Astrocyte-derived vascular endothelial growth factor stabilizes vessels in the developing retinal vasculature.
Vascular endothelial growth factor (VEGF) plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans.


Chemoprevention of hereditary colon cancers: time for new strategies.
Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.


Osteoclast fusion and regulation by RANKL-dependent and independent factors.
Osteoclasts are the bone resorbing cells essential for bone remodeling. Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage. Osteoclastogenesis is composed of several steps including progenitor survival, differentiation to mono-nuclear pre-osteoclasts, fusion to multi-nuclear mature osteoclasts, and activation to bone resorbing osteoclasts. The regulation of osteoclastogenesis has been extensively studied, in which the receptor activator of NF-κB ligand (RANKL)-mediated signaling pathway and downstream transcription factors play essential roles. However, less is known about osteoclast fusion, which is a property of mature osteoclasts and is required for osteoclasts to resorb bone. Several proteins that affect cell fusion have been identified. Among them, dendritic cell-specific transmembrane protein (DC-STAMP) is directly associated to osteoclast fusion in vivo. Cytokines and factors influence osteoclast fusion through regulation of DC-STAMP. Here we review the recently discovered new factors that regulate osteoclast fusion with specific focus on DC-STAMP. A better understanding of the mechanistic basis of osteoclast fusion will lead to the development of a new therapeutic strategy for bone disorders due to elevated osteoclast bone resorption. Cell-cell fusion is essential for a variety of cellular biological processes. In mammals, there is a limited number of cell types that fuse to form multinucleated cells, such as the fusion of myoblasts for the formation of skeletal muscle and the fusion of cells of the monocyte/macrophage lineage for the formation of multinucleated osteoclasts and giant cells. In most cases, cell-cell fusion is beneficial for cells by enhancing function. Myoblast fusion increases myofiber size and diameter and thereby increases contractile strength. Multinucleated osteoclasts have far more bone resorbing activity than their mono-nuclear counterparts. Multinucleated giant cells are much more efficient in the removal of implanted materials and bacteria due to chronic infection than macrophages. Therefore, they are also called foreign-body giant cells. Cell fusion is a complicated process involving cell migration, chemotaxis, cell-cell recognition and attachment, as well as changes into a fusion-competent status. All of these steps are regulated by multiple factors. In this review, we will discuss osteoclast fusion and regulation.


Oral fibrinogen-depleting agent lumbrokinase for secondary ischemic stroke prevention: results from a multicenter, randomized, parallel-group and controlled clinical trial.
Elevated fibrinogen (Fg) level is a known risk factor for ischemic stroke. There are few clinical trials on oral fibrinogen-depleting therapies for secondary ischemic stroke prevention. We aimed to assess the effects of one-year therapy with oral lumbrokinase enteric-coated capsules on secondary ischemic stroke prevention. This is a multicenter, randomized, parallel group and controlled study that began treatment in hospitalized patients with ischemic stroke and continued for 12 months. Patients were randomized to either the control group that received the standard stroke treatment or the fibrinogen-depleting group that received the standard stroke treatment plus enteric-coated lumbrokinase capsules. The NIH Stroke Scale scores (NIHSSs) and plasma Fg level were recorded. The carotid artery intima-media thickness (IMT) and status of plaques were examined through carotid ultrasound examination. Primary outcomes included all-cause mortality, any event of recurrent ischemic stroke/transient ischemic attack (TIA), hemorrhagic stroke, myocardial infarction and angina, and other noncerebral ischemia or hemorrhage. Kaplan-Meier survival analysis and the Long-rank test were used to compare total vascular end point incidence between the two groups. Comparison of median values between two groups was done by the Student t test, one-way analysis of variance (ANOVA), or non-parametric rank sum test. A total of 310 patients were enrolled, 192 patients in the treatment group and 118 patients in the control group. Compared to the control group, the treatment group showed favorable outcomes in the Fg level, carotid IMT, the detection rate of vulnerable plaques, the volume of carotid plaques, NIHSS scores, and incidence of total vascular (6.78% and 2.08%, respectively) and cerebral vascular events (5.93% and 1.04%, respectively) (P < 0.05). In the treatment group, the volume of carotid plaques was significantly related to the carotid IMT, the plaque diameter, width and number (P = 0.000, 0.000, 0.000, 0.022; F = 13.51, 2.52, 11.33, -3.29, but there was a weak correlation with the Fg level (P = 0.056). After 1-year therapy, the incidence of overall vascular end points was reduced by 4.7%. Long-term oral fibrinogen-depleting therapy may be beneficial for secondary ischemic stroke prevention.


Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors.
Lamin A and the B-type lamins, lamin B1 and lamin B2, are translated as pre-proteins that are modified at a carboxyl terminal CAAX motif by farnesylation, proteolysis and carboxymethylation. Lamin A is further processed by proteolysis to remove the farnesyl, but B-type lamins remain permanently farnesylated. Two childhood diseases, Hutchinson Gilford Progeria Syndrome and restrictive dermopathy are caused by defects in the processing of lamin A, resulting in permanent farnesylation of the protein. Farnesyltransferase inhibitors, originally developed to target oncogenic Ras, have recently been used in clinical trials to treat children with Hutchinson Gilford Progeria Syndrome. Lamin B1 and lamin B2 play important roles in cell proliferation and organ development, but little is known about the role of farnesylation in their functions. Treating normal human fibroblasts with farnesyltransferase inhibitors causes the accumulation of unprocessed lamin B2 and lamin A and a decrease in mature lamin B1. Normally, lamins are concentrated at the nuclear envelope/lamina, but when farnesylation is inhibited, the peripheral localization of lamin B2 decreases as its nucleoplasmic levels increase. Unprocessed prelamin A distributes into both the nuclear envelope/lamina and nucleoplasm. Farnesyltransferase inhibitors also cause a rapid cell cycle arrest leading to cellular senescence. This study suggests that the long-term inhibition of protein farnesylation could have unforeseen consequences on nuclear functions.


Cav1.4 encodes a calcium channel with low open probability and unitary conductance.
When transiently expressed in tsA-201 cells, Ca(v)1.4 calcium channels support only modest whole-cell currents with unusually slow voltage-dependent inactivation kinetics. To examine the basis for this unique behavior we used cell-attached patch single-channel recordings using 100 mM external barium as the charge carrier to determine the single-channel properties of Ca(v)1.4 and to compare them to those of the Ca(v)1.2. Ca(v)1.4 channel openings occurred infrequently and were of brief duration. Moreover, openings occurred throughout the duration of the test depolarization, indicating that the slow inactivation kinetics observed at the whole-cell level are caused by sustained channel activity. Ca(v)1.4 and Ca(v)1.2 channels displayed similar latencies to first opening. Because of the rare occurrence of events, the probability of opening could not be precisely determined but was estimated to be <0.015 over a voltage range of -20 to +20 mV. The single-channel conductance of Ca(v)1.4 channels was approximately 4 pS compared with approximately 20 pS for Ca(v)1.2 under the same experimental conditions. Additionally, in the absence of divalent cations, Ca(v)1.4 channels pass cesium ions with a single-channel conductance of approximately 21 pS. Although Ca(v)1.2 opening events were best described kinetically with two open time constants, Ca(v)1.4 open times were best described by a single time constant. BayK8644 slightly enhanced the single-channel conductance in addition to increasing the open time constant for Ca(v)1.4 channels by approximately 45% without, however, causing the appearance of an additional slower gating mode. Overall, our data indicate that single Ca(v)1.4 channels support only minute amounts of calcium entry, suggesting that large numbers of these channels are needed to allow for significant whole-cell current activity, and providing a mechanism to reduce noise in the visual system.


Autistic traits modulate mimicry of social but not nonsocial rewards.
Autism Spectrum Conditions (ASC) are associated with diminished responsiveness to social stimuli, and especially to social rewards such as smiles. Atypical responsiveness to social rewards, which reinforce socially appropriate behavior in children, can potentially lead to a cascade of deficits in social behavior. Individuals with ASC often show diminished spontaneous mimicry of social stimuli in a natural setting. In the general population, mimicry is modulated both by the reward value and the sociality of the stimulus (i.e., whether the stimulus is perceived to belong to a conspecific or an inanimate object). Since empathy and autistic traits are distributed continuously in the general population, this study aimed to test if and how these traits modulated automatic mimicry of rewarded social and nonsocial stimuli. High and low rewards were associated with human and robot hands using a conditioned learning paradigm. Thirty-six participants from the general population then completed a mimicry task involving performing a prespecified hand movement which was either compatible or incompatible with a hand movement presented to the participant. High autistic traits (measured using the Autism Spectrum Quotient, AQ) predicted lesser mimicry of high-reward than low-reward conditioned human hands, whereas trait empathy showed an opposite pattern of correlations. No such relations were observed for high-reward vs. low-reward conditioned robot hands. These results demonstrate how autistic traits and empathy modulate the effects of reward on mimicry of social compared to nonsocial stimuli. This evidence suggests a potential role for the reward system in underlying the atypical social behavior in individuals with ASC, who constitute the extreme end of the spectrum of autistic traits.


