Comparison of hemorheological variables in ST-elevation myocardial infarction versus those in non-ST-elevation myocardial infarction or unstable angina pectoris.
The aim of this study was to evaluate hemorheologic variables in patients with acute coronary syndromes in relation to the occurrence of ST-segment elevation myocardial infarction (STEMI). In 370 consecutive patients with acute coronary syndromes, 215 with STEMIs and 155 with non-ST-segment elevation myocardial infarctions or unstable angina pectoris, who underwent percutaneous coronary intervention, hemorheologic studies were performed by assessing whole-blood viscosity (at shear rates of 0.512 and 94.5 s(-1)), plasma viscosity, and erythrocyte deformability index. A significant difference in hematocrit and in whole-blood viscosity at 0.512 s(-1) was found between the 2 groups of patients. Hematocrit at admission in the highest tertile compared with the lowest tertile remained independently associated with the occurrence of STEMI on multivariate analysis adjusted for traditional cardiovascular risk factors, previous coronary artery disease, multivessel disease, bleeding complications, and leukocyte count. In conclusion, erythrocyte concentration seems to play a role per se in the occurrence of STEMI and complete coronary artery occlusion and might be considered in stratifying high-risk cardiovascular patients and as a possible therapeutic target in patients presenting with acute coronary syndromes.


Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome.
Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event that may result from a FSH-producing pituitary adenoma (FSHoma), activating mutations of the FSH receptor (FSHR), and cross-reactivity of the FSHR to elevated hCG and TSH in the setting of pregnancy or hypothyroidism. The objective of this study was to investigate whether an aberrant FSHR was present in a woman with sOHSS and a non-surgically diagnosed FSHoma whose serum FSH levels and FSH bioactivity were nearly normal. Sequencing of the patient's FSHR gene revealed a heterozygous novel missense mutation c. 1536G>A resulting in an amino acid substitution M512I. We asked whether this mutant FSHR affected FSHR-mediated signaling pathways involving cAMP/protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase (SRC)/ p42/p44 extracellular signal-regulated protein kinases (ERK1/2). Thus, 293T cells expressing wild-type (FSHRwt), the mutant FSHR (FSHRmt), or both (FSHRwt/mt) were treated with FSH and subjected to measurements of intracellular cAMP, cAMP-induced CRE (cAMP response element)-mediated luciferase assays and immunoblot analyses of phosphorylated PI3K and ERK1/2. There were no differences in luciferase activities or phosphorylation levels of ERK1/2 among FSHRwt, FSHRmt cells and FSHwt/mt cells. However, FSHRmt cells showed a significant reduction in both cAMP production and PI3K phosphorylation levels with unchanged phosphorylation of ERK1/2 upon FSH stimulation in comparison to FSHwt cells. Also, FSH treatment did not provoke PI3K phosphorylation in FSHwt/mt cells. These results indicate that the novel missense M512I FSHR mutation identified herein did not participate in hyperactivation of FSHR-mediated signaling pathways but rather in hypoactivation of the FSH-mediated PI3K/AKT pathway. Thus, this study demonstrates a new functional property of this novel mutatnt FSHR, which, however, might not be involved in the pathogenesis of sOHSS in this FSHoma patient.


Global civil aviation black carbon emissions.
Aircraft black carbon (BC) emissions contribute to climate forcing, but few estimates of BC emitted by aircraft at cruise exist. For the majority of aircraft engines the only BC-related measurement available is smoke number (SN)-a filter based optical method designed to measure near-ground plume visibility, not mass. While the first order approximation (FOA3) technique has been developed to estimate BC mass emissions normalized by fuel burn [EI(BC)] from SN, it is shown that it underestimates EI(BC) by >90% in 35% of directly measured cases (R(2) = -0.10). As there are no plans to measure BC emissions from all existing certified engines-which will be in service for several decades-it is necessary to estimate EI(BC) for existing aircraft on the ground and at cruise. An alternative method, called FOX, that is independent of the SN is developed to estimate BC emissions. Estimates of EI(BC) at ground level are significantly improved (R(2) = 0.68), whereas estimates at cruise are within 30% of measurements. Implementing this approach for global civil aviation estimated aircraft BC emissions are revised upward by a factor of ~3. Direct radiative forcing (RF) due to aviation BC emissions is estimated to be ~9.5 mW/m(2), equivalent to ~1/3 of the current RF due to aviation CO2 emissions.


Superimposed video disambiguation for increased field of view.
Many infrared optical systems in wide-ranging applications such as surveillance and security frequently require large fields of view (FOVs). Often this necessitates a focal plane array (FPA) with a large number of pixels, which, in general, is very expensive. In a previous paper, we proposed a method for increasing the FOV without increasing the pixel resolution of the FPA by superimposing multiple sub-images within a static scene and disambiguating the observed data to reconstruct the original scene. This technique, in effect, allows each sub-image of the scene to share a single FPA, thereby increasing the FOV without compromising resolution. In this paper, we demonstrate the increase of FOVs in a realistic setting by physically generating a superimposed video from a single scene using an optical system employing a beamsplitter and a movable mirror. Without prior knowledge of the contents of the scene, we are able to disambiguate the two sub-images, successfully capturing both large-scale features and fine details in each sub-image. We improve upon our previous reconstruction approach by allowing each sub-image to have slowly changing components, carefully exploiting correlations between sequential video frames to achieve small mean errors and to reduce run times. We show the effectiveness of this improved approach by reconstructing the constituent images of a surveillance camera video.


Evidence that central sensitisation is present in patients with shoulder impingement syndrome and influences the outcome after surgery.
Impingement syndrome in the shoulder has generally been considered to be a clinical condition of mechanical origin. However, anomalies exist between the pathology in the subacromial space and the degree of pain experienced. These may be explained by variations in the processing of nociceptive inputs between different patients. We investigated the evidence for augmented pain transmission (central sensitisation) in patients with impingement, and the relationship between pre-operative central sensitisation and the outcomes following arthroscopic subacromial decompression. We recruited 17 patients with unilateral impingement of the shoulder and 17 age- and gender-matched controls, all of whom underwent quantitative sensory testing to detect thresholds for mechanical stimuli, distinctions between sharp and blunt punctate stimuli, and heat pain. Additionally Oxford shoulder scores to assess pain and function, and PainDETECT questionnaires to identify 'neuropathic' and referred symptoms were completed. Patients completed these questionnaires pre-operatively and three months post-operatively. A significant proportion of patients awaiting subacromial decompression had referred pain radiating down the arm and had significant hyperalgesia to punctate stimulus of the skin compared with controls (unpaired t-test, p < 0.0001). These are felt to represent peripheral manifestations of augmented central pain processing (central sensitisation). The presence of either hyperalgesia or referred pain pre-operatively resulted in a significantly worse outcome from decompression three months after surgery (unpaired t-test, p = 0.04 and p = 0.005, respectively). These observations confirm the presence of central sensitisation in a proportion of patients with shoulder pain associated with impingement. Also, if patients had relatively high levels of central sensitisation pre-operatively, as indicated by higher levels of punctate hyperalgesia and/or referred pain, the outcome three months after subacromial decompression was significantly worse.


