys required are costly and labour intensive. This database is an effort to collate published incidence records obtained using active case detection for Plasmodium falciparum and Plasmodium vivax malaria. The literature search methods, data abstraction procedures and data processing procedures are described here. A total of 1,680 spatio-temporally unique incidence records were collected for the database: 1,187 for P. falciparum and 493 for P. vivax. These data were gathered to model the relationship between clinical incidence and prevalence of infection and can be used for a variety of modelling exercises including the assessment of change in disease burden in relation to age and control interventions. The subset of data that have been used for such modelling exercises are described and identified.


Anorexia nervosa in a woman totally blind since the age of two.
A 28 year-old woman, blind since the age of two, had become anorexic at 21. She had eating problems as a child, and weight preoccupation from her teens onwards. Psychiatric admission with other anorexic patients preceded the illness. Inability to see oneself does not protect against anorexia nervosa.


Computerized surveillance of adverse drug events in hospital patients.
To develop a new method to improve the detection and characterization of adverse drug events (ADEs) in hospital patients. Prospective study of all patients admitted to our hospital over an 18-month period. LDS Hospital, Salt Lake City, Utah, a 520-bed tertiary care center affiliated with the University of Utah School of Medicine, Salt Lake City. We developed a computerized ADE monitor, and computer programs were written using an integrated hospital information system to allow for multiple source detection of potential ADEs occurring in hospital patients. Signals of potential ADEs, both voluntary and automated, included sudden medication stop orders, antidote ordering, and certain abnormal laboratory values. Each day, a list of all potential ADEs from these sources was generated, and a pharmacist reviewed the medical records of all patients with possible ADEs for accuracy and causality. Verified ADEs were characterized as mild, moderate, or severe and as type A (dose-dependent or predictable) or type B (idiosyncratic or allergic) reactions, and causality was further measured using a standardized scoring method. The number and characterization of ADEs detected. Over 18 months, we monitored 36,653 hospitalized patients. There were 731 verified ADEs identified in 648 patients, 701 ADEs were characterized as moderate or severe, and 664 were classified as type A reactions. During this same period, only nine ADEs were identified using traditional detection methods. Physicians, pharmacists, and nurses voluntarily reported 92 of the 731 ADEs detected using this automated system. The other 631 ADEs were detected from automated signals, the most common of which were diphenhydramine hydrochloride and naloxone hydrochloride use, high serum drug levels, leukopenia, and the use of phytonadione and antidiarrheals. The most common symptoms and signs were pruritus, nausea and/or vomiting, rash, and confusion-lethargy. The most common drug classes involved were analgesics, anti-infectives, and cardiovascular agents. We believe that screening for ADEs with a computerized hospital information system offers a potential method for improving the detection and characterization of these events in hospital patients.


Bond-Selective and Mode-Specific Dissociation of CH3D and CH2D2 on Pt(111).
Infrared laser excitation of partially deuterated methanes (CH3D and CH2D2) in a molecular beam is used to control their dissociative chemisorption on a Pt(111) single crystal and to determine the quantum state-resolved dissociation probabilities. The exclusive detection of C-H cleavage products adsorbed on the Pt(111) surface by infrared absorption reflection spectroscopy indicates strong bond selectivity for both methane isotopologues upon C-H stretch excitation. Furthermore, the dissociative chemisorption of both methane isotopologues is observed to be mode-specific. Excitation of symmetric C-H stretch modes produces a stronger reactivity increase than excitation of the antisymmetric C-H stretch modes, whereas bend overtone excitation has a weaker effect on reactivity. The observed mode specificity and bond selectivity are rationalized by the sudden vector projection model in terms of the overlap of the reactant's normal mode vectors with the reaction coordinate at the transition state.


Critical windows of exposure for children's health: the reproductive system in animals and humans.
Drugs and environmental chemicals can adversely affect the reproductive system. Currently, available data indicate that the consequences of exposure depend on the nature of the chemical, its target, and the timing of exposure relative to critical windows in development of the reproductive system. The reproductive system is designed to produce gametes in far greater excess than would seem to be necessary for the survival of species. Ten to hundreds of millions of spermatozoa are generated daily by most adult male mammals, yet very few of these germ cells succeed in transmitting their genetic material to the next generation. Although the number of oocytes produced in mammalian females is more limited, and their production occurs only during fetal life, most ovaries contain several orders of magnitude more oocytes than ever will be fertilized. Toxicant exposures may affect critical events in the development of the reproductive system, ranging from early primordial germ cell determination to gonadal differentiation, gametogenesis, external genitalia, or signaling events regulating sexual behavior. Although there are differences between the human reproductive system and that of the usual animal models, such models have been extremely useful in assessing risks for key human reproductive and developmental processes. The objectives for future studies should include the elucidation of the specific cellular and molecular targets of known toxicants; the design of a systematic approach to the identification of reproductive toxicants; and the development of sensitive, specific, and predictive animal models, minimally invasive surrogate markers, or in vitro tests to assess reproductive system function during embryonic, postnatal, and adult life.


Binding and the effect of the red kidney bean lectin, phytohaemagglutinin, in the gastrointestinal tract of suckling rats.
Enteral exposure of suckling rats to phytohaemagglutinin (PHA) has been shown to induce growth and precocious functional maturation of the gastrointestinal tract. The aim of the present study was to explore the mechanism of this action. Suckling rats, 14 d old, were fed a single dose of PHA (0.05 mg/g body weight) or saline. The binding of PHA to the gut epithelium and its effect on the morphology and functional properties of the gut and pancreas were studied up to 3 d after treatment. Initially, at 1-24 h, the PHA bound along the gut mucosal lining, resulting in disturbed gut morphology with villi shortening and rapid decreases in disaccharidase activities and macromolecular absorption capacity. During a later phase, between 1 and 3 d, the PHA binding had declined, and an uptake by enterocytes was observed. An increase in crypt cell proliferation and gut growth became evident during this period, together with a functional maturation, as indicated by increases in disaccharidase (maltase and sucrase) activities and the low macromolecular absorption capacity. Pancreas growth also increased, as did its content of digestive enzymes. We conclude that enteral exposure to PHA in suckling rats temporarily causes mucosal disarrangement and functional impediment of the gut, which may be explained by binding to and disruption of the gut mucosa and a two-fold increase in the plasma corticosterone concentration. These findings may lead to a better understanding of the role of diet in gastrointestinal maturation and may constitute a basis for the treatment of mammals having an immature gut.


Shape analysis of the histone octamer in solution.
The conformation of the histone octamer is shown to depend upon the specific salt used to solubilize it. In 2M sodium chloride the octamer is similar in size and shape to the histone component of crystallized core nucleosomes. In contrast, in 3.5M ammonium sulfate the octamer is elongated, resembling an ellipsoid with approximate dimensions of 114 by 62 by 62 angstroms. These results indicate that the elongated conformation seen in the 3.3 angstroms electron density map of the histone octamer crystallized in ammonium sulfate is due to the particular salt conditions used.


Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption.
Antidepressants are associated with bone loss and fractures in older adults. We treated depressed older adults with an antidepressant and examined its effects on bone turnover by comparing blood samples before and after treatment. Bone resorption increased after antidepressant treatment, which may increase fracture risk. Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression. Seventy-six individuals aged 60 years and older with current major depressive disorder received a 12-week course of venlafaxine XR 150-300 mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (β-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in β-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment. After 12 weeks of venlafaxine, β-CTX increased significantly, whereas P1NP did not significantly change. The increase in β-CTX was significant only in participants whose depression did not remit (increase by 10 % in non-remitters vs. 4 % in remitters). Change in β-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine. Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants' depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults.