The natural history of insomnia: focus on prevalence and incidence of acute insomnia.
Despite Acute Insomnia being classified as a distinct nosological entity since 1979/1980 (ASDC/DSM III-R), there are no published estimates of its prevalence and incidence or data regarding transition to chronic insomnia or remission. This lack of data prevents an understanding of: a) the pathogenesis of insomnia and b) when and how treatment should be initiated. The aim of the present study was to provide such data from two community samples. Samples were recruited in the USA (n = 2861) and the North East of the UK (n = 1095). Additionally, 412 Normal Sleepers from the UK sample were surveyed longitudinally to determine prospectively incidence, transition, and remission rates for acute insomnia and assess whether the acute insomnia was a first episode, recurrent episode, or co-morbid with symptoms of other illnesses. The prevalence of acute insomnia was 9.5% (USA) and 7.9%(UK). The prevalence of three acute insomnia subtypes in the UK were; First-Onset Acute Insomnia 2.6%; Recurrent Acute Insomnia 3.8%; and 1.4% Co-morbid Acute Insomnia. The annual incidence of acute insomnia in the UK sample was between 31.2% and 36.6%. Remission rates fluctuated depending upon the definition of acute insomnia and whether the current episode was first-onset or recurrent. These findings provide preliminary insights into the natural history of insomnia. Such data will serve to inform how and when acute insomnia should be managed and whether such interventions may serve to diminish subsequent morbidity, particularly with respect to Major Depression.


Noise exposure and public health.
Exposure to noise constitutes a health risk. There is sufficient scientific evidence that noise exposure can induce hearing impairment, hypertension and ischemic heart disease, annoyance, sleep disturbance, and decreased school performance. For other effects such as changes in the immune system and birth defects, the evidence is limited. Most public health impacts of noise were already identified in the 1960s and noise abatement is less of a scientific but primarily a policy problem. A subject for further research is the elucidation of the mechanisms underlying noise-induced cardiovascular disorders and the relationship of noise with annoyance and nonacoustical factors modifying health outcomes. A high priority study subject is the effects of noise on children, including cognitive effects and their reversibility. Noise exposure is on the increase, especially in the general living environment, both in industrialized nations and in developing world regions. This implies that in the twenty-first century noise exposure will still be a major public health problem.


A lion lentivirus related to feline immunodeficiency virus: epidemiologic and phylogenetic aspects.
Feline immunodeficiency virus (FIV) is a novel lentivirus that is genetically homologous and functionally analogous to the human AIDS viruses, human immunodeficiency virus types 1 and 2. FIV causes immunosuppression in domestic cats by destroying the CD4 T-lymphocyte subsets in infected hosts. A serological survey of over 400 free-ranging African and Asian lions (Panthera leo) for antibodies to FIV revealed endemic lentivirus prevalence with an incidence of seropositivity as high as 90%. A lion lentivirus (FIV-Ple) was isolated by infection of lion lymphocytes in vitro. Seroconversion was documented in two Serengeti lions, and discordance of mother-cub serological status argues against maternal transmission (in favor of horizontal spread) as a major route of infection among lions. A phylogenetic analysis of cloned FIV-Ple pol gene sequences from 27 lions from four African populations (from the Serengeti reserve, Ngorongoro Crater, Lake Manyara, and Kruger Park) revealed remarkably high intra- and interindividual genetic diversity at the sequence level. Three FIV-Ple phylogenetic clusters or clades were resolved with phenetic, parsimony, and likelihood analytical procedures. The three clades, which occurred not only together in the same population but throughout Africa, were as divergent from each other as were homologous pol sequences of lentivirus isolated from distinct feline species, i.e., puma and domestic cat. The FIV-Ple clades, however, were more closely related to each other than to other feline lentiviruses (monophyletic for lion species), suggesting that the ancestors of FIV-Ple evolved in allopatric (geographically isolated) lion populations that converged recently. To date, there is no clear evidence of FIV-Ple-associated pathology, raising the possibility of a historic genetic accommodation of the lion lentivirus and its host leading to a coevolved host-parasite symbiosis (or commensalism) in the population similar to that hypothesized for endemic simian immunodeficiency virus without pathology in free-ranging African monkey species.


Association between the miRNA signatures in plasma and bronchoalveolar fluid in respiratory pathologies.
The identification of new less invasive biomarkers is necessary to improve the detection and prognostic outcome of respiratory pathological processes. The measurement of miRNA expression through less invasive techniques such as plasma and serum have been suggested to analysis of several lung malignancies including lung cancer. These studies are assuming a common deregulated miRNA expression both in blood and lung tissue. The present study aimed to obtain miRNA representative signatures both in plasma and bronchoalveolar cell fraction that could serve as biomarker in respiratory diseases. Ten patients were evaluated to assess the expression levels of 381 miRNAs. We found that around 50% miRNAs were no detected in both plasma and bronchoalveolar cell fraction and only 20% of miRNAs showed similar expression in both samples. These results show a lack of association of miRNA signatures between plasma and bronchoalveolar cytology in the same patient. The profiles are not comparable; however, there is a similarity in the relative expression in a very small subset of miRNAs (miR-17, miR-19b, miR-195 and miR-20b) between both biological samples in all patients. This finding supports that the miRNAs profiles obtained from different biological samples have to be carefully validated to link with respiratory diseases.


Vitamin D status of psychiatric inpatients at a community teaching hospital in the Midwest.
Vitamin D deficiency is a re-emerging epidemic in North America. It is increasingly linked to the pathology of cognition and mental illness and is also common in psychiatric patients. This study was designed to determine the prevalence of vitamin D deficiency among psychiatric inpatients in Kansas City, to explore the association between vitamin D status and clinical characteristics, and to identify the association of medical problems related to vitamin D deficiency in mental illness. In this descriptive study we recruited 52 psychiatric inpatients at a community teaching hospital in Kansas City between August and November 2013. A vitamin D-deficient state was defined as serum 25-hydroxyvitamin D (25-(OH) D) level ≤ 20 ng/mL. In addition to descriptive statistics, the Student t-test and Pearson test were used in the study. A total of 15 patients (28.8%) were classified as deficient, 20 patients (38.5%) had an insufficiency, 17 patients (32.7%) were categorized as sufficient. Interestingly, there was a statistically significant difference in 25-(OH) D levels between African Americans and Caucasians (t = -2.216, p = 0.03) but no significant relationship between 25-(OH) D level and gender, major psychiatric diagnoses, type 2 diabetes mellitus or obesity. There was also no correlation between 25-(OH) D level and age, body mass index or haemoglobin A1C. Low 25-(OH) D level was found in a high percentage of psychiatric inpatients in Kansas City. Screening for vitamin D deficiency could be a routine work-up for psychiatric inpatients. Vitamin D supplement for African American inpatients with low vitamin D levels could be considered.


Genomic epidemiology of severe community-onset Acinetobacter baumannii infection.
Acinetobacter baumannii causes severe, fulminant, community-acquired pneumonia (CAP) in tropical and subtropical regions. We compared the population structure, virulence and antimicrobial resistance determinants of northern Australian community-onset A. baumannii strains with local and global strains. We performed whole-genome sequencing on 55 clinical and five throat colonization A. baumannii isolates collected in northern Australia between 1994 and 2016. Clinical isolates included CAP (n=41), healthcare-associated pneumonia (n=7) and nosocomial bloodstream (n=7) isolates. We also included 93 publicly available international A. baumannii genome sequences in the analyses. Patients with A. baumannii CAP were almost all critically unwell; 82 % required intensive care unit admission and 18 % died during their inpatient stay. Whole-genome phylogenetic analysis demonstrated that community-onset strains were not phylogenetically distinct from nosocomial strains. Some non-multidrug-resistant local strains were closely related to multidrug-resistant strains from geographically distant locations. Pasteur sequence type (ST)10 was the dominant ST and accounted for 31/60 (52 %) northern Australian strains; the remainder belonged to a diverse range of STs. The most recent common ancestor for ST10 was estimated to have occurred in 1738 (95 % highest posterior density, 1626-1826), with evidence of multiple introduction events between Australia and Southeast Asia between then and the present day. Virulence genes associated with biofilm formation and the type 6 secretion system (T6SS) were absent in many strains, and were not associated with in-hospital mortality. All strains were susceptible to gentamicin and meropenem; none carried an AbaR resistance island. Our results suggest that international dissemination of A. baumannii is occurring in the community on a contemporary timescale. Genes associated with biofilm formation and the T6SS may not be required for survival in community niches. The relative contributions of host and bacterial factors to the clinical severity of community-onset A. baumannii infection require further investigation.


Urinary Metabolites Enable Differential Diagnosis and Therapeutic Monitoring of Pediatric Inflammatory Bowel Disease.
Rates of pediatric Crohn's disease (CD) and ulcerative colitis (UC) are increasing globally. Differentiation of these inflammatory bowel disease (IBD) subtypes however can be challenging when relying on invasive endoscopic approaches. We sought to identify urinary metabolic signatures of pediatric IBD at diagnosis, and during induction treatment. Nontargeted metabolite profiling of urine samples from CD (n = 18) and UC (n = 8) in a pediatric retrospective cohort study was performed using multisegment injection-capillary electrophoresis-mass spectrometry. Over 122 urinary metabolites were reliably measured from pediatric IBD patients, and unknown metabolites were identified by tandem mass spectrometry. Dynamic changes in sum-normalized urinary metabolites were also monitored following exclusive enteral nutrition (EEN) or corticosteroid therapy (CS) in repeat urine samples collected over 8 weeks. Higher urinary excretion of indoxyl sulfate, hydroxyindoxyl sulfate, phenylacetylglutamine, and sialic acid were measured in CD as compared to UC patients, but lower threonine, serine, kynurenine, and hypoxanthine (p < 0.05). Excellent discrimination of CD from UC was achieved based on the urinary serine:indoxylsulfate ratio (AUC = 0.972; p = 3.21 × 10-5). Urinary octanoyl glucuronide, pantothenic acid, and pyridoxic acid were also identified as specific dietary biomarkers of EEN in pediatric IBD patients who achieved clinical remission. This work may complement or replace existing strategies in the diagnosis and early management of children with IBD.