Engagement in Everyday Activities among People Living in Indian Nursing Homes: The Association with Person-Centredness.
It has been reported that residents living in nursing homes are often inactive and lonely and are offered a limited number of activities. However, high engagement in activities has been reported to improve residents' quality of life and engagement in personalized activities can even reduce agitation and enhance positive mood. Information regarding occupational patterns and purpose in life is well established in Western countries. However, we know next to nothing about how people living in Indian nursing homes spend their days. To explore the participation in everyday activities among older people in Indian nursing homes and the extent to which engagement in activities is associated with person-centred care. The study was conducted in 6 nursing homes in India, comprising 147 residents. In all, 23 nursing staff took part and completed a 26-item questionnaire about resident activities based on the Multi-Dimensional Dementia Assessment Scale and the Person-Directed Care Questionnaire. Person-centredness was measured with the Person-Centred Care Assessment Tool. We found low participation in everyday activities among the residents. Participation in religious activities was the most frequent, whereas the least used activities were excursions, participating in cultural activities, taking part in educational programmes, visiting a restaurant and going to the cinema. A significant positive association was found between person-centred care and participation in religious activities, engagement in an activity programme and physical activity. The most frequently attended activity was religious activities. Person-centred care was associated with participation in religious activities, engagement in an activity programme, physical activity, spending time in the garden and playing and listening to music.


IFPA Award in Placentology Lecture: preeclampsia, the decidual battleground and future maternal cardiovascular disease.
The decidua basalis is one of the frontiers between placenta and mother. Its spiral arteries ensure that the placenta and fetus have adequate access to the maternal circulation, without compromising maternal health. Normally this requires a tightly regulated collaboration between tissues of genetically different individuals. But like all frontiers it can become a battlefield. The decidua is difficult to sample systematically. Some of the problems have been resolved by our vacuum suction method. We review the technique and how it has contributed to what we know of decidual tissue, especially when it becomes a battlefield in preeclampsia, with its increased oxidative stress and inflammation. Acute atherosis is a poorly studied decidual lesion of late pregnancy, which mainly affects the decidual tips of spiral arteries in preeclampsia. It is characterized by lipid-filled foam cells and resembles early atherosclerosis. Poorly remodelled spiral arteries seem to be especially susceptible. The underlying mechanisms are largely unknown, but are likely to be similar to those of atherosclerosis and primarily the consequence of vascular inflammation. Acute atherosis also occurs in other pregnancy complications, even in normal pregnancies. It appears not to be confined to maladapted spiral arteries nor be caused by hypertension. It is important that foam cells result from inflammatory stimulation of macrophages. Hence, we propose that decidual inflammation of multiple causes underlies acute atherosis, with or without preeclampsia. Women suffering from preeclampsia have an augmented risk of cardiovascular disease later in life and of premature death. Acute atherosis may more specifically identify those women at augmented risk for such later cardiovascular disorders, whether or not it is associated with preeclampsia.


Prevalence and Trends of Isolated Systolic Hypertension among Korean Adults: the Korea National Health and Nutrition Examination Survey, 1998-2012.
Systolic and diastolic blood pressure may have different effects on cardiovascular disease, but limited data is available for hypertension subtypes in the Korean population. Thus, the prevalence, and absolute number of hypertension subtypes among Korean adults was estimated. The Korea National Health and Nutrition Examination Survey 1998-2012 was used to estimate the prevalence and absolute number of each hypertension subtype among Korean adults aged ≥20 years. Hypertension was classified into four subtypes: treated hypertension (TH), isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and combined systolic and diastolic hypertension (SDH). In 2012, approximately 9.5 million adults were estimated to have hypertension, which consists of 5675671 TH (60.0%), 954253 ISH (10.1%), 1649486 IDH (17.4%), and 1175506 SDH (12.4%). Between 2010 and 2012, the proportion of IDH steadily decreased with age, but ISH increased especially in older ages (≥40). Between 1998 and 2012, TH markedly increased from 1.4 million to 5.7 million while the number of untreated hypertension remained relatively constant. During the same time, the number of hypertensive elderlies increased from 507000 to 2822000 along with rapid ageing of the Korean population. Despite of significant improvement in treatment rate, there are still around 583000 elderlies with untreated hypertension (423000 ISH; 42000 IDH; 118000 SDH) as of 2012. Although the prevalence of hypertension has been constant over the last decades, absolute number of people with hypertension has been increasing. Along with the rapid population ageing, the number of elderly hypertension is increasing and the ISH is also becoming more prevalent.


Proposal for the assessment of quantitative dermal exposure limits in occupational environments: Part 1. Development of a concept to derive a quantitative dermal occupational exposure limit.
Dermal uptake of chemicals at the workplace may contribute considerably to the total internal exposure and so needs to be regulated. At present only qualitative warning signs--the "skin notations"--are available as instruments. An attempt was made to develop a quantitative dermal occupational exposure limit (DOEL) complementary to respiratory occupational exposure limits (OELs). The DOEL refers to the total dose deposited on the skin during a working shift. Based on available data and experience a theoretical procedure for the assessment of a DOEL was developed. A DOEL was derived for cyclophosphamide and 4,4-methylene dianiline (MDA) according to this procedure. The DOEL for MDA was tested for applicability in an actual occupational exposure scenario. An integrated approach is recommended for situations in which both dermal and respiratory exposures contribute considerably to the internal exposure of the worker. The starting point should be an internal health based occupational exposure limit--that is, the maximum dose to be absorbed without leading to adverse systemic effects. The proposed assessment of an external DOEL is then either based on absorption rate or absorption percentage. The estimation of skin penetration seems to be of crucial importance in this concept. If for a specific substance a maximal absorption rate can be estimated a maximal skin surface area to be exposed can be assessed which may then serve the purpose of a DOEL. As long as the actual skin surface exposed is smaller than this maximal skin surface area the internal OEL will not be exceeded, and therefore, no systemic health problems would be expected, independent of the dermal dose/unit area. If not, the DOEL may be interpreted as the product of dermal dose/unit area (mg/cm2) and exposed skin surface area (cm2). The proposed concept for a DOEL is relevant and can be made applicable for health surveillance in the occupational situation where dermal exposure contributes notably to the systemic exposure. Further research should show whether this concept is more generally applicable.