Quantitative Proteomic Analysis of the Central Amygdala in Neuropathic Pain Model Rats.
Pain and emotional distress have a reciprocal relation. The amygdala has been implicated in emotional processing. The central nucleus of the amygdala (CeA) receives nociceptive information from the dorsal horn of spinal cord and is responsible for the central plasticity in chronic pain. Neuropathic pain is a type of severe chronic pain and can be strongly influenced by emotional components. Plastic changes in the CeA may play a key role in the development or maintenance or both of neuropathic pain. We studied the expression levels of proteins in the CeA of spinal nerve transection (SNT) model rats. Total tissue lysate proteins were separated by two-dimensional-gel electrophoresis (2D-PAGE). Gels from different time points were compared using Progenesis SameSpot software, and the spots with Fold Change greater than 2 were excised for protein identification by mass spectrometry. We identified more than 50 cytosolic proteins as significantly altered in their expression levels in the CeA of SNT rats, and most of these changes have been validated at mRNA levels by qRT-PCR. We also identified more than 40 membrane proteins as notably up- or down-regulated in the CeA of SNT model rats relative to a control using stable isotope dimethyl labeling nano-LC-MS/MS based proteomics and found that one such protein, doublecortin (DCX), a microtubule-associated protein expressed by neuronal precursor cells during development, is specifically localized in the membrane fraction without changes in total amount of the protein. Immunohistochemistry showed that doublecortin is expressed in processes in the CeA of rats 7 and 21 days after SNT surgery, suggesting that doublecortin is one of the proteins that may contribute to the plastic changes, namely, redevelopment or rewiring of neural networks, in the CeA in the neuropathic pain model. These dysregulated proteins may play roles in reciprocal relationships between pain and psychological distress in the amygdala and contribute to central sensitization. Data are available via ProteomeXchange with identifier PXD017473.


Proteomics characterization of extracellular space components in the human aorta.
The vascular extracellular matrix (ECM) is essential for the structural integrity of the vessel wall and also serves as a substrate for the binding and retention of secreted products of vascular cells as well as molecules coming from the circulation. Although proteomics has been previously applied to vascular tissues, few studies have specifically targeted the vascular ECM and its associated proteins. Thus, its detailed composition remains to be characterized. In this study, we describe a methodology for the extraction of extracellular proteins from human aortas and their identification by proteomics. The approach is based on (a) effective decellularization to enrich for scarce extracellular proteins, (b) successful solubilization and deglycosylation of ECM proteins, and (c) relative estimation of protein abundance using spectral counting. Our three-step extraction approach resulted in the identification of 103 extracellular proteins of which one-third have never been reported in the proteomics literature of vascular tissues. In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. We also identified extracellular adipocyte enhancer-binding protein 1, the cartilage glycoprotein asporin, and a previously hypothetical protein, retinal pigment epithelium (RPE) spondin. Moreover, our methodology allowed us to screen for proteolysis in the aortic samples based on the identification of proteolytic enzymes and their corresponding degradation products. For instance, we were able to detect matrix metalloproteinase-9 by mass spectrometry and relate its presence to degradation of fibronectin in a clinical specimen. We expect this proteomics methodology to further our understanding of the composition of the vascular extracellular environment, shed light on ECM remodeling and degradation, and provide insights into important pathological processes, such as plaque rupture, aneurysm formation, and restenosis.


Secondary metabolite and mycotoxin production by the Rhizopus microsporus group.
Fast-growing Zygomycetes, most notably Rhizopus oligosporus, are traditionally used in many food fermentations, for example, for soybean tempeh production. R. oligosporus is considered to belong to the Rhizopus microsporus group. Certain R. microsporus strains have been reported to produce either the pharmaceutically active rhizoxins or the highly toxic rhizonins A and B. In this study was investigated the formation of secondary metabolites by R. microsporus, R. oligosporus, and Rhizopus chinensis grown on a wide range of different semisynthetic and natural substrates. Liquid chromatography, combined with photodiode array detection and high-resolution mass spectrometric techniques, was used to identify secondary metabolites. Growth on maize, brown rice, and Pharma agar gave both the highest amounts and the maximum diversity of rhizoxins and rhizonins. Rhizoxins were produced by all four R. microsporus strains, whereas only one strain produced rhizonins. The six R. oligosporus and four R. chinensis strains investigated did not produce any of these two classes of metabolites.


Using skeleton-based tracking to increase the reliability of optical motion capture.
Optical motion capture provides an impressive ability to replicate gestures. However, even with a highly professional system there are many instances where crucial markers are occluded or when the algorithm confuses the trajectory of one marker with that of another. This requires much editing work on the user's part before the complete animation is ready for use. In this paper, we present an approach to increasing the robustness of a motion capture system by using an anatomical human model. It includes a reasonably precise description of the skeleton's mobility and an approximated envelope. It allows us to accurately predict the 3-D location and visibility of markers, thus significantly increasing the robustness of the marker tracking and assignment, and drastically reducing--or even eliminating--the need for human intervention during the 3-D reconstruction process.


Predicting the onset of major depression in primary care: international validation of a risk prediction algorithm from Spain.
The different incidence rates of, and risk factors for, depression in different countries argue for the need to have a specific risk algorithm for each country or a supranational risk algorithm. We aimed to develop and validate a predictD-Spain risk algorithm (PSRA) for the onset of major depression and to compare the performance of the PSRA with the predictD-Europe risk algorithm (PERA) in Spanish primary care. A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multi-level logistic regression and inverse probability weighting to build the PSRA. In Spain (4574), Chile (2133) and another five European countries (5184), 11 891 non-depressed adult primary care attendees formed our at-risk population. The main outcome was DSM-IV major depression (CIDI). Six variables were patient characteristics or past events (sex, age, sex×age interaction, education, physical child abuse, and lifetime depression) and six were current status [Short Form 12 (SF-12) physical score, SF-12 mental score, dissatisfaction with unpaid work, number of serious problems in very close persons, dissatisfaction with living together at home, and taking medication for stress, anxiety or depression]. The C-index of the PSRA was 0.82 [95% confidence interval (CI) 0.79-0.84]. The Integrated Discrimination Improvement (IDI) was 0.0558 [standard error (s.e.)=0.0071, Zexp=7.88, p<0.0001] mainly due to the increase in sensitivity. Both the IDI and calibration plots showed that the PSRA functioned better than the PERA in Spain. The PSRA included new variables and afforded an improved performance over the PERA for predicting the onset of major depression in Spain. However, the PERA is still the best option in other European countries.


Omega-3 Polyunsaturated Fatty Acids Trigger Cell Cycle Arrest and Induce Apoptosis in Human Neuroblastoma LA-N-1 Cells.
Omega-3 (n-3) fatty acids are dietary long-chain fatty acids with an array of health benefits. Previous research has demonstrated the growth-inhibitory effect of n-3 fatty acids on different cancer cell lines in vitro, yet their anti-tumor effects and underlying action mechanisms on human neuroblastoma LA-N-1 cells have not yet been reported. In this study, we showed that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exhibited time- and concentration-dependent anti-proliferative effect on the human neuroblastoma LA-N-1 cells, but had minimal cytotoxicity on the normal or non-tumorigenic cells, as measured by MTT reduction assay. Mechanistic studies indicated that DHA and EPA triggered G0/G1 cell cycle arrest in LA-N-1 cells, as detected by flow cytometry, which was accompanied by a decrease in the expression of CDK2 and cyclin E proteins. Moreover, DHA and EPA could also induce apoptosis in LA-N-1 cells as revealed by an increase in DNA fragmentation, phosphatidylserine externalization and mitochondrial membrane depolarization. Up-regulation of Bax, activated caspase-3 and caspase-9 proteins, and down-regulation of Bcl-XL protein, might account for the occurrence of apoptotic events. Collectively, our results suggest that the growth-inhibitory effect of DHA and EPA on LA-N-1 cells might be mediated, at least in part, via triggering of cell cycle arrest and apoptosis. Therefore, DHA and EPA are potential anti-cancer agents which might be used for the adjuvant therapy or combination therapy with the conventional anti-cancer drugs for the treatment of some forms of human neuroblastoma with minimal toxicity.


Translational research to prevent internalizing problems early in childhood.
This article discusses the importance of and one approach to translational research to prevent internalizing problems very early in life. The World Health Organisation (WHO) predicts that by 2,030 internalizing problems will be second only to HIV/AIDS in the international burden of disease. Internalizing problems affect one in every seven school age children, with negative impacts on peer relations, school engagement, and later mental health, adult relationships, and employment. There is persuasive evidence that intervention in the preschool years can have a cost-effective impact on general developmental outcomes, compared to later school or adult intervention. However, the development of early childhood prevention for internalizing problems is in its infancy. Two significant risk factors for child internalizing problems are temperamental inhibition (characterized by fearfulness and withdrawal) and overinvolved/protective parenting practices. Rapee et al. have conducted two randomized "efficacy" trials with inhibited preschoolers in which a parenting group intervention reduced internalizing disorders up to 3 years later. Translational "effectiveness" research is now underway at the population level, to determine the balance of benefits and harms of systematically screening preschoolers for inhibition and subsequent intervention for all those affected. This rigorous public health research, followed by effective dissemination, addresses gaps identified in the WHO Prevention of Mental Disorders report.