Development of a model of situational leadership in residential care for older people.
The aim of the present study was to present the process used to develop a composite model of situational leadership enacted within a person-centred nursing framework in residential care. Transforming the culture of the residential unit from a restrictive institution to a vibrant community of older adults requires transformational leadership. Situational leadership is one form of transformational leadership, which claims that there is not one leadership style that works in all situations. A model of situational leadership in residential care was developed through a series of systematic steps that identified direct linkages between situational leadership and the main constructs of the Person-Centred Nursing Framework. The process included reviewing the evidence, undertaking a comparative analysis, identifying key concepts, connecting the concepts and developing a model. A conceptual model is presented which integrates person-centredness with leadership thinking in order to effectively impact on the follower's performance in managing the care environment and delivering person-centred care. Currently the model is being utilized in an action research study to evaluate the role of leaders in the practice setting of long-term care. While some of the connecting concepts have been identified in the present study, more work needs to be done to unravel these connections in further study of leaders in practice.


Early-Life Adversity and Physical and Emotional Health Across the Lifespan: A Neuroimmune Network Hypothesis.
Children who experience chronic stressors are vulnerable to emotional and physical health problems across the lifespan. This phenomenon raises questions for scientists and clinicians alike. How does adversity get under the skin of the developing child? Through what mechanisms does it confer vulnerability to a heterogeneous set of mental and physical illnesses? And how does it instantiate risk across different life stages, engendering vulnerability to conditions that develop shortly after stressor exposure-like depression-and conditions that manifest decades later, like heart disease? Although answers to these questions have started to emerge, research has typically focused on single diseases or organ systems. To understand the plethora of health problems associated with childhood adversity, we argue that the field needs a second generation of research that recognizes multidirectional transactions among biological systems. To help facilitate this process, we propose a neuroimmune network hypothesis as a heuristic framework for organizing knowledge from disparate literatures and as a springboard for generating integrative research. Drawing on existing data, we argue that early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems.


Comparative analysis of the vaginal microbiome of pregnant women with either Trichomonas vaginalis or Chlamydia trachomatis.
Although the significance of the human vaginal microbiome for health and disease is increasingly acknowledged, there is paucity of data on the differences in the composition of the vaginal microbiome upon infection with different sexually transmitted pathogens. The composition of the vaginal bacterial community of women with Trichomonas vaginalis (TV, N = 18) was compared to that of women with Chlamydia trachomatis (CT, N = 14), and to that of controls (N = 21) (women negative for TV, CT and bacterial vaginosis). The vaginal bacterial composition was determined using high throughput sequencing with the Ion 16S metagenomics kit of the variable regions 2, 4 and 8 of the bacterial 16S ribosomal RNA gene from the vaginal swab DNA extract of the women. QIIME and R package "Phyloseq" were used to assess the α- and β-diversity and absolute abundance of the 16S rRNA gene per sample in the three groups. Differences in taxa at various levels were determined using the independent T-test. A total of 545 operational taxonomic units (OTUs) were identified in all the three groups of which 488 occurred in all three groups (core OTUs). Bacterial α-diversity, by both Simpson's and Shannon's indices, was significantly higher, (p = 0.056) and (p = 0.001) respectively, among women with either TV or CT than among controls (mean α-diversity TV-infected > CT-infected > Controls). At the genus level, women infected with TV had a significantly (p < 0.01) higher abundance of Parvimonas and Prevotella species compared to both controls and CT-infected women, whereas women infected with CT had a significantly (p < 0.05) higher abundance of Anaerococcus, Collinsella, Corynebacterium and Dialister. The vaginal microbiomes of TV and CT-infected women were markedly different from each other and from women without TV and CT. Future studies should determine whether the altered microbiomes are merely markers of disease, or whether they actively contribute to the pathology of the two genital infections.


Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study.
Subcutaneous malignant tumors are often treated by non-specialized clinicians in musculoskeletal oncology. While the resection of subcutaneous tumors appears technically feasible, unplanned resection of malignant tumors can result in a devastating clinical outcome. The aim of this study was to evaluate the potential estrangement in the awareness of and the treatment strategy for the patients with subcutaneous soft tissue tumors between musculoskeletal oncologists and non-specialized clinicians. A questionnaire probing the clinical assessment of subcutaneous tumors was sent to orthopedic surgeons, dermatologists, plastic surgeons, and general surgeons. Results of the questionnaire were statistically analyzed. One hundred sixteen clinicians out of 150 responded to the questionnaire; the response rate was 77.3%. Among those, 46 clinicians had treated subcutaneous tumors. Thirty-nine of these 46 clinicians (27 musculoskeletal oncologists and 12 non-specialized clinicians) preoperatively performed enhanced MRI for diagnostic evaluation. Preoperative incisional biopsy to confirm the pathological diagnosis was performed by 36 of the 46 clinicians (29 musculoskeletal oncologists and seven non-specialized clinicians). These results indicate that musculoskeletal oncologists perform preoperative enhanced MRI (P = 0.08) and biopsy (P < 0.01) more frequently than non-specialized clinicians. The recognition rate of 'myxofibrosarcoma' was 60.8% among clinicians with an experience with sarcoma treatment (25 musculoskeletal oncologists and three non-specialized clinicians). The recognition rate of 'myxofibrosarcoma' between musculoskeletal oncologists and non-specialized clinicians was statistically significant (P < 0.01). Preoperative evaluations for subcutaneous tumors are more often inappropriate in non-specialized clinicians than those who are. Therefore, it will be mandatory to raise the awareness of this condition to improve the clinical outcome of patients with subcutaneous tumors.


Oesophageal squamous cell carcinoma (ESCC): Advances through omics technologies, towards ESCC salivaomics.
Oesophageal Squamous Cell Carcinoma (ESCC) is one of the two main subtypes of oesophageal cancer, affecting mainly populations in Asia. Though there have been great efforts to develop methods for a better prognosis, there is still a limitation in the staging of this affection. As a result, ESCC is detected at advances stages, when the interventions on the patient do not have such a positive outcome, leading in many cases to recurrence and to a very low 5-year survival rate, causing high mortality. A way to decrease the number of deaths is the use of biomarkers that can trace the advance of the disease at early stages, when surgical or chemotherapeutic methodologies would have a greater effect on the evolution of the subject. The new high throughput omics technologies offer an unprecedented chance to screen for thousands of molecules at the same time, from which a new set of biomarkers could be developed. One of the most convenient types of samples is saliva, an accessible body fluid that has the advantage of being non-invasive for the patient, being easy to store or to process. This review will focus on the current status of the new omics technologies regarding salivaomics in ESCC, or when not evaluated yet, the achievements in related diseases.


Divergent double chirp pulses for refocusing quadrupolar interactions.
To excite and refocus single quantum coherences in a three-level system with a quadrupolar interaction, it is possible to use frequency-modulated pulses with two diverging frequency components that are swept simultaneously through the two single-quantum transitions. This is achieved by time-dependent amplitude-modulation of the carrier frequency, so as to generate two sidebands with frequencies that are diverging (or converging) symmetrically with respect to the carrier frequency. Simulations and experiments show that such modulated pulses can be used to refocus single quantum coherences to form quadrupole echoes, using much weaker RF amplitudes than in conventional echo sequences. To visualize the evolution of the coherences in a three-level system, a graphical representation of the density operator components is proposed.


Pleasure and orgasm in women with Female Genital Mutilation/Cutting (FGM/C).
Female genital mutilation/cutting (FGM/C) violates human rights. FGM/C women's sexuality is not well known and often it is neglected by gynecologists, urologists, and sexologists. In mutilated/cut women, some fundamental structures for orgasm have not been excised. The aim of this report is to describe and analyze the results of four investigations on sexual functioning in different groups of cut women. semistructured interviews and the Female Sexual Function Index (FSFI). 137 adult women affected by different types of FGM/C; 58 young FGM/C ladies living in the West; 57 infibulated women; 15 infibulated women after the operation of defibulation. The group of 137 women, affected by different types of FGM/C, reported orgasm in almost 86%, always 69.23%; 58 mutilated young women reported orgasm in 91.43%, always 8.57%; after defibulation 14 out of 15 infibulated women reported orgasm; the group of 57 infibulated women investigated with the FSFI questionnaire showed significant differences between group of study and an equivalent group of control in desire, arousal, orgasm, and satisfaction with mean scores higher in the group of mutilated women. No significant differences were observed between the two groups in lubrication and pain. Embryology, anatomy, and physiology of female erectile organs are neglected in specialist textbooks. In infibulated women, some erectile structures fundamental for orgasm have not been excised. Cultural influence can change the perception of pleasure, as well as social acceptance. Every woman has the right to have sexual health and to feel sexual pleasure for full psychophysical well-being of the person. In accordance with other research, the present study reports that FGM/C women can also have the possibility of reaching an orgasm. Therefore, FGM/C women with sexual dysfunctions can and must be cured; they have the right to have an appropriate sexual therapy.