Sexual network drivers of HIV and herpes simplex virus type 2 transmission.
HIV and herpes simplex virus type 2 (HSV-2) infections are sexually transmitted and propagate in sexual networks. Using mathematical modeling, we aimed to quantify effects of key network statistics on infection transmission, and extent to which HSV-2 prevalence can be a proxy of HIV prevalence. An individual-based simulation model was constructed to describe sex partnering and infection transmission, and was parameterized with representative natural history, transmission, and sexual behavior data. Correlations were assessed on model outcomes (HIV/HSV-2 prevalences) and multiple linear regressions were conducted to estimate adjusted associations and effect sizes. HIV prevalence was one-third or less of HSV-2 prevalence. HIV and HSV-2 prevalences were associated with a Spearman's rank correlation coefficient of 0.64 (95% confidence interval: 0.58-0.69). Collinearities among network statistics were detected, most notably between concurrency versus mean and variance of number of partners. Controlling for confounding, unmarried mean/variance of number of partners (or alternatively concurrency) were the strongest predictors of HIV prevalence. Meanwhile, unmarried/married mean/variance of number of partners (or alternatively concurrency), and clustering coefficient were the strongest predictors of HSV-2 prevalence. HSV-2 prevalence was a strong predictor of HIV prevalence by proxying effects of network statistics. Network statistics produced similar and differential effects on HIV/HSV-2 transmission, and explained most of the variation in HIV and HSV-2 prevalences. HIV prevalence reflected primarily mean and variance of number of partners, but HSV-2 prevalence was affected by a range of network statistics. HSV-2 prevalence (as a proxy) can forecast a population's HIV epidemic potential, thereby informing interventions.


18-month outcome of clozapine treatment for 100 patients in a state psychiatric hospital.
The atypical antipsychotic medication clozapine is an effective treatment for refractory psychosis; however, the efficacy of clozapine when used in public mental health programs has yet to be fully characterized. This study assessed the outcome of clozapine treatment in a state hospital. The medical records of the first 100 patients to receive clozapine in a state hospital, from six months before clozapine treatment through 18 months of treatment, were reviewed. The patients had chronic psychotic disorders that had responded poorly to treatment with conventional antipsychotic medication. Eighteen months after beginning clozapine, 45 patients were much improved, and 18 were somewhat improved. All except one of the improved patients were continuing clozapine treatment. Forty patients were living in community settings, 59 remained hospitalized, and one had died of an illness unrelated to clozapine. Violent episodes in the hospital decreased during the first six months of clozapine treatment. Thirteen patients had one or two seizures while taking clozapine, 12 of whom successfully continued clozapine treatment. One patient developed agranulocytosis, and one developed leucopenia; each recovered fully after clozapine treatment was discontinued. Clozapine was an effective treatment for refractory psychotic disorders when given as a part of routine state hospital treatment.


GTP cyclohydrolase I prevents diabetic-impaired endothelial progenitor cells and wound healing by suppressing oxidative stress/thrombospondin-1.
Endothelial progenitor cell (EPC) dysfunction is a key contributor to diabetic refractory wounds. Endothelial nitric oxide synthase (eNOS), which critically regulates the mobilization and function of EPCs, is uncoupled in diabetes due to decreased cofactor tetrahydrobiopterin (BH4). We tested whether GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme of BH4 synthesis, preserves EPC function in type 1 diabetic mice. Type 1 diabetes was induced in wild-type (WT) and GTPCH I transgenic (Tg-GCH) mice by intraperitoneal injection of streptozotocin (STZ). EPCs were isolated from the peripheral blood and bone marrow of WT, Tg-GCH, and GTPCH I-deficient hph-1 mice. The number of EPCs was significantly lower in STZ-WT mice and hph-1 mice and was rescued in STZ Tg-GCH mice. Furthermore, GTPCH I overexpression improved impaired diabetic EPC migration and tube formation. EPCs from WT, Tg-GCH, and STZ-Tg-GCH mice were administered to diabetic excisional wounds and accelerated wound healing significantly, with a concomitant augmentation of angiogenesis. Flow cytometry measurements showed that intracellular nitric oxide (NO) levels were reduced significantly in STZ-WT and hph-1 mice, paralleled by increased superoxide anion levels; both were rescued in STZ-Tg-GCH mice. Western blot analysis revealed that thrombospondin-1 (TSP-1) was significantly upregulated in the EPCs of STZ-WT mice and hph-1 mice and suppressed in STZ-treated Tg-GCH mice. Our results demonstrate that the GTPCH I/BH4 pathway is critical to preserve EPC quantity, function, and regenerative capacity during wound healing in type 1 diabetic mice at least partly through the attenuation of superoxide and TSP-1 levels and augmentation of NO level.


Proteomic and network analysis characterize stage-specific metabolism in Trypanosoma cruzi.
Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of research and published in the literature. We present a validated, constraint-based model of the core metabolism of Trypanosoma cruzi strain CL Brener. The model includes four compartments (extracellular space, cytosol, mitochondrion, glycosome), 51 transport reactions, and 93 metabolic reactions covering carbohydrate, amino acid, and energy metabolism. In addition, we make use of several replicate high-throughput proteomic data sets to specifically examine metabolism of the morphological form of T. cruzi in the insect gut (epimastigote stage). This work demonstrates the utility of constraint-based models for integrating various sources of data (e.g., genomics, primary biochemical literature, proteomics) to generate testable hypotheses. This model represents an approach for the systematic study of T. cruzi metabolism under a wide range of conditions and perturbations, and should eventually aid in the identification of urgently needed novel chemotherapeutic targets.


Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins.
Margit Fischer reported in 1971 that the risk of schizophrenia in the offspring of her Danish schizophrenic monozygotic twins and their normal cotwins was equal and not different from the risks in the children of schizophrenics in the literature. All of her identical and fraternal twins who had children and all of their offspring have been followed up through the Danish National Psychiatric Register as of 1985, some 18 years after study by Fischer. The morbid risk (age-corrected) for schizophrenia and schizophrenia-related disorders in the offspring of schizophrenic identical twins is 16.8%; it is 17.4% in their normal cotwins' offspring. The risks in the offspring of schizophrenic fraternal twins and their normal cotwins are 17.4% and 2.1%, respectively. The results suggest that discordance in identical twins may primarily be explained by the capacity of a schizophrenic genotype or diathesis to be unexpressed unless it is released by some kinds of environmental, including nonfamilial, stressors. Sporadic cases and phenocopies caused by cerebral abnormalities, diseases, or viruses would thus be deemphasized as necessary or sufficient explanatory causes for schizophrenia in our study but could account for some of the remaining discordance, infrequent phenocopies should encourage linkage researchers, but unexpression of genotypes will frustrate them.


Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase.
Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr(1472) on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.


Maximizing exosome colloidal stability following electroporation.
Development of exosome-based semisynthetic nanovesicles for diagnostic and therapeutic purposes requires novel approaches to load exosomes with cargo. Electroporation has previously been used to load exosomes with RNA. However, investigations into exosome colloidal stability following electroporation have not been considered. Herein, we report the development of a unique trehalose pulse media (TPM) that minimizes exosome aggregation following electroporation. Dynamic light scattering (DLS) and RNA absorbance were employed to determine the extent of exosome aggregation and electroextraction post electroporation in TPM compared to common PBS pulse media or sucrose pulse media (SPM). Use of TPM to disaggregate melanoma exosomes post electroporation was dependent on both exosome concentration and electric field strength. TPM maximized exosome dispersal post electroporation for both homogenous B16 melanoma and heterogeneous human serum-derived populations of exosomes. Moreover, TPM enabled heavy cargo loading of melanoma exosomes with 5nm superparamagnetic iron oxide nanoparticles (SPION5) while maintaining original exosome size and minimizing exosome aggregation as evidenced by transmission electron microscopy. Loading exosomes with SPION5 increased exosome density on sucrose gradients. This provides a simple, label-free means of enriching exogenously modified exosomes and introduces the potential for MRI-driven theranostic exosome investigations in vivo.


Is there Complex Trauma Experience typology for Australian's experiencing extreme social disadvantage and low housing stability?
Traumatic childhood experiences predict many adverse outcomes in adulthood including Complex-PTSD. Understanding complex trauma within socially disadvantaged populations has important implications for policy development and intervention implementation. This paper examined the nature of complex trauma experienced by disadvantaged individuals using a latent class analysis (LCA) approach. Data were collected through the large-scale Journeys Home Study (N=1682), utilising a representative sample of individuals experiencing low housing stability. Data on adverse childhood experiences, adulthood interpersonal trauma and relevant covariates were collected through interviews at baseline (Wave 1). Latent class analysis (LCA) was conducted to identify distinct classes of childhood trauma history, which included physical assault, neglect, and sexual abuse. Multinomial logistic regression investigated childhood relevant factors associated with class membership such as biological relationship of primary carer at age 14 years and number of times in foster care. Of the total sample (N=1682), 99% reported traumatic adverse childhood experiences. The most common included witnessing of violence, threat/experience of physical abuse, and sexual assault. LCA identified six distinct childhood trauma history classes including high violence and multiple traumas. Significant covariate differences between classes included: gender, biological relationship of primary carer at age 14 years, and time in foster care. Identification of six distinct childhood trauma history profiles suggests there might be unique treatment implications for individuals living in extreme social disadvantage. Further research is required to examine the relationship between these classes of experience, consequent impact on adulthood engagement, and future transitions though homelessness.


Methods and design of the Chennai Glaucoma Study.
To describe the methodology of a population-based study to estimate the prevalence of glaucoma in a rural and urban South Indian population and to study the genetics of glaucoma in this population. A sample size of 4758 each for rural and urban populations in the Indian state of Tamil Nadu was calculated. Eligible subjects aged 40 years and above from the rural study area covering 32 contiguous villages and the urban area comprising five random clusters in Chennai city are enumerated. Demographic data are collected in the field. A detailed clinical examination, including glaucoma diagnostic procedures, is conducted at the examination centre. Pedigree ascertainment and genetic studies are performed for subjects with occludable angles or glaucoma. Data are recorded in a computerised database. This study is expected to result in an estimation of the prevalence and a better understanding of the genetics of glaucoma in this region.


Cost Effectiveness of Paliperidone Long-Acting Injectable Versus Other Antipsychotics for the Maintenance Treatment of Schizophrenia in France.
French clinical recommendations suggest prescribing long-acting injectable (LAI) antipsychotics to patients with a maintenance treatment indication in schizophrenia. Despite this, and due to their relatively high acquisition and administration costs, LAIs are still underused in clinical practice in France, thus highlighting the need for pharmacoeconomic evaluations. Our objective was to estimate the cost effectiveness of paliperidone LAI (or paliperidone palmitate), a once-monthly second-generation LAI antipsychotic, compared with the most common antipsychotic medications for the maintenance treatment of schizophrenia in France. A Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and to consider up to three lines of treatment to account for changes in treatment management. Paliperidone LAI was compared with risperidone LAI, aripiprazole LAI, olanzapine LAI, haloperidol LAI (or haloperidol decanoate) and oral olanzapine. Costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over 5 years based on 3-month cycles with a discount rate of 4% and from a French health insurance perspective. Patients were considered to be stabilised after a schizophrenic episode and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on real-life French data to capture adherence effects. Safety and utility data were derived from international publications. Additionally, costs were retrieved from French health insurance databases and publications. Finally, expert opinion was used for validation purposes or in case of gaps in data. The robustness of results was assessed through deterministic and probabilistic sensitivity analyses. All LAI antipsychotics were found to have similar costs over 5 years: approximatively €55,000, except for paliperidone LAI which had a discounted cost of €50,880. Oral olanzapine was less costly than LAIs (i.e. €50,379 after 5 years) but was associated with fewer QALYs gained and relapses avoided. Paliperidone LAI dominated aripiprazole LAI, olanzapine LAI and haloperidol LAI in terms of costs per QALY, and it was associated with slightly fewer QALYs when compared with risperidone LAI (i.e. 3.763 vs 3.764). This resulted in a high incremental cost-effectiveness ratio (ICER) (i.e. €4,770,018 per QALY gained) for risperidone LAI compared with paliperidone LAI. Paliperidone LAI was more costly than olanzapine oral but associated with more QALYs (i.e. ICER of €2411 per QALY gained for paliperidone LAI compared with oral olanzapine). Paliperidone LAI had a probability of being the optimal strategy in more than 50% of cases for a willingness-to-pay threshold of €8000 per QALY gained. This analysis, to the best of our knowledge, is the first of its kind to assess the cost effectiveness of antipsychotics based on French observational data. Paliperidone LAI appeared to be a cost-effective option in the treatment of schizophrenia from the French health insurance perspective.