Mutation of lysine-48 to arginine in the yeast RAD3 protein abolishes its ATPase and DNA helicase activities but not the ability to bind ATP.
The RAD3 gene of Saccharomyces cerevisiae is required for excision repair of DNA damaged by UV radiation and is also essential for cell viability. The approximately 89 kd protein encoded by RAD3 possesses single-stranded DNA dependent ATPase and DNA helicase activities. The sequence Gly-X-Gly-Lys-Thr, believed to be involved in the interaction with purine nucleotides in proteins that bind and hydrolyze the nucleotides, is present in the RAD3 primary structure between amino acids 45 and 49. We report here that the point mutation of Lys-48 to arginine abolishes the RAD3 ATPase and DNA helicase activities but not the ability to bind ATP. These observations highlight the involvement of this lysine residue in the hydrolysis of ATP and indicate that the positive charge on arginine can replace that of the lysine residue in the binding of ATP but not in its hydrolysis. The rad3 Arg-48 mutant is apparently defective in a step subsequent to incision at the damage site in DNA; it can incise UV damaged DNA, but does not remove pyrimidine dimers. The role of the ATPase and DNA helicase activities of the RAD3 protein in its DNA repair and viability functions is discussed.


General principles in the medical and surgical management of spinal infections: a multidisciplinary approach.
Infections along the spinal axis are characterized by an insidious onset, and the resulting delays in diagnosis are associated with serious neurological consequences and even death. Infections of the spine can affect the vertebral bodies, intervertebral discs, spinal canal, and surrounding soft tissues. Neurological dysfunction occurs when the spinal cord becomes compressed, edematous, or ischemic due to compression by abscess or vascular compromise. The aim of this paper was to detail general diagnostic and management principles for this disease. Recent progress in medical technologies, including the development of potent antimicrobial drugs, advanced imaging, and improved surgical methods, have dramatically reduced morbidity and mortality rates for spinal infections; however, debate still exists on the proper management of this disease. In this paper, the authors review the current management protocols for spinal infections at their institution, focusing on medical and surgical treatments for vertebral osteomyelitis, intervertebral disc space infections, and spinal canal and soft-tissue abscesses. Technological advances in imaging modalities, pharmaceutics, and surgery have resulted in excellent outcomes and have greatly reduced the morbidity and mortality rates associated with spinal infections. Currently, treatment of spinal infections requires a multidisciplinary team that includes infectious diseases experts, neuroradiologists, and spine surgeons. The key to successful management of spinal infections is early detection.


Tumor regression in cancer patients by very low doses of a T cell-engaging antibody.
Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non-Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell-engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.


The effects of cigarette smoking and abstinence on auditory verbal learning.
Smoking has been associated with both enhanced and impaired cognitive performance; across a variety of domains, but there is limited evidence demonstrating the effects on verbal learning. The current study assessed the effect of smoking and abstinence on verbal learning, immediate memory and retention using the Auditory Verbal Learning Test (AVLT). Three groups: 20 smokers, 20 abstaining smokers and 20 non-smoking adults were assessed on the AVLT on two occasions. At session one, abstaining smokers refrained from smoking for 12 h (pre-cigarette), whilst smokers had continued to smoke to satiety. Session two commenced after a 15-min break when both smoking groups were instructed to smoke a cigarette, followed by administration of the second version of the AVLT (post-cigarette). Abstaining smokers showed significant deficits in learning compared to smokers during the pre-cigarette session. Following re-initiation of smoking in the abstaining smokers, these learning decrements were no longer evident. There were trends towards significant group findings in immediate memory and retention during the pre-cigarette session, which again were no longer evident in the post-cigarette session. These findings provide further evidence that smoking abstinence affects verbal learning and furthermore smoking simply restores cognitive performance to pre-abstinence levels.


From Psychoacoustics to Brain Waves: A Longitudinal Approach to Novel Word Learning.
Musical expertise has been shown to positively influence high-level speech abilities such as novel word learning. This study addresses the question whether low-level enhanced perceptual skills causally drives successful novel word learning. We used a longitudinal approach with psychoacoustic procedures to train 2 groups of nonmusicians either on pitch discrimination or on intensity discrimination, using harmonic complex sounds. After short (approximately 3 hr) psychoacoustic training, discrimination thresholds were lower on the specific feature (pitch or intensity) that was trained. Moreover, compared to the intensity group, participants trained on pitch were faster to categorize words varying in pitch. Finally, although the N400 components in both the word learning phase and in the semantic task were larger in the pitch group than in the intensity group, no between-group differences were found at the behavioral level in the semantic task. Thus, these results provide mixed evidence that enhanced perception of relevant features through a few hours of acoustic training with harmonic sounds causally impacts the categorization of speech sounds as well as novel word learning. These results are discussed within the framework of near and far transfer effects from music training to speech processing.


A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study.
Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients. DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0-3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910). The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability. We developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.


Culture shapes a mesolimbic response to signals of dominance and subordination that associates with behavior.
It has long been understood that culture shapes individuals' behavior, but how this is accomplished in the human brain has remained largely unknown. To examine this, we made use of a well-established cross-cultural difference in behavior: American culture tends to reinforce dominant behavior whereas, conversely, Japanese culture tends to reinforce subordinate behavior. In 17 Americans and 17 Japanese individuals, we assessed behavioral tendencies towards dominance versus subordination and measured neural responses using fMRI during the passive viewing of stimuli related to dominance and subordination. In Americans, dominant stimuli selectively engaged the caudate nucleus, bilaterally, and the medial prefrontal cortex (mPFC), whereas these were selectively engaged by subordinate stimuli in Japanese. Correspondingly, Americans self-reported a tendency towards more dominant behavior whereas Japanese self-reported a tendency towards more subordinate behavior. Moreover, activity in the right caudate and mPFC correlated with behavioral tendencies towards dominance versus subordination, such that stronger responses in the caudate and mPFC to dominant stimuli were associated with more dominant behavior and stronger responses in the caudate and mPFC to subordinate stimuli were associated with more subordinate behavior. The findings provide a first demonstration that culture can flexibly shape functional activity in the mesolimbic reward system, which in turn may guide behavior.


Bovine thrombin: history, use, and risk in the surgical patient.
Thrombin is a common hemostatic drug used in surgical practice for over 100 years because of its simplicity and efficacy. Thrombin converts fibrinogen to fibrin, activates platelets, and induces vascular contraction. It is available in multiple forms, including human thrombin, bovine thrombin, and, most recently, human recombinant thrombin. Over 100 case reports of adverse reactions to bovine thrombin include hemorrhage, thrombosis, and substantial immune reaction when used on cardiovascular surgery patients. Approximately 30% of patients exposed to bovine thrombin develop cross-reacting antibodies. Thirty percent of patients with anticlotting factor antibodies develop abnormal coagulation that can be detected by prothrombin time, partial thromboplastin time, or thrombin time, which makes anticoagulation monitoring difficult. Patients with multiple elevated antibodies prior to surgery are also more likely to sustain adverse events. Animal studies confirm these immunological responses seen in humans. With the available clinical and laboratory data, a less immunogenic yet biologically effective thrombin should be available for use in our surgical patients.