A low-effort, clinic-wide intervention improves attendance for HIV primary care.
Retention in care for human immunodeficiency virus (HIV)-infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10,018 patients in 2008-2009 (preintervention period) and 11,039 patients in 2009-2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept (P < .0001). Larger relative improvement for both outcomes was observed for new or reengaging patients, young patients and patients with elevated viral loads. Improved attendance among the new or reengaging patients was consistent across the 6 clinics, and less consistent across clinics for active patients. Targeted messages on staying in care, which were delivered at minimal effort and cost, improved clinic attendance, especially for new or reengaging patients, young patients, and those with elevated viral loads.


The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1.
Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.


Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: A novel approach to study metabolism in human neurons.
Alterations in the cellular metabolic machinery of the brain are associated with neurodegenerative disorders such as Alzheimer's disease. Novel human cellular disease models are essential in order to study underlying disease mechanisms. In the present study, we characterized major metabolic pathways in neurons derived from human induced pluripotent stem cells (hiPSC). With this aim, cultures of hiPSC-derived neurons were incubated with [U-13C]glucose, [U-13C]glutamate or [U-13C]glutamine. Isotopic labeling in metabolites was determined using gas chromatography coupled to mass spectrometry, and cellular amino acid content was quantified by high-performance liquid chromatography. Additionally, we evaluated mitochondrial function using real-time assessment of oxygen consumption via the Seahorse XFe96 Analyzer. Moreover, in order to validate the hiPSC-derived neurons as a model system, a metabolic profiling was performed in parallel in primary neuronal cultures of mouse cerebral cortex and cerebellum. These serve as well-established models of GABAergic and glutamatergic neurons, respectively. The hiPSC-derived neurons were previously characterized as being forebrain-specific cortical glutamatergic neurons. However, a comparable preparation of predominantly mouse cortical glutamatergic neurons is not available. We found a higher glycolytic capacity in hiPSC-derived neurons compared to mouse neurons and a substantial oxidative metabolism through the mitochondrial tricarboxylic acid (TCA) cycle. This finding is supported by the extracellular acidification and oxygen consumption rates measured in the cultured human neurons. [U-13C]Glutamate and [U-13C]glutamine were found to be efficient energy substrates for the neuronal cultures originating from both mice and humans. Interestingly, isotopic labeling in metabolites from [U-13C]glutamate was higher than that from [U-13C]glutamine. Although the metabolic profile of hiPSC-derived neurons in vitro was particularly similar to the profile of mouse cortical neurons, important differences between the metabolic profile of human and mouse neurons were observed. The results of the present investigation establish hallmarks of cellular metabolism in human neurons derived from iPSC.


Detection and identification of fungal pathogens in blood by using molecular probes.
A PCR assay was developed for the detection and identification of Candida and Aspergillus species. The design of the oligonucleotide primer pair as well as the species-specific probes used for species identification was derived from a comparison of the sequences of the 18S rRNA genes of various fungal pathogens. The primers targeted a consensus sequence for a variety of fungal pathogens. The assay was tested for sensitivity and specificity with 134 fungal and 85 nonfungal isolates. To assess clinical applicability, 601 blood samples from four defined groups were tested: group A (n = 35), controls; groups B to D (n = 86), patients with febrile neutropenia, without fungal colonization (group B; n = 29) and with fungal colonization (group C; n = 36); and patients with documented invasive fungal infection (IFI) (group D; n = 21). The assay detected and, by species-specific hybridization, identified most of the clinically relevant Candida and Aspergillus species at 1 CFU/ml of blood. Amplification was 100% sensitive for all molds and yeasts tested, with Histoplasma capsulatum being the only non-Aspergillus species hybridizing with the Aspergillus spp. probe. None of 35 group A patients and only 3 of 65 group B and C patients were PCR positive. The sensitivity of the assay for specimens from patients with IFI (21 patients in group D) was 100% if two specimens were tested. For specificity, 3 of 189 specimens from patients at risk but with negative cultures were positive by the assay, for a specificity of 98%. PCR preceded radiological signs by a median of 4 days (range, 4 to 7 days) for 12 of 17 patients with hepatosplenic candidiasis or pulmonary aspergillosis. For the 10 patients with IFI responding to antifungal therapy, PCR assays became persistently negative after 14 days of treatment, in contrast to the case for 11 patients, who remained PCR positive while not responding to antifungal therapy. Thus, the described PCR assay allows for the highly sensitive and specific detection and identification of fungal pathogens in vitro and in vivo. Preliminary data from the screening of a selected group of patients revealed some value in the early diagnosis and monitoring of antifungal therapy.


A preliminary evaluation of cognitive-behaviour therapy for clinical perfectionism: a case series.
The construct of 'clinical perfectionism' has been developed in response to criticisms that other approaches have failed to yield advances in the treatment of the type of self-oriented perfectionism that poses a clinical problem. The primary aim of this study was to conduct a preliminary investigation into the efficacy of a theory-driven, cognitive-behavioural intervention for 'clinical perfectionism'. A multiple baseline single case series design was used. A specific, 10-session cognitive-behavioural intervention to address clinical perfectionism in eating disorders was adapted to allow its use in nine patients referred with a range of axis I disorders and clinical perfectionism. The intervention led to clinically significant improvements in self-referential perfectionism from pretreatment to follow-up for six of the nine participants on two perfectionism measures and for three of the nine participants on the measure of clinical perfectionism. Statistically significant improvements from pre- to post-intervention for the group as a whole were found on all three measures. The improvements were maintained at follow-up. The finding that clinical perfectionism is improved in the majority of participants is particularly encouraging given that perfectionism has traditionally been viewed as a personality characteristic resistant to change. These preliminary findings warrant replication in a larger study.


Effects on quality of life with comprehensive rehabilitation after acute myocardial infarction.
This investigation was designed to determine the impact of a brief period of cardiac rehabilitation, initiated within 6 weeks of acute myocardial infarction (AMI), on both disease-specific and generic health-related quality of life, exercise tolerance and return to work after AMI. With a stratified, parallel group design, 201 low-risk patients with evidence of depression or anxiety, or both, after AMI, were randomized to either an 8-week program of exercise conditioning and behavioral counseling or to conventional care. Although the differences were small, significantly greater improvement was seen in rehabilitation group patients at 8 weeks in the emotions dimension of a new disease-specific, health-related Quality of Life Questionnaire, in their state of anxiety and in exercise tolerance. All measures of health-related quality of life in both groups improved significantly over the 12-month follow-up period. However, the 95% confidence intervals around differences between groups at the 12-month follow-up effectively excluded sustained, clinically important benefits of rehabilitation in disease-specific (limitations, -2.70, 1.40; emotions, -4.86, 1.10, where negative values favor conventional care and positive values favor rehabilitation) and generic health-related quality of life (time trade-off, -0.062, 0.052; quality of well-being, -0.042, 0.035) or in exercise tolerance (-38.5, 52.1 kpm/min); also, return to work was similar in the 2 groups (relative risk, 0.93; confidence interval, 0.71, 1.64).(ABSTRACT TRUNCATED AT 250 WORDS)


[Effect of chronic altitude hypoxia on the behavior of the respiratory center. Study on normal subjects living at the altitude of Mexico City (2,240 meters)].
Respiratory center (RC) output has been shown to be increased in hypoxemic Chronic Obstructive patients at sea level. In order to asses the separate role of chronic hypoxia on the RC output we studied 30 normal subjects all of them native and residents of Mexico City (altitude: 2,240 m, PaO2: 65-70 torr.). The parameters studied were: occlussion pressure (P0.1), mean inspiratory flow (Vi), and the ratio inspiratory time to total duration of the respiratory cycle (Ti/Ttot). The inspiratory impedance of the respiratory system as well as the minute ventilation (VE) and lastly to ensure isocapnic conditions, the end-tidal CO2 (PECO2), were also measured. These parameters were determined: 1) While breathing room air (RA), 2) after 30 min of breathing an inspired oxygen fraction (FiO2) of 30% and again 3) after 30 min of breathing and FiO2 of 100%. Fifteen of the subjects were studied on supine and the other 15 in the seated position. In most of the subjects the baseline (RA) values of P0.1 were found to be higher than those reported for normals at sea level. In every case, independent of body position, the P0.1 decreased (less than 0.01) to normal sea level values after 30 min of breathing O2 30%. Likewise, Vi and mechanical impedance also decreased (p less than 0.01) and no changes in Ti/Ttot were noted at this FiO2. No further changes occurred after breathing 100%. The above results show that: 1) The RC output in normal people at altitude (i.e. without mechanical abnormalities but with chronic hypoxia) is increased as compared to sea level.(ABSTRACT TRUNCATED AT 250 WORDS)


Aged rats: sex differences and responses to chronic stress.
Cognitive, as well as physiological, sex differences exist in young adult rats under both basal conditions and following chronic stress; however, few studies have examined whether sex differences remain in aged subjects and whether responses to stress are altered. We compared aged male and female Fischer 344 rats (21.5 months at testing) without stress and when given 21 days of restraint for 6 h/day on locomotion, anxiety-related behaviors, object recognition (non-spatial memory), object placement (spatial memory), body weight and serum steroid hormone levels. Control (unstressed) females had lower levels of estradiol and testosterone and higher corticosterone than males, and stress had no lasting effect on hormone concentrations. Females weighed less than males and showed less weight loss with stress. Locomotion measures on an open field were similar in the sexes and unaffected by stress. Anxiety-related behavior measures on the field showed that males were generally more anxious and that stress increased male, but decreased, female anxiety-related behaviors. In memory testing, exploration of objects was not different between the sexes, with or without stress, while stress increased exploration in both sexes during object recognition trials. Both males and females, regardless of treatment, discriminated between old and new objects at short, but not long, inter-trial delays. The typical advantage of young males for spatial memory performance was not observed in aged subjects on the object placement tasks. Stress-dependent enhancements in females and impairments in males for object placement are reported for young rats, but in aged rats, neither sex was altered by stress. Current data suggest that aging is associated with changes in the pattern of sex differences present in young adult rats in some behaviors and in the behavioral responses to stress.