Evaluation of 3 T pelvic MRI imaging in prostate cancer patients receiving post-prostatectomy IMRT.
The purpose of the study was to evaluate the utility of a 3 T pelvic magnetic resonance imaging (MRI) in detecting a local recurrence in post-prostatectomy prostate cancer patients prior to receiving adjuvant or salvage intensity-modulated radiation therapy (IMRT). Ninety prostate cancer patients status post-prostatectomy with rising prostate-specific antigen (PSA) had a 3 T pelvic MRI prior to IMRT. The following variables were analyzed for predicting positive findings on MRI: initial presenting and initial post-op PSA, PSA at the time of imaging, PSA velocity, surgical margins, Gleason score, pathological stage, pre-RT digital rectal examination, and type of surgical prostatectomy. The only significant variable predictive of a positive MRI was positive margins. Specifically, 15 of 46 (33 %) patients with positive margins had a positive MRI, while 5 of 44 (11 %) patients with negative margins had a positive MRI. In the MRI positive group, the location of the positive findings on MRI corresponded with the pathology report in 9 of 12 (75 %) cases. Post-prostatectomy patients with pathologic positive margins are three times more likely to have positive findings on a 3 T MRI.


Worth a quick look? Initial scene previews can guide eye movements as a function of domain-specific expertise but can also have unforeseen costs.
Rapid scene recognition is a global visual process we can all exploit to guide search. This ability is thought to underpin expertise in medical image perception yet there is no direct evidence that isolates the expertise-specific contribution of processing scene previews on subsequent eye movement performance. We used the flash-preview moving window paradigm (Castelhano & Henderson, 2007) to investigate this issue. Expert radiologists and novice observers underwent 2 experiments whereby participants viewed a 250-ms scene preview or a mask before searching for a target. Observers looked for everyday objects from real-world scenes (Experiment 1), and searched for lung nodules from medical images (Experiment 2). Both expertise groups exploited the brief preview of the upcoming scene to more efficiently guide windowed search in Experiment 1, but there was only a weak effect of domain-specific expertise in Experiment 2, with experts showing small improvements in search metrics with scene previews. Expert diagnostic performance was better than novices in all conditions but was not contingent on seeing the scene preview, and scene preview actually impaired novice diagnostic performance. Experiment 3 required novice and experienced observers to search for a variety of abnormalities from different medical images. Rather than maximizing the expertise-specific advantage of processing scene previews, both novices and experienced radiographers were worse at detecting abnormalities with scene previews. We discuss how restricting access to the initial glimpse can be compensated for by subsequent search and discovery processing, but there can still be costs in integrating a fleeting glimpse of a medical scene. (PsycINFO Database Record


Bioenergetic and kinematic consequences of limblessness in larval Diptera.
We report the cost of transport and kinematics of terrestrial locomotion by larval blowflies (Protophormia terraenovae, Diptera: Calliphoridae). We contrast inter- and intra-individual methods for estimating minimum cost of transport (MCOT) and the relationship between speed, contraction frequency and distance traveled per contraction. The minimum cost of transport calculated from intra-individual data is 2297 +/- 317 J kg-1 m-1 (S.E.M.) and the MCOT calculated from inter-individual comparisons is statistically indistinguishable at 1910 +/- 327 J kg-1 m-1. These values are almost ten times higher than the predicted value for a similar-sized limbed arthropod. Fly larvae travel by repeated peristaltic contractions and individual contractions cost about the same amount as individual strides in limbed insects. Both contraction frequency and distance traveled per contraction increase linearly with speed. Doubling the contraction frequency or the distance traveled per contraction approximately doubles speed. The cost of transport in fly larvae is among the highest recorded for terrestrial locomotion, confirming the suggestion that biomechanical and kinematic properties of limbless organisms with hydraulic skeletons lead to very high costs of transport.


Angiotensin converting enzyme inhibitors and hepatocellular carcinoma incidence in the General Practice Research Database.
Laboratory findings demonstrate anticancer effects of angiotensin converting enzyme (ACE) inhibitors, including anti-angiogenic activity and inhibition of liver cancer growth in rodent models. Small studies in humans indicate potential for therapeutic anticancer effects and warrant further larger studies. A case-control study using the General Practice Research Database examined whether prior ACE inhibitor usage was associated with a reduction in incidence of hepatocellular carcinoma (HCC). Two hundred twenty-four HCC cases were identified, each matched to up to 10 controls by age, sex, and general practice. The data show that HCC is associated with a small, nonsignificant increase in prior use of ACE inhibitors (OR = 1.16, CI = 0.67-2.00). ACE inhibitor use was 7.1% (of 224) in cases and 5.9% (of 2,313) in controls. No significant effects were found when investigating the effect of dose and exposure duration. We found no clear protective effect of ever or long term use of ACE inhibitors against the development of HCC. Our study suggests that it is unlikely that this class of drugs will be a clinically useful cancer chemoprevention therapy.


Diminished renal function and the incidence of heart failure.
Heart failure is one of the most common, costly, disabling and deadly diseases. During the last decade, several different indices reflecting renal function such as creatinine-based glomerular filtration rate, circulating levels of cystatin C and low-grade albuminuria have been demonstrated to be independent risk factors for heart failure. This review summarizes our current knowledge of the relationship between diminished renal function and the incidence of heart failure in the community, and also in individuals with increased risk of heart failure such as patients with overt cardiovascular disease, hypertension or diabetes. This review will also put forward important areas of future research in this field.


The influence of Community Access to Child Health (CATCH) program on community pediatrics.
The CATCH (Community Access to Child Health) Program, which supports pediatricians who engage with the community to improve child health, increase access to health care, and promote advocacy through small seed grants, was last evaluated in 1998. The objective was to describe the characteristics of CATCH grant recipients and projects and assess the community impact of funded projects. Prospective data was collected from CATCH applications (grantee characteristics, topic area and target population for projects funded from 2006-2012) and post-project 2-year follow-up survey (project outcomes, sustainability, and impact for projects funded from 2008 through 2010). From 2006 through 2012, the CATCH Program awarded 401 projects to grantees working mostly in general pediatrics. Eighty-five percent of projects targeted children covered by Medicaid, 33% targeted uninsured children, and 75% involved a Latino population. Main topic areas addressed were nutrition, access to health care, and medical home. Sixty-nine percent of grantees from 2008 to 2010 responded to the follow-up survey. Ninety percent reported completing their projects, and 86% of those projects continued to exist in some form. Grantees reported the development of community partnerships (77%) and enhanced recognition of child health issues in the community (73%) as the most frequent changes due to the projects. The CATCH Program funds community-based projects led by pediatricians that address the medical home and access to care. A majority of these projects and community partnerships are sustained beyond their original CATCH funding and, in many cases, are leveraged into additional financial or other community support.