Expression of functional Schistosoma mansoni Smad4: role in Erk-mediated transforming growth factor beta (TGF-beta) down-regulation.
Members of the transforming growth factor (TGF)-beta superfamily play pivotal roles in cell migration, differentiation, adhesion, pattern formation, and apoptosis. The family of Smad proteins acts as intracellular signal transducers of TGF-beta and related peptides. Smad4, a common mediator Smad (co-Smad), performs a central role in transmitting signals from TGF-beta, BMP, and activins. Schistosoma mansoni receptor-regulated Smad1 and SmSmad2 were previously identified and shown to act in TGF-beta signaling. Herein, we report the identification and characterization of a Smad4 homologue from S. mansoni and provide details about its role in mediation and down-regulation of TGF-beta signaling in schistosomes. In order to identify the schistosome co-Smad, we designed degenerate primers based on the sequence of the conserved MH1/MH2 domains of Smad4 proteins, which were used in PCR to amplify a 137-bp PCR product. A S. mansoni adult worm pair cDNA library was screened resulting in the isolation of a cDNA clone that encodes a 738 amino acid protein (SmSmad4). SmSmad4 was shown to interact with schistosome R-Smads (SmSmad1 and SmSmad2) in vivo and in vitro. The interaction with SmSmad2 was dependent on the receptor-mediated phosphorylation of SmSmad2. In addition, several potential phosphorylation sites for Erk1/2 kinases were identified in the SmSmad4 linker region and shown to be phosphorylated in vitro by an active mutant of mammalian Erk2. Furthermore, Erk-mediated phosphorylation of SmSmad4 decreased its interaction with the receptor-activated form of SmSmad2, in vitro. SmSmad4 was shown to complement a human Smad4 deficiency through the restoration of TGF-beta-responsiveness in MDA-MB-468 breast cancer cells.


Temporal trends in presentation for outpatient HIV medical care 2000-2010: implications for short-term mortality.
Many newly diagnosed patients present to outpatient care with advanced HIV infection. More timely HIV diagnosis and initiation of care has the potential to improve individual health outcomes and has public health implications. To assess temporal trends in late presentation for outpatient HIV medial care as measured by CD4 count <200 cells/mm(3) and the implications on short-term (1-year) mortality. We conducted a cohort study nested in a prospective HIV clinical cohort including patients establishing initial outpatient HIV treatment between 2000-2010. Time series regression analysis evaluated temporal trends in late presentation for care measured by the proportion of patients with a CD4 count <200 cells/mm(3) or an opportunistic infection at enrollment, and also evaluated trends in short-term mortality. Patients establishing initial outpatient HIV treatment between 2000-2010 at an academic HIV clinic. The proportion of patients with a CD4 count <200 cells/mm(3) or an opportunistic infection at initial presentation and short-term (1-year) mortality following clinic enrollment. Among 1121 patients, 41% had an initial CD4 count <200 cells/mm(3), 25% had an opportunistic infection and 2.4% died within 1-year of their initial visit. Time series regression analysis demonstrated significant reductions in late presentation for HIV care and decreases in short-term mortality with temporal improvement preceding updated CDC HIV testing recommendations. We observed a significant decline in the number of patients presenting for outpatient HIV care with advanced disease, particularly in 2006-2010. A significant trend in improved short-term survival among patients establishing HIV care was also observed, likely related to more timely presentation for outpatient care in more recent years.


Patient perspectives of care and process and outcome quality measures for heart failure admissions in US hospitals: how are they related in the era of public reporting?
Process quality measure performance has improved significantly with public reporting, requiring reevaluation of process-outcome relationships and the emerging role of patient perspectives on care. To evaluate associations between heart failure patient perspectives of care and publicly reported processes and outcomes. Cross-sectional study, July 2008-June 2011. US hospitals in the Press Ganey database. Heart failure inpatients. Outcomes were Hospital Compare hospital-level risk-adjusted 30-day heart failure mortality and readmissions. Predictors included Hospital Compare heart failure processes of care, a weighted process composite and Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) domains for heart failure. Hospital characteristics included volume of heart failure patients and race, health status and education. Among 895 included hospitals, performance on process measures was high (median by hospital for composite, 95.6%); the median HCAHPS overall rating was 86.9. Median mortality was 11.3% and readmissions was 24.8%. No process measures were statistically significantly associated with lower mortality or readmissions in adjusted analyses. Higher ratings on HCAHPS patient perspectives of care were significantly correlated with lower readmissions in adjusted analyses, particularly those publicly reported domains conceptually related to readmissions. The magnitude was small (1.8 points higher on a 100-point scale between the highest and lowest quartiles of hospital readmissions). Publicly reported process quality measures were no longer associated with outcomes, but higher patient perspectives of care were associated with lower heart failure readmissions. These associations support continued reevaluation of these measures and increased emphasis on patient experience and outcomes, as planned for Value-Based Purchasing.


Lead, cadmium, smoking, and increased risk of peripheral arterial disease.
Lead and cadmium exposure may promote atherosclerosis, although the cardiovascular effects of chronic low-dose exposure are largely unknown. The objective of the present study was to evaluate the association between blood levels of lead and cadmium and peripheral arterial disease. We analyzed data from 2125 participants who were > or =40 years of age in the 1999 to 2000 National Health and Nutrition Examination Survey (NHANES). Peripheral arterial disease was defined as an ankle brachial index <0.9 in at least 1 leg. Lead and cadmium levels were measured by atomic absorption spectrometry. After adjustment for demographic and cardiovascular risk factors, the ORs of peripheral arterial disease comparing quartiles 2 to 4 of lead with the lowest quartile were 1.63 (95% CI, 0.51 to 5.15), 1.92 (95% CI, 0.62 to 9.47), and 2.88 (95% CI, 0.87 to 9.47), respectively (P for trend=0.02). The corresponding ORs for cadmium were 1.07 (95% CI, 0.44 to 2.60), 1.30 (95% CI, 0.69 to 2.44), and 2.82 (95% CI, 1.36 to 5.85), respectively (P for trend=0.01). The OR of peripheral arterial disease for current smokers compared with never smokers was 4.13. Adjustment for lead reduced this OR to 3.38, and adjustment for cadmium reduced it to 1.84. Blood lead and cadmium, at levels well below current safety standards, were associated with an increased prevalence of peripheral arterial disease in the general US population. Cadmium may partially mediate the effect of smoking on peripheral arterial disease.


Multiple mechanisms collaborate to repress nanos translation in the Drosophila ovary and embryo.
Translational control of gene expression is essential for development in organisms that rely on maternal mRNAs. In Drosophila, translation of maternal nanos (nos) mRNA must be restricted to the posterior of the early embryo for proper patterning of the anterior-posterior axis. Spatial control of nos translation is coordinated through the localization of a small subset of nos mRNA to the posterior pole late in oogenesis, activation of this localized mRNA, and repression of the remaining unlocalized nos mRNA throughout the bulk cytoplasm. Translational repression is mediated by the interaction of a cis-acting element in the nos 3' untranslated region with two proteins, Glorund (Glo) and Smaug (Smg), that function in the oocyte and embryo, respectively. The mechanism of Glo-dependent repression is unknown. Previous work suggests that Smg represses translation initiation but this model is not easily reconciled with evidence for polysome association of repressed nos mRNA. Using an in vitro translation system, we have decoupled translational repression of nos imposed during oogenesis from repression during embryogenesis. Our results suggest that both Glo and Smg regulate translation initiation, but by different mechanisms. Furthermore, we show that, during late oogenesis, nos translation is also repressed post-initiation and provide evidence that Glo mediates this event. This post-initiation block is maintained into embryogenesis during the transition to Smg-dependent regulation. We propose that the use of multiple modes of repression ensures inactivation of nos RNA that is translated at earlier stages of oogenesis and maintenance of this inactivate state throughout late oogenesis into embryogenesis.


An ethical framework adapted for infection prevention and control.
The ethical implications of infection prevention and control (IPAC) are recognized, yet a framework to guide the application of ethical principles is lacking. We adapted an ethical framework to provide a systematic approach for fair and transparent IPAC decision making. We conducted a literature search for existing ethical frameworks in IPAC. Working with practicing healthcare ethicists, an existing ethical framework was adapted for use in IPAC. Indications were developed for application to practice, with integration of ethical principles and process conditions specifically relevant to IPAC. Practical refinements were made to the framework based on end-user feedback and application to 2 real-world situations. In total, 7 articles were identified that discussed ethical principles within IPAC, but none proposed a systematic framework to guide ethical decision making. The adapted framework, named the Ethical Infection Prevention and Control (EIPAC) framework, takes the user through 4 intuitive and actionable steps, centering key ethical principles that facilitate reasoned and just decision making. In applying the EIPAC framework to practice, weighing the predefined ethical principles in different scenarios was a challenge. Although no hierarchy of principles can apply to all contexts in IPAC, our experience highlighted that the equitable distribution of benefits and burdens, and the proportional impacts of options under review, are particularly important considerations for IPAC. The EIPAC framework can serve as an actionable ethical principles-based decision-making tool for use by IPAC professionals encountering complex situations in any healthcare context.


Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.
Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.


Upregulation of miR-133a by adiponectin inhibits pyroptosis pathway and rescues acute aortic dissection.
Acute aortic dissection (AAD) is a cardiovascular emergency caused by the formation of hematoma in the middle layer of the aortic wall. Adiponectin (APN) is an adipose tissue-specific protein that has anti-inflammation and anti-atherosclerosis functions. Pyroptosis, as an inflammatory cell death, depends on the activation of caspase1, while nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) is a typical representative of the pyroptosis pathway. In this study, we aimed to find whether APN affects the AAD process. The results showed that APN overexpression (OE) inhibited the AAD development and the levels of glucose, triglyceride, and total cholesterol in mice model. In addition, APN OE inhibited the productions of gasdermin D (GSDMD), NLRP3, caspase1, interleukin-1β (IL-1β), IL-18, and osteopontin (OPN), as well as α-smooth muscle actin (α-SMA) downregulation in vitro and in vivo. In addition, NLRP3 was found to be a target gene of miR-133a and miR-133a OE showed similar effects to APN OE in attenuating the LPS-induced productions of GSDMD, NLRP3, caspase1, IL-1β, IL-18, and OPN, as well as α-SMA downregulation in vascular smooth muscle cells (vSMCs). Moreover, the beneficial effects of APN OE were abolished by miR-133a knockdown in vSMCs. In conclusion, our present results indicated that the upregulation of miR-133a by APN inhibits pyroptosis pathway, which potentially rescues AAD.


The association between implementation strategy use and the uptake of hepatitis C treatment in a national sample.
Hepatitis C virus (HCV) is a common and highly morbid illness. New medications that have much higher cure rates have become the new evidence-based practice in the field. Understanding the implementation of these new medications nationally provides an opportunity to advance the understanding of the role of implementation strategies in clinical outcomes on a large scale. The Expert Recommendations for Implementing Change (ERIC) study defined discrete implementation strategies and clustered these strategies into groups. The present evaluation assessed the use of these strategies and clusters in the context of HCV treatment across the US Department of Veterans Affairs (VA), Veterans Health Administration, the largest provider of HCV care nationally. A 73-item survey was developed and sent to all VA sites treating HCV via electronic survey, to assess whether or not a site used each ERIC-defined implementation strategy related to employing the new HCV medication in 2014. VA national data regarding the number of Veterans starting on the new HCV medications at each site were collected. The associations between treatment starts and number and type of implementation strategies were assessed. A total of 80 (62%) sites responded. Respondents endorsed an average of 25 ± 14 strategies. The number of treatment starts was positively correlated with the total number of strategies endorsed (r = 0.43, p < 0.001). Quartile of treatment starts was significantly associated with the number of strategies endorsed (p < 0.01), with the top quartile endorsing a median of 33 strategies, compared to 15 strategies in the lowest quartile. There were significant differences in the types of strategies endorsed by sites in the highest and lowest quartiles of treatment starts. Four of the 10 top strategies for sites in the top quartile had significant correlations with treatment starts compared to only 1 of the 10 top strategies in the bottom quartile sites. Overall, only 3 of the top 15 most frequently used strategies were associated with treatment. These results suggest that sites that used a greater number of implementation strategies were able to deliver more evidence-based treatment in HCV. The current assessment also demonstrates the feasibility of electronic self-reporting to evaluate ERIC strategies on a large scale. These results provide initial evidence for the clinical relevance of the ERIC strategies in a real-world implementation setting on a large scale. This is an initial step in identifying which strategies are associated with the uptake of evidence-based practices in nationwide healthcare systems.


Antitumor effects of nano-bubble hydrogen-dissolved water are enhanced by coexistent platinum colloid and the combined hyperthermia with apoptosis-like cell death.
In order to erase reactive oxygen species (ROS) related with the proliferation of tumor cells by reducing activity of hydrogen, we developed functional water containing nano-bubbles (diameters: <900 nm for 71%/population) hydrogen of 1.1-1.5 ppm (the theoretical maximum: 1.6 ppm) with a reducing ability (an oxidation-reduction potential -650 mV, normal water: +100-200 mV) using a microporous-filter hydrogen-jetting device. We showed that hydrogen water erased ROS indispensable for tumor cell growth by ESR/spin trap, the redox indicator CDCFH-DA assay, and was cytotoxic to Ehrlich ascites tumor cells as assessed by WST-8 assay, crystal violet dye stain and scanning electron microscopy, after 24-h or 48-h incubation sequent to warming at 37°C or 42°C. Hydrogen water supplemented with platinum colloid (0.3 ppm Pt in 4% polyvinylpyrrolidone) had more antitumor activity than hydrogen water alone, mineral water alone (15.6%), hydrogen water plus mineral water, or platinum colloid alone as observed by decreased cell numbers, cell shrinkage and pycnosis (nuclear condensation)/karyorrhexis (nuclear fragmentation) indicative of apoptosis, together with cell deformation and disappearance of microvilli on the membrane surface. These antitumor effects were promoted by combination with hyperthermia at 42°C. Thus, the nano-bubble hydrogen water with platinum colloid is potent as an anti-tumor agent.


Nurses joining family doctors in primary care practices: perceptions of patients with multimorbidity.
Among the strategies used to reform primary care, the participation of nurses in primary care practices appears to offer a promising avenue to better meet the needs of vulnerable patients. The present study explores the perceptions and expectations of patients with multimorbidity regarding nurses' presence in primary care practices. 18 primary (health) care patients with multimorbidity participated in semi-directed interviews, in order to explore their perceptions and expectations in regard to the involvement of nurses in primary care practices. Interviews were audio-recorded and transcribed. After reviewing the transcripts, the principal investigator and research assistants performed thematic analysis independently and reached consensus on the retained themes. Patients with multimorbidity were open to the participation of nurses in primary care practices. They expected greater accessibility, for both themselves and for new patients. However, the issue of shared roles between nurses and doctors was a source of concern. Many patients held the traditional view of the nurse's role as an assistant to the doctor in his or her various duties. In general, participants said they were confident about nurses' competency but expressed concern about nurses performing certain acts that their doctor used to, notwithstanding a close collaboration between the two professionals. Patients with multimorbidity are open to the involvement of nurses in primary care practices. However, they expect this participation to be established using clear definitions of professional roles and fields of practice.


Abnormalities of endothelial function in patients with predialysis renal failure.
Endothelial dysfunction plays an important role in the development of atherosclerotic vascular disease, which is the leading cause of mortality in patients with chronic renal failure. To examine the relation between predialysis renal failure and endothelial function. Two groups were studied: 80 patients with non-diabetic chronic renal failure and 26 healthy controls, with similar age and sex distributions. Two indices of endothelial function were assessed: high resolution ultrasonography to measure flow mediated endothelium dependent dilatation of the brachial artery following reactive hyperaemia, and plasma concentration of von Willebrand factor. Endothelium independent dilatation was also assessed following sublingual glyceryl trinitrate. The patients were divided into those with and without overt atherosclerotic vascular disease. Although patients with chronic renal failure had significantly impaired endothelium dependent dilatation compared with controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to 8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87 to 138) iu/dl; p < 0.001), there was no difference between renal failure patients with and without atherosclerotic vascular disease. Within the chronic renal failure group, endothelium dependent dilatation and von Willebrand factor were similar in patients in the upper and lower quartiles of glomerular filtration rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209 to 292) iu/dl, respectively). Endothelium independent dilatation did not differ between the renal failure or control groups and was also similar in patients with renal failure irrespective of the degree of renal failure or the presence of atherosclerotic vascular disease. Endothelial function is abnormal in chronic renal failure, even in patients with mild renal insufficiency and those without atherosclerotic vascular disease, suggesting that uraemia may directly promote the development of atherosclerosis early in the progression of chronic renal failure.