Deliberate Design of TiO2 Nanostructures towards Superior Photovoltaic Cells.
TiO2 nanostructures are being sought after as flexibly utilizable building blocks for the fabrication of the mesoporous thin-film photoelectrodes that are the heart of the third-generation photovoltaic devices, such as dye-sensitized solar cells (DSSCs), quantum-dot-sensitized solar cells (QDSSCs), and the recently promoted perovskite-type solar cells. Here, we report deliberate tailoring of TiO2 nanostructures for superior photovoltaic cells. Morphology engineering of TiO2 nanostructures is realized by designing synthetic protocols in which the precursor hydrolysis, crystal growth, and oligomer self-organization are precisely controlled. TiO2 nanostructures in forms varying from isolated nanocubes, nanorods, and cross-linked nanorods to complex hierarchical structures and shape-defined mesoporous micro-/nanostructures were successfully synthesized. The photoanodes made from the shape-defined mesoporous TiO2 microspheres and nanospindles presented superior performances, owing to the well-defined overall shapes and the inner ordered nanochannels, which allow not only a high amount of dye uptake, but also improved visible-light absorption. This study provides a new way to seek an optimal synthetic protocol to meet the required functionality of the nanomaterials.


Two-dimensional flow nanometry of biological nanoparticles for accurate determination of their size and emission intensity.
Biological nanoparticles (BNPs) are of high interest due to their key role in various biological processes and use as biomarkers. BNP size and composition are decisive for their functions, but simultaneous determination of both properties with high accuracy remains challenging. Optical microscopy allows precise determination of fluorescence/scattering intensity, but not the size of individual BNPs. The latter is better determined by tracking their random motion in bulk, but the limited illumination volume for tracking this motion impedes reliable intensity determination. Here, we show that by attaching BNPs to a supported lipid bilayer, subjecting them to hydrodynamic flows and tracking their motion via surface-sensitive optical imaging enable determination of their diffusion coefficients and flow-induced drifts, from which accurate quantification of both BNP size and emission intensity can be made. For vesicles, the accuracy of this approach is demonstrated by resolving the expected radius-squared dependence of their fluorescence intensity for radii down to 15 nm.


Cold responsive EARLI1 type HyPRPs improve freezing survival of yeast cells and form higher order complexes in plants.
Plants have large families of proteins sharing a conserved eight-cysteine-motif (8CM) domain. The biological functions of these proteins are largely unknown. EARLI1 is a cold responsive Arabidopsis gene that encodes a hybrid proline-rich protein (HyPRP) with a three-domain architecture: a putative signal peptide at the N-terminus, a proline-rich domain (PRD) in the middle, and an 8CM domain at the C-terminus. We report here that yeast cells expressing different EARLI1 genes had significantly higher rates of freezing survival than empty-vector transformed controls. Arabidopsis plants with knocked down EARLI1 genes had an increased tendency for freezing-induced cellular damage. EARLI1-GFP fluorescence in transgenic plants and immunoblot analyses using protoplasts suggested cell wall localization for EARLI1 proteins. Immunoblot analyses showed that EARLI1 proteins form higher order complexes in plants, and that the PRD is a soluble and the 8CM an insoluble protein domain. We propose that EARLI1 proteins have a bimodular architecture in which the PRD may interact with the cell wall and the 8CM domain with the plasma membrane to protect the cells during freezing stress.


Assessing the congruence of thermal niche estimations derived from distribution and physiological data. A test using diving beetles.
A basic aim of ecology is to understand the determinants of organismal distribution, the niche concept and species distribution models providing key frameworks to approach the problem. As temperature is one of the most important factors affecting species distribution, the estimation of thermal limits is crucially important for inferring range constraints. It is expectable that thermal physiology data derived from laboratory experiments and species' occurrences may express different aspects of the species' niche. However, there is no study systematically testing this prediction in a given taxonomic group while controlling by potential phylogenetic inertia. We estimate the thermal niches of twelve Palaearctic diving beetles species using physiological data derived from experimental analyses in order to examine the extent to which these coincided with those estimated from distribution models based on observed occurrences. We found that thermal niche estimates derived from both approaches lack general congruence, and these results were similar before and after controlling by phylogeny. The congruence between potential distributions obtained from the two different procedures was also explored, and we found again that the percentage of agreement were not very high (~60%). We confirm that both thermal niche estimates derived from geographical and physiological data are likely to misrepresent the true range of climatic variation that these diving beetles are able to tolerate, and so these procedures could be considered as incomplete but complementary estimations of an inaccessible reality.


Human γδ T cells recognize CD1b by two distinct mechanisms.
γδ T cells form an abundant part of the human cellular immune system, where they respond to tissue damage, infection, and cancer. The spectrum of known molecular targets recognized by Vδ1-expressing γδ T cells is becoming increasingly diverse. Here we describe human γδ T cells that recognize CD1b, a lipid antigen-presenting molecule, which is inducibly expressed on monocytes and dendritic cells. Using CD1b tetramers to study multiple donors, we found that many CD1b-specific γδ T cells use Vδ1. Despite their common use of Vδ1, three CD1b-specific γδ T cell receptors (TCRs) showed clear differences in the surface of CD1b recognized, the requirement for lipid antigens, and corecognition of butryophilin-like proteins. Several Vγ segments were present among the CD1b-specific TCRs, but chain swap experiments demonstrated that CD1b specificity was mediated by the Vδ1 chain. One of the CD1b-specific Vδ1+ TCRs paired with Vγ4 and shows dual reactivity to CD1b and butyrophilin-like proteins. αβ TCRs typically recognize the peptide display platform of MHC proteins. In contrast, our results demonstrate the use of rearranged receptors to mediate diverse modes of recognition across the surface of CD1b in ways that do and do not require carried lipids.


Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency.
Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.


Bookshelf: a simple curation system for the storage of biomolecular simulation data.
Molecular dynamics simulations can now routinely generate data sets of several hundreds of gigabytes in size. The ability to generate this data has become easier over recent years and the rate of data production is likely to increase rapidly in the near future. One major problem associated with this vast amount of data is how to store it in a way that it can be easily retrieved at a later date. The obvious answer to this problem is a database. However, a key issue in the development and maintenance of such a database is its sustainability, which in turn depends on the ease of the deposition and retrieval process. Encouraging users to care about meta-data is difficult and thus the success of any storage system will ultimately depend on how well used by end-users the system is. In this respect we suggest that even a minimal amount of metadata if stored in a sensible fashion is useful, if only at the level of individual research groups. We discuss here, a simple database system which we call 'Bookshelf', that uses python in conjunction with a mysql database to provide an extremely simple system for curating and keeping track of molecular simulation data. It provides a user-friendly, scriptable solution to the common problem amongst biomolecular simulation laboratories; the storage, logging and subsequent retrieval of large numbers of simulations. Download URL: http://sbcb.bioch.ox.ac.uk/bookshelf/


Schistosomiasis epidemiology and control: how did we get here and where should we go?
Although a disease of great antiquity, scientific studies of schistosomiasis began only 150 years ago. The complete life-cycle was not described until just before the First World War, making it possible at last to plan proper community control programmes. Inadequate tools prevented their effective implementation until well after the Second World War when new tools became available, thanks to the newly formed World Health Organization. Molluscicides spearheaded control programmes until the late 1970s but were then replaced by the newly developed, safe drugs still used today. Whatever the method used, the initial goal of eradication was, in the light of experience and cost, gradually replaced by less ambitious targets; first to stop transmission and then to reduce morbidity. The most successful programmes combined several methods to minimise reinfection after chemotherapy. Comparisons between different programmes are difficult without using appropriate, standardised diagnostic techniques and the correct epidemiological measurements. Some examples will be presented, mainly from our studies on Schistosoma mansoni in Kenya. Drug resistance on a scale comparable with malaria has not occurred in schistosomiasis but the likely withdrawal of all drugs except praziquantel leaves its control extremely vulnerable to this potential problem. An effective, affordable vaccine for use in endemic countries is unlikely to be ready for at least 5 years, and developing strategies for its use could take a further decade or more, judging from experience with drugs and molluscicides. In the interim, by analogy with malaria, the most cost-effective approach would the use of drugs combined with other methods to stop transmission, including molluscicides. The cost of molluscicides needs to be reduced and fears allayed about their supposedly adverse ecological effects.