Highly efficient full-length hepatitis C virus genotype 1 (strain TN) infectious culture system.
Chronic infection with hepatitis C virus (HCV) is an important cause of end stage liver disease worldwide. In the United States, most HCV-related disease is associated with genotype 1 infection, which remains difficult to treat. Drug and vaccine development was hampered by inability to culture patient isolates representing HCV genotypes 1-7 and subtypes; only a recombinant 2a genome (strain JFH1) spontaneously replicated in vitro. Recently, we identified three mutations F1464L/A1672S/D2979G (LSG) in the nonstructural (NS) proteins, essential for development of full-length HCV 2a (J6) and 2b (J8) culture systems in Huh7.5 cells. Here, we developed a highly efficient genotype 1a (strain TN) full-length culture system. We initially found that the LSG substitutions conferred viability to an intergenotypic recombinant composed of TN 5' untranslated region (5'UTR)-NS5A and JFH1 NS5B-3'UTR; recovered viruses acquired two adaptive mutations located in NS3 and NS4B. Introduction of these changes into a replication-deficient TN full-length genome, harboring LSG, permitted efficient HCV production. Additional identified NS4B and NS5B mutations fully adapted the TN full-length virus. Thus, a TN genome with 8 changes (designated TN cell-culture derived, TNcc) replicated efficiently and released infectious particles of ∼5 log(10) focus-forming units per mL; passaged TNcc did not require additional changes. IFN-α and directly acting antivirals targeting the HCV protease, NS5A, and NS5B, each inhibited full-length TN infection dose-dependently. Given the unique importance of genotype 1 for pathogenesis, this infectious 1a culture system represents an important advance in HCV research. The approach used and the mutations identified might permit culture development for other HCV isolates, thus facilitating vaccine development and personalized treatment.


Atmospheric dispersion compensation for extremely large telescopes.
Achieving diffraction limited imaging with future ground-based optical telescopes will require adaptive optics for correction of atmospheric turbulence and also efficient techniques for atmospheric dispersion compensation. We study the benefit of using a linear atmospheric dispersion corrector (ADC) coupled with a deformable mirror on a 42-m Extremely Large Telescope (ELT) operating in the VIRJ spectral bands. The ADC design consists of two identical thin wedges made of F5 glass. The amount of dispersion introduced by the ADC is adjusted by translating one of the wedges along the optical axis so that it always cancels atmospheric dispersion as it varies with telescope elevation. We show that the ADC working in conjunction with a deformable mirror provides diffraction-limited image quality over a 1-arcmin field.


Inferior Breast-Chest Contour Detection in 3-D Images of the Female Torso.
Stereophotogrammetry is finding increased use in clinical breast surgery, both for breast reconstruction after oncological procedures and cosmetic augmentation and reduction. The ability to visualize and quantify morphological features of the breast facilitates pre-operative planning and post-operative outcome assessment. The contour outlining the lower half of the breast is important for the quantitative assessment of breast aesthetics. Based on this inferior breast contour, relevant morphological measures, such as breast symmetry, volume, and ptosis, can be determined. In this paper, we present an approach for automatically detecting the inferior contour of the breast in 3D images. Our approach employs surface curvature analysis and is able to detect the breast contour with high accuracy, achieving an average error of 1.64 mm and a dice coefficient in the range of 0.72-0.87 when compared with the manually annotated contour (ground truth). In addition, the detected contour is used to facilitate the detection of the lowest visible point on the breast, which is an important landmark for breast morphometric analysis.


MaxAlign: maximizing usable data in an alignment.
The presence of gaps in an alignment of nucleotide or protein sequences is often an inconvenience for bioinformatical studies. In phylogenetic and other analyses, for instance, gapped columns are often discarded entirely from the alignment. MaxAlign is a program that optimizes the alignment prior to such analyses. Specifically, it maximizes the number of nucleotide (or amino acid) symbols that are present in gap-free columns - the alignment area - by selecting the optimal subset of sequences to exclude from the alignment. MaxAlign can be used prior to phylogenetic and bioinformatical analyses as well as in other situations where this form of alignment improvement is useful. In this work we test MaxAlign's performance in these tasks and compare the accuracy of phylogenetic estimates including and excluding gapped columns from the analysis, with and without processing with MaxAlign. In this paper we also introduce a new simple measure of tree similarity, Normalized Symmetric Similarity (NSS) that we consider useful for comparing tree topologies. We demonstrate how MaxAlign is helpful in detecting misaligned or defective sequences without requiring manual inspection. We also show that it is not advisable to exclude gapped columns from phylogenetic analyses unless MaxAlign is used first. Finally, we find that the sequences removed by MaxAlign from an alignment tend to be those that would otherwise be associated with low phylogenetic accuracy, and that the presence of gaps in any given sequence does not seem to disturb the phylogenetic estimates of other sequences. The MaxAlign web-server is freely available online at http://www.cbs.dtu.dk/services/MaxAlign where supplementary information can also be found. The program is also freely available as a Perl stand-alone package.


First Report of Fusarium commune Causing Damping-off, Seed Rot, and Seedling Root Rot on Soybean (Glycine max) in the United States.
During 2007 to 2009, symptomatic and asymptomatic soybean plants were collected from fields in 18 Iowa counties. Fusarium isolates were recovered from surface-sterilized root tissue on peptone PCNB agar (2). Single-spore isolates were transferred to synthetic low nutrient agar (SNA) overlain with pieces (1 × 2 cm) of sterile filter paper, and to potato dextrose agar (PDA), and placed in the dark for 10 to 14 days for morphological identification (4). Twenty-three isolates were identified as Fusarium commune K. Skovg., O'Donnell & Nirenberg, previously in the F. oxysporum species complex (4). Colonies on PDA had white, fluffy, aerial mycelium with magenta to violet pigmentation in the medium. On SNA, macroconidia, chlamydospores, and microconidia on monophialides and polyphialides were consistent with the species description (4). Identification of all 23 isolates was confirmed by DNA sequencing of the translation elongation factor (EF1-α) gene, using ef1 and ef2 primers, and the mitochondrial small subunit (mtSSU), using primers MS1 and MS2 (4) [GenBank accessions for two representative isolates: EF1-α (JX289892 and JX289893), and mtSSU (JX289894 and, JX289895)]. Pathogenicity of two representative isolates of F. commune was tested on soybean (cv. AG2403) in a greenhouse, in water baths set at 18°C, using autoclaved soil mixed with infested sand-cornmeal inoculum (3). The experiment entailed a completely randomized design (CRD) with five replications (single plant/150 ml cone) per treatment, and was conducted three times. Dry root and shoot weights, and root rot severity (visual estimate of percent root rot on the entire root system) were evaluated after 6 weeks. Mean seedling emergence in soil infested with F. commune was 47 and 40% for the two isolates; in contrast, non-inoculated control plants had 100% emergence. There were significant differences in root (P < 0.0001) and shoot (P < 0.0001) weights, and root rot severity (P < 0.0001), between inoculated and non-inoculated plants. Seedlings that emerged were severely stunted and had dark brown lesions. F. commune was reisolated from infected roots of inoculated plants, but not from non-inoculated plants. Pathogenicity of both isolates to soybean (cv. MN1805) was also tested using a petri dish assay, in which eight seeds were placed on a plate with a 4-day-old culture growing on 2% water agar (1). Plates were rated 7 days later for seed germination, seed rot, and lesion development, using an ordinal scale (1). The experiment entailed a CRD with three replicate plates/treatment, and was conducted three times. Germination of inoculated seeds ranged from 37.5 to 75.0%, and germinated seedlings had dark brown lesions on the taproots. There was a significant difference between isolates in the petri dish assay (P = 0.0030); one isolate was less aggressive, but both isolates resulted in significantly more disease than on the non-inoculated control plants, which had 100% germination and no symptoms (P < 0.0001). F. oxysporum is a known soybean pathogen (1), but isolates of F. commune may have been misidentified as F. oxysporum in previous studies. To our knowledge, this is the first report of F. commune as a pathogen on soybean in the U.S.A. References: (1) K. E. Broders et al. Plant Dis. 91:727, 2007. (2) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Oxford, UK, 2006. (3) G. P. Munkvold and J. K. O'Mara. Plant Dis. 86:143, 2002. (4) K. Skovgaard et al. Mycologia. 94:630, 2003.


Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells.
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem among breast cancer patients. Previously, we have reported that TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) showed increased angiogenic intensity through Pin1-dependent vascular endothelial growth factor (VEGF) production. Among six flavonoids tested in the current study, VEGF gene transcription in MCF-7 cells with stable Pin1 overexpression was inhibited most effectively by quercetin. Reporter gene assays using minimal reporters containing hypoxia response elements and activator protein-1 (AP-1) elements revealed that the activities of hypoxia inducible factor-1α (HIF-1α) and AP-1, key transcription factors for VEGF gene transcription, were suppressed by quercetin. Western blot analyses confirmed that the increased nuclear levels of c-Jun and HIF-1α in TAMR-MCF-7 cells were blocked by quercetin. Moreover, quercetin inhibited the enhanced VEGF secretion and Pin1 expression in TAMR-MCF-7 cells, which was dependent on its phosphatidyl inositol 3-kinase inhibiting effect. Chick chorioallantoic membrane assays demonstrated that the enhanced angiogenesis intensity of TAMR-MCF-7 cells was also suppressed significantly by quercetin. These results demonstrate that quercetin may have therapeutic potential for the treatment of TAM-resistant breast cancer via Pin1 inhibition.


Nanobiosensing with graphene and carbon quantum dots: Recent advances.
Graphene and carbon quantum dots (GQDs and CQDs) are relatively new nanomaterials that have demonstrated impact in multiple different fields thanks to their unique quantum properties and excellent biocompatibility. Biosensing, analyte detection and monitoring wherein a key feature is coupled molecular recognition and signal transduction, is one such field that is being greatly advanced by the use of GQDs and CQDs. In this review, recent progress on the development of biotransducers and biosensors enabled by the creative use of GQDs and CQDs is reviewed, with special emphasis on how these materials specifically interface with biomolecules to improve overall analyte detection. This review also introduces nano-enabled biotransducers and different biosensing configurations and strategies, as well as highlights key properties of GQDs and CQDs that are pertinent to functional biotransducer design. Following relevant introductory material, the literature is surveyed with emphasis on work performed over the last 5 years. General comments and suggestions to advance the direction and potential of the field are included throughout the review. The strategic purpose is to inspire and guide future investigations into biosensor design for quality and safety, as well as serve as a primer for developing GQD- and CQD-based biosensors.


Synaesthetic colour in the brain: beyond colour areas. A functional magnetic resonance imaging study of synaesthetes and matched controls.
In synaesthesia, sensations in a particular modality cause additional experiences in a second, unstimulated modality (e.g., letters elicit colour). Understanding how synaesthesia is mediated in the brain can help to understand normal processes of perceptual awareness and multisensory integration. In several neuroimaging studies, enhanced brain activity for grapheme-colour synaesthesia has been found in ventral-occipital areas that are also involved in real colour processing. Our question was whether the neural correlates of synaesthetically induced colour and real colour experience are truly shared. First, in a free viewing functional magnetic resonance imaging (fMRI) experiment, we located main effects of synaesthesia in left superior parietal lobule and in colour related areas. In the left superior parietal lobe, individual differences between synaesthetes (projector-associator distinction) also influenced brain activity, confirming the importance of the left superior parietal lobe for synaesthesia. Next, we applied a repetition suppression paradigm in fMRI, in which a decrease in the BOLD (blood-oxygenated-level-dependent) response is generally observed for repeated stimuli. We hypothesized that synaesthetically induced colours would lead to a reduction in BOLD response for subsequently presented real colours, if the neural correlates were overlapping. We did find BOLD suppression effects induced by synaesthesia, but not within the colour areas. Because synaesthetically induced colours were not able to suppress BOLD effects for real colour, we conclude that the neural correlates of synaesthetic colour experience and real colour experience are not fully shared. We propose that synaesthetic colour experiences are mediated by higher-order visual pathways that lie beyond the scope of classical, ventral-occipital visual areas. Feedback from these areas, in which the left parietal cortex is likely to play an important role, may induce V4 activation and the percept of synaesthetic colour.


A new piece of the Shigella Pathogenicity puzzle: spermidine accumulation by silencing of the speG gene [corrected].
The genome of Shigella, a gram negative bacterium which is the causative agent of bacillary dysentery, shares strong homologies with that of its commensal ancestor, Escherichia coli. The acquisition, by lateral gene transfer, of a large plasmid carrying virulence determinants has been a crucial event in the evolution towards the pathogenic lifestyle and has been paralleled by the occurrence of mutations affecting genes, which negatively interfere with the expression of virulence factors. In this context, we have analysed to what extent the presence of the plasmid-encoded virF gene, the major activator of the Shigella regulon for invasive phenotype, has modified the transcriptional profile of E. coli. Combining results from transcriptome assays and comparative genome analyses we show that in E. coli VirF, besides being able to up-regulate several chromosomal genes, which potentially influence bacterial fitness within the host, also activates genes which have been lost by Shigella. We have focused our attention on the speG gene, which encodes spermidine acetyltransferase, an enzyme catalysing the conversion of spermidine into the physiologically inert acetylspermidine, since recent evidence stresses the involvement of polyamines in microbial pathogenesis. Through identification of diverse mutations, which prevent expression of a functional SpeG protein, we show that the speG gene has been silenced by convergent evolution and that its inactivation causes the marked increase of intracellular spermidine in all Shigella spp. This enhances the survival of Shigella under oxidative stress and allows it to better face the adverse conditions it encounters inside macrophage. This is supported by the outcome of infection assays performed in mouse peritoneal macrophages and of a competitive-infection assay on J774 macrophage cell culture. Our observations fully support the pathoadaptive nature of speG inactivation in Shigella and reveal that the accumulation of spermidine is a key determinant in the pathogenicity strategy adopted by this microrganism.