Conditions Influencing Collaboration Among the Primary Care Disciplines as They Prepare the Future Primary Care Physician Workforce.
Much can be gained by the three primary care disciplines collaborating on efforts to transform residency training toward interprofessional collaborative practice. We describe findings from a study designed to align primary care disciplines toward implementing interprofessional education. In this mixed methods study, we included faculty, residents and other interprofessional learners in family medicine, internal medicine, and pediatrics from nine institutions across the United States. We administered a web-based survey in April/May of 2018 and used qualitative analyses of field notes to study resident exposure to team-based care during training, estimates of career choice in programs that are innovating, and supportive and challenging conditions that influence collaboration among the three disciplines. Complete data capture was attained for 96.3% of participants. Among family medicine resident graduates, an estimated 87.1% chose to go into primary care compared to 12.4% of internal medicine, and 36.5% of pediatric resident graduates. Qualitative themes found to positively influence cross-disciplinary collaboration included relationship development, communication of shared goals, alignment with health system/other institutional initiatives, and professional identity as primary care physicians. Challenges included expressed concerns by participants that by working together, the disciplines would experience a loss of identity and would be indistinguishable from one another. Another qualitative finding was that overwhelming stressors plague primary care training programs in the current health care climate-a great concern. These include competing demands, disruptive transitions, and lack of resources. Uniting the primary care disciplines toward educational and clinical transformation toward interprofessional collaborative practice is challenging to accomplish.


Changing cardiac arrest and hospital mortality rates through a medical emergency team takes time and constant review.
To determine the long-term impact of a medical emergency team on survival and to assess the utility of administrative data to monitor outcomes. Prospective study of cardiac arrests and survival. Retrospective study of administrative data. University affiliated tertiary referral hospital in Melbourne, Australia. All patients admitted to hospital in three 6-month periods between 2002-2007 (prospective) and 1993-2007 (retrospective). Implementation of a medical emergency team in November 2002. In the prospective analysis, rates of unexpected cardiac arrest and hospital mortality (referenced to 1000 patient-care days) were measured before (July-August 2002) and after (December 2002-May 2003, December 2004-May 2005, December 2006-May 2007) the introduction of the medical emergency team. Cardiac arrest rates decreased progressively from 0.78 per 1000 (95% confidence interval, 0.50-1.16) to 0.25 per 1000 (95% confidence interval, 0.15-0.39, p < .001), and hospital mortality from 0.58 per 1000 (95% confidence interval, 0.35-0.92) to 0.30 per 1000 (95% confidence interval, 0.20-0.46, p < .05); cardiac arrest rates achieved statistical significance at 2 yrs and hospital mortality at 4 yrs. Using administrative data adjusted for age, sex, case-mix, and comorbidity, hazard ratios for mortality for the three post implementation periods were statistically lower than for the 10 yrs pre implementation (0.85, 0.74, 0.65). The intensity of calling (calls/1000 patient-days) inversely correlated with cardiac arrest rate, unexpected mortality rate, and total hospital mortality rate. The introduction of a medical emergency team was associated with a progressive decline of unexpected cardiac arrests within 2 yrs, and of unexpected mortality within 4 yrs. This suggests that changes to organizational practice take time and benefits may not be immediately obvious. Such changes are reflected in total hospital mortality measured from administrative data and make monitoring simpler in the longer term. Finally, efforts to increase calling of emergency teams should reduce cardiac arrests and mortality.


Influencing public nutrition for non-communicable disease prevention: from community intervention to national programme--experiences from Finland.
A global health transition is currently underway. The burden of non-communicable diseases (NCDs) is increasing rapidly in the developing world, very much as a result of changes in lifestyles. In addition to changes in tobacco use and physical activity, major changes are taking place in diets, contributing greatly to the growing epidemic of NCD. Thus, a huge global public health challenge is how to influence the trends in diet and nutrition for effective global NCD prevention. The health transition took place rapidly in Finland after World War II and mortality from cardiovascular disease (CVD) was exceptionally high. The North Karelia Project was launched in 1972 as a community-based, and later as a national, programme to influence diet and other lifestyles that are crucial in the prevention of CVD. The intervention had a strong theory base and it employed comprehensive strategies. Broad community organisation and the strong participation of people were the key elements. Evaluation has shown how the diet (particularly fat consumption) has changed and how these changes have led to a major reduction in population serum cholesterol and blood pressure levels. It has also shown how ischaemic heart disease mortality in a working-age population has declined by 73% in North Karelia and by 65% in the whole country from 1971 to 1995. Although Finland is an industrialised country, North Karelia was rural, of rather low socio-economic level and with many social problems in the 1970s and 1980s. The project was based on low-cost intervention activities, where people's participation and community organisations played a key role. Comprehensive interventions in the community were eventually supported by national activities--from expert guidelines and media activities to industry collaboration and policy. Similar principles for nutrition intervention programmes could be used in developing countries, obviously tailored to the local conditions. This paper discusses the experiences of the North Karelia Project in the light of needs from the less-industrialised countries and makes some general recommendations.


Monitoring of representational difference analysis subtraction procedures by global microarrays.
Various approaches to the study of differential gene expression are applied to compare cell lines and tissue samples in a wide range of biological contexts. The compromise between focusing on only the important genes in certain cellular processes and achieving a complete picture is critical for the selection of strategy. We demonstrate how global microarray technology can be used for the exploration of the differentially expressed genes extracted through representational difference analysis (RDA). The subtraction of ubiquitous gene fragments from the two samples was demonstrated using cDNA microarrays including more than 32 000 spotted, PCR-amplified human clones. Hybridizations indicated the expression of 9100 of the microarray elements in a macrophage/foam cell atherosclerosis model system, of which many were removed during the RDA process. The stepwise subtraction procedure was demonstrated to yield an efficient enrichment of gene fragments overrepresented in either sample (18% in the representations, 86% after the first subtraction, and 88% after the second subtraction), many of which were impossible to detect in the starting material. Interestingly, the method allowed for the observation of the differential expression of several members of the low-abundant nuclear receptor gene family. We also observed a certain background level in the difference products of nondifferentially expressed gene fragments, warranting a verification strategy for selected candidate genes. The differential expression of several genes was verified by real-time PCR.


Factors affecting compliance to management of diabetes in Urban Health Center of a tertiary care teaching hospital of south India.
To Study the Factors affecting compliance to diabetes management and study risk factors and complications of type II diabetes. Primary health center, Descriptive study. A descriptive study of previously diagnosed diabetics (n = 135) attending the chronic disease clinic of Urban Health Center, Jawaharlal Institute of Postgraduate Medical Education and Research (JIUHC) was carried out during October 2011 to December 2011. Data were collected by personal interview on demographic parameters, duration of diabetes, number of doses missed in the last 15 days, co-morbidities, knowledge and practice of dietary modification, physical activity, self-care, family support, awareness about risk factors and complications of diabetes. The findings were expressed in terms of proportions. Chi-square test was used to study the association between socio-demographic factors and compliance. Majority of patients were in the age group of 50-59, of which 80% were females. Compliance (defined as not missing more than two doses in the last 15 days) to oral hypoglycemic agents was found in 103 (76%; 68.5-82.9). Dietary modifications was practiced by 110 (81.4%; 74.2-87.3) and 37% (29.2-45.4) practice physical activity. Annual eye check-up was carried out by 43.7%, renal function test by 46.6% and foot care by 54%. Knowledge regarding risk factors (66%; 42.7-59.4) and complications (79%; 71.8-85.4) was comparatively better than knowledge about self-care. Three-fourth of patients were compliant to medications and diet, but less than half follows modifications in physical activity and other self-care practices. Hence, it is essential to educate and motivate people in primary health-care level about self-care and life-style modifications.


Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment.
Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium requires further study. Altered tryptophan metabolism has been described in schizophrenia, possibly linked to inflammation and glutamate-directed excitotoxicity. Social isolation rearing (SIR) in rats induces various behavioural manifestations akin to schizophrenia, as well as altered frontal cortical glutamate N-methyl-d-aspartate (NMDA) receptor binding and increased oxidative stress, all reversed by antipsychotic treatment. Tryptophan is catabolized via the kynurenine pathway to kynurenine, 3-hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3-hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in post-natal SIR rats, and its response to clozapine treatment. Male Sprague-Dawley (SD) rats (10 rats/group) were exposed to SIR or social rearing for 8 weeks, whereupon they received either sub-chronic vehicle or clozapine (5 mg/kg i.p) treatment. Plasma tryptophan metabolites were analysed by liquid-chromatography electrospray ionization tandem mass spectrometry. Plasma tryptophan, kynurenine, anthranilic acid, 3-OHAA and QA were significantly elevated in SIR vs. socially housed rats. KYNA and the neuroprotective ratio were significantly decreased. The latter implies a decrease in KYNA (neuroprotective) but an increase in QA (neurodegenerative) directed components of the pathway. Clozapine significantly reversed all the above alterations in SIR animals. Concluding, SIR in rats significantly disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative changes in the brain. These changes are reversed by clozapine, emphasising the importance of these findings for the neurobiology and treatment of schizophrenia.