High plasma levels and effective lymphatic uptake of docetaxel in an orally available nanotransporter formulation.
Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5-mg/kg dose. The batches (B) I and II NC formulations elicited C(max) values that were 1,735% and 2,254%, respectively; higher than the C(max) value of the oral docetaxel solution combined with blank microparticles, a 10-mg/kg dose. No significant difference in AUC (area under curve) was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery.


Probability mapping of scarred myocardium using texture and intensity features in CMR images.
The myocardium exhibits heterogeneous nature due to scarring after Myocardial Infarction (MI). In Cardiac Magnetic Resonance (CMR) imaging, Late Gadolinium (LG) contrast agent enhances the intensity of scarred area in the myocardium. In this paper, we propose a probability mapping technique using Texture and Intensity features to describe heterogeneous nature of the scarred myocardium in Cardiac Magnetic Resonance (CMR) images after Myocardial Infarction (MI). Scarred tissue and non-scarred tissue are represented with high and low probabilities, respectively. Intermediate values possibly indicate areas where the scarred and healthy tissues are interwoven. The probability map of scarred myocardium is calculated by using a probability function based on Bayes rule. Any set of features can be used in the probability function. In the present study, we demonstrate the use of two different types of features. One is based on the mean intensity of pixel and the other on underlying texture information of the scarred and non-scarred myocardium. Examples of probability maps computed using the mean intensity of pixel and the underlying texture information are presented. We hypothesize that the probability mapping of myocardium offers alternate visualization, possibly showing the details with physiological significance difficult to detect visually in the original CMR image. The probability mapping obtained from the two features provides a way to define different cardiac segments which offer a way to identify areas in the myocardium of diagnostic importance (like core and border areas in scarred myocardium).


Thiol-oxidant monochloramine mobilizes intracellular Ca2+ in parietal cells of rabbit gastric glands.
In Helicobacter pylori-induced gastritis, oxidants are generated through the interactions of bacteria in the lumen, activated granulocytes, and cells of the gastric mucosa. In this study we explored the ability of one such class of oxidants, represented by monochloramine (NH(2)Cl), to serve as agonists of Ca(2+) accumulation within the parietal cell of the gastric gland. Individual gastric glands isolated from rabbit mucosa were loaded with fluorescent reporters for Ca(2+) in the cytoplasm (fura-2 AM) or intracellular stores (mag-fura-2 AM). Conditions were adjusted to screen out contributions from metal cations such as Zn(2+), for which these reporters have affinity. Exposure to NH(2)Cl (up to 200 microM) led to dose-dependent increases in intracellular Ca(2+) concentration ([Ca(2+)](i)), in the range of 200-400 nM above baseline levels. These alterations were prevented by pretreatment with the oxidant scavenger vitamin C or a thiol-reducing agent, dithiothreitol (DTT), which shields intracellular thiol groups from oxidation by chlorinated oxidants. Introduction of vitamin C during ongoing exposure to NH(2)Cl arrested but did not reverse accumulation of Ca(2+) in the cytoplasm. In contrast, introduction of DTT or N-acetylcysteine permitted arrest and partial reversal of the effects of NH(2)Cl. Accumulation of Ca(2+) in the cytoplasm induced by NH(2)Cl is due to release from intracellular stores, entry from the extracellular fluid, and impaired extrusion. Ca(2+)-handling proteins are susceptible to oxidation by chloramines, leading to sustained increases in [Ca(2+)](i). Under certain conditions, NH(2)Cl may act not as an irritant but as an agent that activates intracellular signaling pathways. Anti-NH(2)Cl strategies should take into account different effects of oxidant scavengers and thiol-reducing agents.


The relationships of character strengths with coping, work-related stress, and job satisfaction.
Personality traits have often been highlighted to relate to how people cope with stressful events. The present paper focuses on character strengths as positive personality traits and examines two basic assumptions that were derived from a core characteristic of character strengths (i.e., to determine how individuals deal with adversities): (1) character strengths correlate with coping and (2) buffer the effects of work-related stress on job satisfaction. Two different samples (i.e., a mixed sample representing various occupations [N = 214] and a nurses sample [N = 175]) filled in measures for character strengths, coping, work-related stress, and job satisfaction. As expected, intellectual, emotional, and interpersonal strengths were related to coping. Interpersonal strengths played a greater role for coping among nurses, as interactions with others are an essential part of their workday. Furthermore, intellectual strengths partially mediated the negative effect of work-related stress on job satisfaction. These findings open a new field for research on the role of personality in coping with work-related stress. Character strengths are trainable personal characteristics, and therefore valuable resources to improve coping with work-related stress and to decrease the negative effects of stress. Further research is needed to investigate this assumed causality.


Inactivation of PITX2 transcription factor induced apoptosis of gonadotroph tumoral cells.
Nonfunctioning pituitary adenomas (NFPA; gonadotroph derived), even not inducing hormonal hypersecretion, cause significant morbidity by compression neighboring structures. No effective and specific medical methods are available so far for treating these tumors. The pituitary homeobox 2 (PITX2) gene is a member of the bicoid-like homeobox transcription factor family, which is involved in the Wnt/Dvl/β-catenin pathway. PITX2 is overexpressed in NFPA. PITX2 mutations are known to be responsible for Axenfield Rieger syndrome, a genetic disorder in which pituitary abnormalities have been detected. The R91P mutant identified in Axenfeld Rieger syndrome is a dominant-negative factor, which is able to block the expression of several pituitary genes activated by PITX2. To better understand the role of Pitx2 on gonadotroph tumorigenesis and to explore new approach for inhibiting tumoral growth, the R91P mutant was transferred via a lentiviral vector in tumoral gonadotroph cells of two kinds: the αT3-1 cell line and human adenoma cells. R91P mutant and small interfering RNA directed against Pitx2 both decreased the viability of αT3-1 cells via an apoptotic mechanism involving the activation of executioner caspase. Similar effects of the R91P mutant were observed on human gonadotroph cells in primary culture. Therefore, Pitx2 overexpression may play an antiapoptotic role during NFPA tumorigenesis.


Hot spots of retroviral integration in human CD34+ hematopoietic cells.
Insertional oncogenesis is a possible consequence of the integration of gamma-retroviral (RV) or lentiviral (LV) vectors into the human genome. RV common insertion sites (CISs) have been identified in hematopoietic malignancies and in the nonmalignant progeny of transduced hematopoietic stem/progenitor cells (HSCs), possibly as a consequence of clonal selection in vivo. We have mapped a large number of RV and LV integrations in human CD34(+) HSCs, transduced in vitro and analyzed without selection. Recurrent insertion sites (hot spots) account for more than 21% of the RV integration events, while they are significantly less frequent in the case of LV vectors. RV but not LV hot spots are highly enriched in proto-oncogenes, cancer-associated CISs, and growth-controlling genes, indicating that at least part of the biases observed in the HSC progeny in vivo are characteristics of RV integration, already present in nontransplanted cells. Genes involved in hematopoietic and immune system development are targeted at high frequency and enriched in hot spots, suggesting that the CD34(+) gene expression program is instrumental in directing RV integration. The lower propensity of LV vectors for integrating in potentially dangerous regions of the human genome may be a factor determining a better safety profile for gene therapy applications.


The association between asthma and rhinitis is stable over time despite diverging trends in prevalence.
Despite the well-known association between asthma and rhinitis, in Swedish adults the prevalence of rhinitis rose from 22% to 31% between 1990 and 2008 while asthma prevalence was unchanged. We tested whether the association of rhinitis with asthma was stable over time using the same population-based databases. Two surveys of adults (20-44 years) living in three regions of Sweden, carried out in 1990 (n = 8982) and 2008 (n = 9156) were compared. Identical questions regarding respiratory symptoms, asthma and rhinitis were used. Asthmatic wheeze: Wheeze with breathlessness apart from colds. Current asthma: Asthma attacks and/or asthma medication use. Subjects with rhinitis had level time trends in asthmatic wheeze, current asthma and most nocturnal respiratory symptoms between 1990 and 2008, adjusted for age, sex, area and smoking. Any wheeze however decreased slightly. In never-smokers asthma symptoms were similarly associated with rhinitis in 1990 and 2008: any wheeze OR 4.0 vs. 4.4 (p = 0.339); asthmatic wheeze OR 6.0 vs. 5.9 (p = 0.937); and current asthma OR 9.6 vs. 7.7 (p = 0.213). In the whole population there were decreases in the asthma symptoms most closely associated to smoking, which decreased by half 1990-2008. Conversely current asthma, which was strongly associated with rhinitis and not with smoking, increased (p < 0.001). The association of rhinitis with asthma was stable between 1990 and 2008. The pattern in the time trends of asthma outcomes strongly suggests that decreased smoking counterbalanced the driving effect of increased rhinitis on asthma prevalence. The findings illustrate the public health benefits of decreased smoking.


A simplified severity scale for age-related macular degeneration: AREDS Report No. 18.
To develop a simplified clinical scale defining risk categories for development of advanced age-related macular degeneration (AMD). Following development of a detailed scale for individual eyes based on gradings of fundus photographs in the Age-Related Eye Disease Study, rates of progression to advanced AMD were assessed in cross-tabulations of presence or absence in each eye of 2 easily identified retinal abnormalities, drusen and pigment abnormalities. Large drusen and any pigment changes were particularly predictive of developing advanced AMD. The scoring system developed for patients assigns to each eye 1 risk factor for the presence of 1 or more large (> or = 125 microm, width of a large vein at disc margin) drusen and 1 risk factor for the presence of any pigment abnormality. Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases in this easily remembered sequence: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%. For persons with no large drusen, presence of intermediate drusen in both eyes is counted as 1 risk factor. This simplified scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less demanding photographic procedures than used in the Age-Related Eye Disease Study.


Draft genome sequence of the oilseed species Ricinus communis.
Castor bean (Ricinus communis) is an oilseed crop that belongs to the spurge (Euphorbiaceae) family, which comprises approximately 6,300 species that include cassava (Manihot esculenta), rubber tree (Hevea brasiliensis) and physic nut (Jatropha curcas). It is primarily of economic interest as a source of castor oil, used for the production of high-quality lubricants because of its high proportion of the unusual fatty acid ricinoleic acid. However, castor bean genomics is also relevant to biosecurity as the seeds contain high levels of ricin, a highly toxic, ribosome-inactivating protein. Here we report the draft genome sequence of castor bean (4.6-fold coverage), the first for a member of the Euphorbiaceae. Whereas most of the key genes involved in oil synthesis and turnover are single copy, the number of members of the ricin gene family is larger than previously thought. Comparative genomics analysis suggests the presence of an ancient hexaploidization event that is conserved across the dicotyledonous lineage.


Winter rainfall predicts phenology in widely separated populations of a migrant songbird.
Climate change is affecting behaviour and phenology in many animals. In migratory birds, weather patterns both at breeding and at non-breeding sites can influence the timing of spring migration and breeding. However, variation in responses to weather across a species range has rarely been studied, particularly among populations that may winter in different locations. We used prior knowledge of migratory connectivity to test the influence of weather from predicted non-breeding sites on bird phenology in two breeding populations of a long-distance migratory bird species separated by 3,000 km. We found that winter rainfall showed similar associations with arrival and egg-laying dates in separate breeding populations on an east-west axis: greater rainfall in Jamaica and eastern Mexico was generally associated with advanced American redstart (Setophaga ruticilla) phenology in Ontario and Alberta, respectively. In Ontario, these patterns of response could largely be explained by changes in the behaviour of individual birds, i.e., phenotypic plasticity. By explicitly incorporating migratory connectivity into responses to climate, our data suggest that widely separated breeding populations can show independent and geographically specific associations with changing weather conditions. The tendency of individuals to delay migration and breeding following dry winters could result in population declines due to predicted drying trends in tropical areas and the tight linkage between early arrival/breeding and reproductive success in long-distance migrants.


SIR2 regulates recombination between different rDNA repeats, but not recombination within individual rRNA genes in yeast.
It is known that mutations in gene SIR2 increase and those in FOB1 decrease recombination within rDNA repeats as assayed by marker loss or extrachromosomal rDNA circle formation. SIR2-dependent chromatin structures have been thought to inhibit access and/or function of recombination machinery in rDNA. We measured the frequency of FOB1-dependent arrest of replication forks, consequent DNA double-strand breaks, and formation of DNA molecules with Holliday junction structures, and found no significant difference between sir2Delta and SIR2 strains. Formal genetic experiments measuring mitotic recombination rates within individual rRNA genes also showed no significant difference between these two strains. Instead, we found a significant decrease in the association of cohesin subunit Mcd1p (Scc1p) to rDNA in sir2Delta relative to SIR2 strains. From these and other experiments, we conclude that SIR2 prevents unequal sister-chromatid recombination, probably by forming special cohesin structures, without significant effects on recombinational events within individual rRNA genes.


Centers for Disease Control and the epidemiology of violence.
Violence is a major cause of morbidity and mortality in the United States. The Center for Health Promotion and Education, the Centers for Disease Control (CDC) has begun to apply epidemiologic techniques to study the problems of child abuse, child homicide, homicide, and suicide. CDC's involvement in these areas has evolved in association with significant shifts in emphasis in public health policy and planning, from areas of acute and infectious diseases to areas of chronic diseases and premature mortality. We have recently addressed the problems of reporting biases and definitional variability in regard to child abuse and have characterized child homicide in the United States. We are currently epidemiologically investigating the underrecording of child homicide in this country. Our future work will include delineation and evaluation of programs to prevent violence toward children and examination of the relationship between intrafamilial violence and extrafamilial, noncrime related violence.


The HCV Synthesis Project: scope, methodology, and preliminary results.
The hepatitis C virus (HCV) is hyper-endemic in injecting drug users. There is also excess HCV among non-injection drug users who smoke, snort, or sniff heroin, cocaine, crack, or methamphetamine. To summarize the research literature on HCV in drug users and identify gaps in knowledge, we conducted a synthesis of the relevant research carried out between 1989 and 2006. Using rigorous search methods, we identified and extracted data from published and unpublished reports of HCV among drug users. We designed a quality assurance system to ensure accuracy and consistency in all phases of the project. We also created a set of items to assess study design quality in each of the reports we included. We identified 629 reports containing HCV prevalence rates, incidence rates and/or genotype distribution among injecting or non-injecting drug user populations published between January 1989 and December 2006. The majority of reports were from Western Europe (41%), North America (26%), Asia (11%) and Australia/New Zealand (10%). We also identified reports from Eastern Europe, South America, the Middle East, and the Caribbean. The number of publications reporting HCV rates in drug users increased dramatically between 1989 and 2006 to 27-52 reports per year after 1998. The data collection and quality assurance phases of the HCV Synthesis Project have been completed. Recommendations for future research on HCV in drug users have come out of our data collection phase. Future research reports can enhance their contributions to our understanding of HCV etiology by clearly defining their drug user participants with respect to type of drug and route of administration. Further, the use of standard reporting methods for risk factors would enable data to be combined across a larger set of studies; this is especially important for HCV seroconversion studies which suffer from small sample sizes and low power to examine risk factors.


Demonstration and treatment of hyperventilation causing asthma.
Ambulant, transcutaneous PCO2 monitoring has been used to show that hyperventilation precedes exacerbation of asthma in a patient. Brief treatment was shown to give him greater control of his breathing and enable him to avoid attacks of asthma.


The role of stride frequency for walk-to-run transition in humans.
It remains unclear why humans spontaneously shift from walking to running at a certain point during locomotion at gradually increasing velocity. We show that a calculated walk-to-run transition stride frequency (70.6 ± 3.2 strides min-1) agrees with a transition stride frequency (70.8 ± 3.1 strides min-1) predicted from the two stride frequencies applied during treadmill walking and running at freely chosen velocities and freely chosen stride frequencies. The agreement is based on Bland and Altman's statistics. We found no essential mean relative difference between the two transition frequencies, i.e. -0.5% ± 4.2%, as well as limits of agreement of -8.7% and 7.7%. The particular two freely chosen stride frequencies used for prediction are considered behavioural attractors. Gait is predicted to be shifted from walking to running when the stride frequency starts getting closer to the running attractor than to the walking attractor. In particular, previous research has focussed on transition velocity and optimisation theories based on minimisation of, e.g., energy turnover or biomechanical loadings of the legs. Conversely, our data support that the central phenomenon of walk-to-run transition during human locomotion could be influenced by behavioural attractors in the form of stride frequencies spontaneously occurring during behaviourally unrestricted gait conditions of walking and running.


THE PROPHYLAXIS OF WEIL'S DISEASE (SPIROCHAETOSIS ICTEROHAEMORRHAGICA).
We have already described briefly the portals of entry and of excretion of the pathogenic spirochetes. We may mention here that we have twice prevented epidemics by disinfection of the ground and the removal of the inundated water in certain places in coal mines. In one mine 19 out of 50 workmen, and in another 9 out of 30 workmen came down with Weil's disease in about 2 weeks. We have already pointed out that the period during which the pathogenic spirochetes are excreted in the urine continues, as a rule, for 40 days, and that we must, therefore, apply disinfection for at least 40 days after the first appearance of the disease. Lately we have found that in 21 cases out of 24 the spirochetes were excreted in the urine for 40 days, in one case until the 42nd day, in one case until the 45th day, and in still another case until the 63rd day. Another important fact concerning the prophylaxis which has been brought out is that both house and ditch rats (brown) carry virulent Spirochaeta icterohamorrhagae, the causal spirochete of Weil's disease, in their kidneys. Miyajima has reported that field rats have the pathogenic organisms in their kidneys; he will report these findings in detail later. The spirochetes which he described are less virulent than ours. On his advice we have carefully examined house and ditch rats in the city and rats in the coal mines of Kyushu, where Weil's disease prevails, and found that 39.5 per cent carried highly virulent pathogenic spirochetes in their kidneys, thus confirming Miyajima's experiments. The kidneys were examined microscopically under the dark-field microscope, and in the cases in which we did not find the pathogenic spirochete, we made inoculations into guinea pigs. Thus we found Spirochaeta icterohaemorrhagiae microscopically in the kidneys or in the urine in 32.4 per cent, and by means of inoculation in 7 per cent, making a total of 39.5 per cent carrying the pathogenic organisms, out of a total number of 86 rats examined. In some instances, rats were made to bite guinea pigs and in two instances caused Weil's disease. Among fifty-five patients in our clinic, twelve were cooks; and in Europe many cases arise among butchers-indicating the relation of the disease to rats. Moreover, during the present year we observed two patients who acquired Weil's disease, one in 1 week, the other 8 to 9 days after they had been bitten by rats. These facts point to a relation between Weil's disease and rats. The infection is transmitted probably from rats to man by means of the urine of the rats, directly or indirectly. On the injection of 0.1 gm. of rat urine which contains Spirochaeta icterohaemorrhagiae into the peritoneal cavity of guinea pigs, the infection arises, while the injection of the liver or the blood of the rats into guinea pigs does not produce the typical disease. The finding that the kidneys of rats contain the pathogenic organisms of the disease is important from the point of view of prophylaxis. The large number of rats in the trenches of the European battle-fields suggests the possibility that many cases of Weil's disease may arise. We shall report on this point in more detail later.