Can passive stretch inhibit motoneuron facilitation in the human plantar flexors?
The purpose of the present study was to examine the possible inhibitory effect of passive plantar flexor muscle stretching on the motoneuron facilitatory system. Achilles tendon vibration (70 Hz) and triceps surae electrical stimulation (20 Hz) were imposed simultaneously in 11 subjects to elicit contraction through reflexive pathways in two experiments. In experiment 1, a vibration-stimulation protocol was implemented with the ankle joint plantar flexed (+10°), neutral (0°), and dorsiflexed (-10°). In experiment 2, the vibration-stimulation protocol was performed twice before (control), then immediately, 5, 10, and 15 min after a 5-min intermittent muscle stretch protocol. Plantar flexor torque and medial and lateral gastrocnemius and soleus (EMGSol) EMG amplitudes measured during and after (i.e., self-sustained motor unit firing) the vibration protocol were used as an indicator of this facilitatory pathway. In experiment 1, vibration torque, self-sustained torque and EMGSol were higher with the ankle at -10° compared with 0° and +10°, suggesting that this method is valid to assess motoneuronal facilitation. In experiment 2, torque during vibration was reduced by ∼ 60% immediately after stretch and remained depressed by ∼ 35% at 5 min after stretch (P < 0.05). Self-sustained torque was also reduced by ∼ 65% immediately after stretch (P < 0.05) but recovered by 5 min. Similarly, medial gastrocnemius EMG during vibration was reduced by ∼ 40% immediately after stretch (P < 0.05), and EMGSol during the self-sustained torque period was reduced by 44% immediately after stretch (P < 0.05). In conclusion, passive stretch negatively affected the motoneuronal amplification for at least 5 min, suggesting that motoneuron disfacilitation is a possible mechanism influencing the stretch-induced torque loss.


Environmentally related diseases and the possibility of valuation of their social costs.
The risks of the morbidity of the asbestos-related lung cancer was estimated in the general population of Poles as the result of increased exposure to asbestos fibers during the removal of asbestos-cement products and the possibility of the valuation of the social costs related to this risk. The prediction of the new incidences was made using linear regression model. The forecast shows that to the end of 2030 about 3,500 new cases of lung cancer can be expected as a result of occupational exposure to asbestos in the past which makes together with paraoccupational exposure about 14.000 new cases. The forecast shows the increasing number of asbestos-related lung cancer in Poland and indicates the priority areas where preventive action should be implemented.


TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation.
The discovery of hydroxymethyl-, formyl- and carboxylcytosine, generated through oxidation of methylcytosine by TET dioxygenases, raised the question how these modifications contribute to epigenetic regulation. As they are subjected to complex regulation in vivo, we dissected links to gene expression with in vitro modified reporter constructs. We used an Oct4 promoter-driven reporter gene and demonstrated that in vitro methylation causes gene silencing while subsequent oxidation with purified catalytic domain of TET1 leads to gene reactivation. To identify proteins involved in this pathway we screened for TET interacting factors and identified TDG, PARP1, XRCC1 and LIG3 that are involved in base-excision repair. Knockout and rescue experiments demonstrated that gene reactivation depended on the glycosylase TDG, but not MBD4, while NEIL1, 2 and 3 could partially rescue the loss of TDG. These results clearly show that oxidation of methylcytosine by TET dioxygenases and subsequent removal by TDG or NEIL glycosylases and the BER pathway results in reactivation of epigenetically silenced genes.


Drug seeking becomes compulsive after prolonged cocaine self-administration.
Compulsive drug use in the face of adverse consequences is a hallmark feature of addiction, yet there is little preclinical evidence demonstrating the actual progression from casual to compulsive drug use. Presentation of an aversive conditioned stimulus suppressed drug seeking in rats with limited cocaine self-administration experience, but no longer did so after an extended cocaine-taking history. In contrast, after equivalent extended sucrose experience, sucrose seeking was still suppressed by an aversive conditioned stimulus. Persistent cocaine seeking in the presence of signals of environmental adversity after a prolonged cocaine-taking history was not due to impaired fear conditioning, nor to an increase in the incentive value of cocaine, and may reflect the establishment of compulsive behavior.


Measuring underreporting and under-ascertainment in infectious disease datasets: a comparison of methods.
Efficient and reliable surveillance and notification systems are vital for monitoring public health and disease outbreaks. However, most surveillance and notification systems are affected by a degree of underestimation (UE) and therefore uncertainty surrounds the 'true' incidence of disease affecting morbidity and mortality rates. Surveillance systems fail to capture cases at two distinct levels of the surveillance pyramid: from the community since not all cases seek healthcare (under-ascertainment), and at the healthcare-level, representing a failure to adequately report symptomatic cases that have sought medical advice (underreporting). There are several methods to estimate the extent of under-ascertainment and underreporting. Within the context of the ECDC-funded Burden of Communicable Diseases in Europe (BCoDE)-project, an extensive literature review was conducted to identify studies that estimate ascertainment or reporting rates for salmonellosis and campylobacteriosis in European Union Member States (MS) plus European Free Trade Area (EFTA) countries Iceland, Norway and Switzerland and four other OECD countries (USA, Canada, Australia and Japan). Multiplication factors (MFs), a measure of the magnitude of underestimation, were taken directly from the literature or derived (where the proportion of underestimated, under-ascertained, or underreported cases was known) and compared for the two pathogens. MFs varied between and within diseases and countries, representing a need to carefully select the most appropriate MFs and methods for calculating them. The most appropriate MFs are often disease-, country-, age-, and sex-specific. When routine data are used to make decisions on resource allocation or to estimate epidemiological parameters in populations, it becomes important to understand when, where and to what extent these data represent the true picture of disease, and in some instances (such as priority setting) it is necessary to adjust for underestimation. MFs can be used to adjust notification and surveillance data to provide more realistic estimates of incidence.


Genomic insights into the virulence and salt tolerance of Staphylococcus equorum.
To shed light on the genetic background behind the virulence and salt tolerance of Staphylococcus equorum, we performed comparative genome analysis of six S. equorum strains. Data on four previously published genome sequences were obtained from the NCBI database, while those on strain KM1031 displaying resistance to multiple antibiotics and strain C2014 causing haemolysis were determined in this study. Examination of the pan-genome of five of the six S. equorum strains showed that the conserved core genome retained the genes for general physiological processes and survival of the species. In this comparative genomic analysis, the factors that distinguish the strains from each other, including acquired genomic factors in mobile elements, were identified. Additionally, the high salt tolerance of strains enabling growth at a NaCl concentration of 25% (w/v) was attributed to the genes encoding potassium voltage-gated channels. Among the six strains, KS1039 does not possess any of the functional virulence determinants expressed in the other strains.


Digital interventions to promote self-management in adults with hypertension systematic review and meta-analysis.
To synthesize the evidence for using interactive digital interventions (IDIs) to support patient self-management of hypertension, and to determine their impact on control and reduction of blood pressure. Systematic review with meta-analysis was undertaken with a search performed in MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Library, DoPHER, TROPHI, Social Science Citation Index and Science Citation Index. The population was adults (>18 years) with hypertension, intervention was an IDI and the comparator was usual care. Primary outcomes were change in SBP and DBP. Only randomized controlled trials and studies published in journals and in English were eligible. Eligible IDIs included interventions accessed through a computer, smartphone or other hand-held device. Four out of seven studies showed a significantly greater reduction for intervention compared to usual care for SBP, with no difference found for three. Overall, IDIs significantly reduced SBP, with the weighted mean difference being -3.74 mmHg [95% confidence interval (CI) -2.19 to -2.58] with no heterogeneity observed (I-squared = 0.0%, P = 0.990). For DBP, four out of six studies indicated a greater reduction for intervention compared to controls, with no difference found for two. For DBP, a significant reduction of -2.37 mmHg (95% CI -0.40 to -4.35) was found, but considerable heterogeneity was noted (I-squared = 80.1%, P = <0.001). IDIs lower both SBP and DBP compared to usual care. Results suggest these findings can be applied to a wide range of healthcare systems and populations. However, sustainability and long-term clinical effectiveness of these interventions remain uncertain.


Thermoresponsive nanofabricated substratum for the engineering of three-dimensional tissues with layer-by-layer architectural control.
Current tissue engineering methods lack the ability to properly recreate scaffold-free, cell-dense tissues with physiological structures. Recent studies have shown that the use of nanoscale cues allows for precise control over large-area 2D tissue structures without restricting cell growth or cell density. In this study, we developed a simple and versatile platform combining a thermoresponsive nanofabricated substratum (TNFS) incorporating nanotopographical cues and the gel casting method for the fabrication of scaffold-free 3D tissues. Our TNFS allows for the structural control of aligned cell monolayers which can be spontaneously detached via a change in culture temperature. Utilizing our gel casting method, viable, aligned cell sheets can be transferred without loss of anisotropy or stacked with control over individual layer orientations. Transferred cell sheets and individual cell layers within multilayered tissues robustly retain structural anisotropy, allowing for the fabrication of scaffold-free, 3D tissues with hierarchical control of overall tissue structure.


Modulation of the ARF-p53 pathway by the small DNA tumor viruses.
The small DNA tumor viruses encode proteins that subvert many of the pivotal growth regulatory pathways within the cell to facilitate their own replication. The cell responds to viral infection/proteins by activating the p53 tumor suppressor pathway. Activation of p53 could impair a productive viral infection at many levels, including the inhibition of viral DNA replication and/or the premature death of infected cells. Therefore, DNA viruses encode proteins that inactivate the p53 tumor suppressor pathway. Understanding how DNA viral proteins activate/inactivate the p53 pathway has provided invaluable insights into tumorigenesis. Recent studies with polyoma virus have identified a viral protein (PyST) that inhibits ARF-mediated activation of p53, and revealed a novel role for PP2A in the regulation of the ARF-p53 tumor suppressor pathway.


Evidence of Muscovy duck parvovirus in Muscovy ducklings in California.
Muscovy duck parvovirus (MDPV) has been demonstrated in tissue samples from one- to four-week-old commercially reared Muscovy ducks that were weak, unable to walk and had a high mortality rate. On postmortem examination, the thigh and leg muscles, and the myocardium were found to be pale, and there was a fibrinous exudate on the capsule of the liver, and ascites. The parvovirus was isolated in embryonated Muscovy duck eggs and visualised by negative stain electron microscopy, detected by polymerase chain reaction (PCR) directly from the tissues, and antibodies to it were detected by immunoelectron microscopy, ELISA and immunofluorescence. In addition, the PCR products obtained that represented 1625 bp (74 per cent) of the capsid vP1 gene, including a hypervariable region between Derzsy's disease virus or goose parvovirus and MDPV, were sequenced and shown to be 100 per cent homologous with the MDPV 89384 reference strain, but only 82.3 per cent homologous with Derzsy's disease virus.


Asymmetric superoxide release inside and outside the mitochondria in skeletal muscle under conditions of aging and disuse.
Superoxide released from mitochondria forms reactive oxygen species that can cause severe oxidative damage and have been associated with aging- and disuse-induced muscle dysfunction. Superoxide is released to both the exterior and the matrix of mitochondria, where oxidative damage is not necessarily the same. This complicates determining the role of mitochondrial superoxide in eliciting oxidative stress in skeletal muscle. A newly developed capillary electrophoretic method analyzes hydroxytriphenylphosphonium ethidium, a superoxide-specific product of triphenylphosphonium hydroethidine, released to outside the mitochondria (supernatant) and retained in the matrix (pellet). In this study, we investigated the mitochondrial superoxide production of soleus (type I) and semimembranosus (type II) muscles of Fischer 344 rats affected by aging (13 vs. 26 mo) and disuse (hindlimb unloading). In agreement with previous studies, overall superoxide production increased with aging and disuse. On the other hand, the new experimental method revealed that superoxide production outside the mitochondria of the soleus does not show a significant age-related increase. Another observation was that the superoxide production increase in the matrix occurs earlier (7 days of disuse) compared with the outside mitochondria (14 days of disuse) in both muscle types. These findings indicate that superoxide release is complex as it occurs asymmetrically at both sides of the mitochondrial inner membrane, and that such release has muscle type and temporal specificity. These findings are important to refine current concepts on oxidative stress associated with muscle aging and disuse.


Medical Leadership: A Manifesto for Radiologists.
Leadership is much discussed but also often misunderstood. For radiologists, leadership may seem irrelevant or, even worse, an onerous addition to their busy careers. It is important that radiologists understand the relevance and importance of good leadership for the success of departments and groups. There are many obstacles to radiologists becoming effective leaders, including personal resistance that is due to myths and misunderstandings, the time and effort (and money) required to learn to lead well, as well as others including the shift in perspective that comes from focusing on organizational success rather than individual career success. This manifesto will explore the what, the why, and the how of becoming a leader in radiology and why it is critical for individuals, their organizations, academic departments, private practice groups, and others, as well as the larger house of radiology.


Psychiatric symptoms correlate with metabolic indices in the hippocampus and cingulate in patients with mitochondrial disorders.
There is increasing recognition that mitochondrial dysfunction may have a critical role in the pathophysiology of major psychiatric illnesses. Patients with mitochondrial disorders offer a unique window through which we can begin to understand the association between psychiatric symptoms and mitochondrial dysfunction in vivo. Using proton magnetic resonance spectroscopy ((1)H-MRS), we investigated metabolic indices in mitochondrial patients in regions of the brain that have been implicated in psychiatric illness: the caudate, cingulate cortex and hippocampus. In all, 15 patients with mitochondrial disorders and 15 age- and sex-matched controls underwent a comprehensive psychiatric assessment, including the administration of standardized psychiatric rating scales, followed by single voxel (1)H-MRS of the caudate, cingulate cortex and hippocampus to measure N-acetyl aspartate (NAA), creatine (Cr), glycerophosphocholine (GPC), myoinositol and glutamate+glutamine (Glx). Pearson's correlation coefficients were used to determine correlations between metabolites and the psychiatric rating scales. Anxiety symptoms in these patients correlated with higher GPC, Glx, myoinositol and Cr in the hippocampus. Impaired level of function as a result of psychiatric symptoms correlated with higher Glx and GPC in the cingulate cortex. In summary, we found remarkably consistent, and statistically significant, correlations between anxiety and metabolic indices in the hippocampus in patients with mitochondrial disorders, while overall impairment of functioning due to psychiatric symptoms correlated with metabolic markers in the cingulate cortex. These findings lend support to the notion that mitochondrial dysfunction in specific brain regions can give rise to psychiatric symptoms. In particular, they suggest that metabolic processes in the hippocampus may have an important role in the neurobiology of anxiety.


Single-molecule magnet engineering: building-block approaches.
Tailoring the specific magnetic properties of any material relies on the topological control of the constituent metal ion building blocks. Although this general approach does not seem to be easily applied to traditional inorganic bulk magnets, coordination chemistry offers a unique tool to delicately tune, for instance, the properties of molecules that behave as "magnets", the so-called single-molecule magnets (SMMs). Although many interesting SMMs have been prepared by a more or less serendipitous approach, the assembly of predesigned, isolatable molecular entities into higher nuclearity complexes constitutes an elegant and fascinating strategy. This Feature article focuses on the use of building blocks or modules (both terms being used indiscriminately) to direct the structure, and therefore also the magnetic properties, of metal ion complexes exhibiting SMM behaviour.


E center in silicon has a donor level in the band gap.
It has been an accepted fact for more than 40 years that the E center in Si (the group-V impurity--vacancy pair)--one of the most studied defects in semiconductors--has only one energy level in the band gap: namely, the acceptor level at about 0.45 eV below the conduction band. We now demonstrate that it has a second level, situated in the lower half of the band gap at 0.27 eV above the valence band. The existence of this level, having a donor character, is disclosed by a combination of different transient-capacitance techniques and electronic-structure calculations. The finding seriously questions some diffusion-modeling approaches performed in the past.


HPV-associated lung cancers: an international pooled analysis.
Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12-0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.