Prevention of Adriamycin-induced hepatic and renal toxicity in male BALB/c mice by a nutrient mixture.
Adriamycin (ADR), an antineoplastic antibiotic used in cancer therapy, is associated with toxicity to vital organs with long-term use. A nutrient mixture (NM) has previously been shown to exhibit a broad spectrum of therapeutic properties. The aim of the present study was to determine whether the NM is useful for preventing ADR-induced hepatic and nephric toxicity. Six-week-old male BALB/c mice were divided into four groups of six animals each. Groups A and C were fed a regular diet for three weeks and groups B and D were fed a diet supplemented with 1% NM. After three weeks, the mice in groups C and D received 20 mg/kg body weight ADR intraperitoneally, while those in groups A and B received saline alone. Animals were sacrificed after 24 h, blood samples were collected and serum was obtained for clinical chemistry. Organs were also excised and weighed. Administration of ADR to group C (control diet) resulted in a marked increase in hepatic alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase levels and renal blood urea nitrogen, creatinine and uric acid serum markers. However, in group D (NM 1% diet), the serum markers were comparable with the levels of group A and B. Therefore, the results indicate that NM has the potential to protect against ADR-induced hepatic and nephric damage.


Serum protein expression profiling for cancer detection: validation of a SELDI-based approach for prostate cancer.
Multiple studies have reported that analysis of serum and other bodily fluids using surface enhanced laser desorption/ionization time of flight mass spectroscopy (SELDI-TOF-MS) can identify a "fingerprint" or "signature" of spectral peaks that can separate patients with a specific disease from normal control patients. Ultimately, classification by SELDI-TOF-MS relies on spectral differences in position and amplitude of resolved peaks. Since the reproducibility of quantitation, resolution and mass accuracy of the SELDI-TOF-MS, or any high throughput mass spectrometric technique, has never been determined this method has come under some skepticism as to its clinical usefulness. This manuscript describes a detailed design of a three-phase study to validate the clinical usefulness of SELDI-TOF-MS in the identification of patients with prostatic adenocarcinoma (PCA). At the end of this validation study, the usefulness of the general SELDI-TOF-MS approach to identifying patients with PCA will be demonstrated and how it compares with PCA diagnosis by measuring prostate specific antigen.


Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I.
In Chinese hamster ovary cells, stable mutants that exhibit 250- to 350-fold resistance to camptothecin (CptR mutants) have been isolated from mutagen-treated cultures. The CptR mutants exhibited no cross-resistance towards drugs such as colchicine, vinblastine, taxol, or puromycin but showed slightly (2- to 3-fold) enhanced sensitivity towards various drugs that inhibit DNA topoisomerase II (namely teniposide, etoposide, doxorubicin, mitoxantrone, amsacrine, ellipticine), suggesting that the genetic lesion in these mutants was highly specific. In contrast to the wild-type cells, the CptR line was resistant to camptothecin-induced DNA strand breaks as measured by alkaline elution. Biochemical studies revealed that in CptR mutants the cellular activity as well as protein content of DNA topoisomerase I were reduced to about 40-50% of the level in wild-type cells. Normal levels of activity and content were observed for the related enzyme DNA topoisomerase II. Studies with DNA topoisomerase I purified from the wild-type and the mutant cells showed that the enzyme from the CptR cells was markedly resistant to camptothecin as assayed by the drug's effects either on relaxation of supercoiled DNA or on stabilization of the covalent enzyme-DNA intermediate. The presence of a camptothecin-resistant form of DNA topoisomerase I in the mutant cells provides further evidence that this enzyme is the cellular target of camptothecin. Cell hybridization studies between the CptR and CptS cells showed that the hybrids formed between these two cell lines were sensitive to camptothecin. The recessive behavior of the CptR mutation provides a plausible explanation for the reduced topoisomerase I content (about one-half of wild-type cells) of the mutant cells and also for their enhanced sensitivity towards inhibitors of topoisomerase II.


Cytogenetic effects of 50 Hz magnetic fields of different magnetic flux densities.
Cytogenetic investigations were performed in human peripheral blood lymphocytes following exposure to 50 Hz magnetic fields alone or in combination with the chemical mutagen mitomycin C or with X-rays. It was found that magnetic fields up to 2500 microT did not significantly influence the chromosome aberration and sister chromatid exchange frequency. Also, the combined treatments failed to indicate the presence of any synergistic, potentiating, or antagonistic effect between the ELF magnetic fields and the mutagens. However, there were two exceptions: Cells exposed to 504 microT magnetic fields before and during cultivation displayed a statistically significant decrease in sister chromatid exchange frequency. Also, when cells were cultivated in the presence of 88.4 microT magnetic fields following X-ray exposures there was a significant increase in chromosome aberration frequency compared to X-ray exposure alone.


Perspectives of college students on their childhood ADHD.
To determine what successful young adults perceive was helpful to them when they were struggling with their attention-deficit hyperactivity disorder (ADHD) symptoms as children. Sixteen young adult -college students with a history of ADHD participated in semistructured interviews that asked them which people and what strategies they had found most helpful to them during their childhood. Data were analyzed -using content analysis. The most helpful people were parents and teachers; the most helpful strategies were caring behaviors and active teaching/learning strategies. Participants remembered helpful people as "giving me strategies to help me keep my mind focused on something; keep me involved, keep me interested." Children with ADHD need the support of caring adults who use active teaching strategies. Nurses working with children and adolescents in any setting can educate parents about the best ways to help children with ADHD succeed, using some of the results of this research.


A precision measurement of the mass of the top quark.
The standard model of particle physics contains parameters--such as particle masses--whose origins are still unknown and which cannot be predicted, but whose values are constrained through their interactions. In particular, the masses of the top quark (M(t)) and W boson (M(W)) constrain the mass of the long-hypothesized, but thus far not observed, Higgs boson. A precise measurement of M(t) can therefore indicate where to look for the Higgs, and indeed whether the hypothesis of a standard model Higgs is consistent with experimental data. As top quarks are produced in pairs and decay in only about 10(-24) s into various final states, reconstructing their masses from their decay products is very challenging. Here we report a technique that extracts more information from each top-quark event and yields a greatly improved precision (of +/- 5.3 GeV/c2) when compared to previous measurements. When our new result is combined with our published measurement in a complementary decay mode and with the only other measurements available, the new world average for M(t) becomes 178.0 +/- 4.3 GeV/c2. As a result, the most likely Higgs mass increases from the experimentally excluded value of 96 to 117 GeV/c2, which is beyond current experimental sensitivity. The upper limit on the Higgs mass at the 95% confidence level is raised from 219 to 251 GeV/c2.


Preoperative parameters to predict incidental (T1a and T1b) prostate cancer.
Prostate cancer has been found incidentally in transurethral resection of the prostate (TURP) specimens without prior diagnosis in 5% to 13% of the patients. We evaluated whether incidental prostate cancer (stages T1a and T1b) could be predicted preoperatively. TURP was performed in 307 patients between 2006 and 2011. Patient age, prostate-specific antigen (PSA) level, total prostate volume, transitional zone volume, PSA density, history of needle biopsy, and pathological diagnosis on TURP specimen were assessed. We analyzed the association between these parameters and prostate cancer detection. Incidental prostate cancer was found in 31 patients (10.1%), and 13 cases (4.2%) had cancer with T1b and/or Gleason ≥7. Multivariate analysis demonstrated that age ≥75 years (odds ratio [OR] 2.58, p = 0.022), prostate volume ≤50 cc (OR 4.11, p < 0.001), and the absence of preoperative needle biopsy despite PSA ≥4 ng/mL (OR 2.65, p = 0.046) were independent risk factors. In patients who had 2 or 3 of these risk factors, incidental prostate cancer and cancer with T1b and/or Gleason ≥7 were observed in 25% to 50% and 16% to 25% cases, respectively. Older patient age, small prostate volume, and the absence of previous needle biopsy (despite a high PSA level) might be independent risk factors for detecting incidental prostate cancer, although external validation is warranted to confirm our results.