Promoting mental health recovery and improving clinical assessment using video technology.
Although individuals with medical problems (e.g., diabetes, hypertension) can monitor their symptoms using objective measures (e.g., blood glucose, blood pressure), objective measures are not typically used by individuals with psychotic disorders to monitor symptoms of mental illness. To examine the benefits and limitations of the use of video self-observation for treatment of individuals with psychotic disorders. The authors reviewed studies examining video self-observation among individuals with severe mental illnesses. Individuals with psychotic disorders who viewed videos of themselves while symptomatic reported some benefit to this approach, with 1 study showing sustained improvement in understanding of mental illness. Still, some individuals reported negative feelings about the process, and also attributed symptoms to stress or drug abuse rather than their psychotic disorder. The authors found no studies examining the potential for video self-observation as a strategy to improve clinical decision-making in the context of mental health care. Implications of this approach for mental health recovery and clinical practice are discussed. (PsycINFO Database Record


Self-efficacy and self-esteem as predictors of participation in spinal cord injury--an ICF-based study.
A multi-centre cross-sectional study. To examine the relationship of self-efficacy and self-esteem with participation of persons with spinal cord injury (SCI) from a comprehensive bio-psycho-social perspective, based on the conceptual framework of the International Classification of Functioning, Disability and Health (ICF). Community-dwelling participants, <5 years post discharge, recruited through three SCI rehabilitation centers in Switzerland. Data were collected by means of standardized self-report questionnaires sent to the eligible participants by postal mail. The questionnaires covered the different components of the ICF's bio-psycho-social model, namely health conditions, body functions, participation, environmental and personal factors. Bivariate correlations and multivariate linear regression analyses with participation as the dependent variable have been conducted. In all, 102 persons with SCI answered the survey, response rate 25.9%. Self-esteem (r=0.61) and self-efficacy (r=0.54) correlated highly with participation and were the strongest correlates of participation. They were stronger correlates of participation than symptoms of anxiety, depressive symptoms, pain, health conditions, social support, coping styles or sense of coherence. Participation seemed to be independent of gender, age, level or completeness of injury. Self-efficacy and self-esteem explained together with time since discharge and years of education 48% of the variance in participation adjusting for health condition, depressive symptoms, pain interference and social support. Considering self-efficacy and self-esteem within the comprehensive framework of the ICF can contribute to a better understanding of functioning, disability and health in SCI, which in turn may facilitate the development of interventions to support the persons' adjustment and reintegration.


L-Asparaginase and inhibitors of glutamine synthetase disclose glutamine addiction of β-catenin-mutated human hepatocellular carcinoma cells.
Selected oncogenic mutations support unregulated growth enhancing glutamine availability but increasing the dependence of tumor cells on the amino acid. Data from literature indicate that a subset of HepatoCellular Carcinomas (HCC) is characterized by mutations of β-catenin and overexpression of Glutamine Synthetase (GS). To assess if this phenotype may constitute an example of glutamine addiction, we treated four human HCC lines with the enzyme L-Asparaginase (ASNase), a glutaminolytic drug. ASNase had a significant antiproliferative effect only in the β-catenin mutated HepG2 cells, which were partially rescued by the anaplerotic intermediates pyruvate and α-ketoglutarate. The enzyme severely depleted cell glutamine, caused eIF2α phosphorylation, inhibited mTOR activity, and increased autophagy in both HepG2 and in the β-catenin wild type cell line Huh-7. When used with ASNase, the GS inhibitor methionine sulfoximine (MSO) emptied cell glutamine pool, arresting proliferation in ASNase-insensitive Huh-7 cells and activating caspase-3 and apoptosis in HepG2 cells. Compared with Huh-7 cells, HepG2 cells accumulated much higher levels of glutamine and MSO, due to the higher expression and activity of SNAT2, a concentrative transporter for neutral amino acids, but were much more sensitive to glutamine withdrawal from the medium. In the presence of ASNase, MSO caused a paradoxical maintenance of rapamycin-sensitive mTOR activity in both HepG2 and Huh-7 cells. β-catenin silencing lowered ASNase sensitivity of HepG2 cells and of Huh-6 cells, another β-catenin-mutated cell line, which also exhibited high sensitivity to ASNase. Thus, β-catenin mutated HCC cells are more sensitive to glutamine depletion and accumulate higher levels of GS inhibitors. These results indicate that glutamine deprivation may constitute a targeted therapy for β-catenin-mutated HCC cells addicted to the amino acid.


Dosimetry of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 - impact on the feasibility of insulinoma internal radiotherapy.
[(68)Ga]-DO3A-VS-Cys(40)-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the (177)Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses.


Minor depression and physical outcome trajectories in heart failure and pulmonary disease.
We examined conjoint trajectories of depression-physical illness outcomes in elderly inpatients with minor depression and heart failure or pulmonary disease, and identified demographic, psychosocial, physical, and treatment predictors of trajectory. Consecutively admitted patients over age 50 with heart failure and/or chronic pulmonary disease were screened for minor depression using the Structured Clinical Interview for Depression. Follow-up evaluations were performed at 6 and 12 weeks using the Longitudinal Interview Follow-Up Evaluation, Hamilton Depression Scale, and Chronic Heart Failure-Chronic Respiratory Disease Questionnaire. Patients were placed into four depression-physical illness outcome trajectories: (T#1) depression better, illness better; (T#2) depression better, illness same; (T#3) depression same, illness better; and (T#4) depression same, illness same. Bivariate and multivariate predictors were examined. Minor depression was identified in 587 patients. Of these, 487 were evaluated at 6 weeks and 444 at 12 weeks. By 6 weeks, 39.4% of patients improved both on depression and physical illness (T#1), and 27.3% improved on neither (T#4). By 12 weeks, 49.6% had improved on both and 20.5% on neither. Race, admitting hospital, past psychiatric history, family psychiatric history, comorbid physical illnesses, and antidepressant drug treatment independently predicted outcome trajectory. Improvements in depression and physical illness track closely together in elderly inpatients with heart failure or pulmonary disease. Baseline patient characteristics predict which outcome trajectory they are likely to follow after hospital discharge, and may be useful in diagnosis and management.


IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques.
Human immunodeficiency virus (HIV) infection is characterized by a progressive loss of memory CD4(+) T cells in multiple tissues, especially at mucosal surfaces where most of these cells reside. Although antiretroviral therapy (ART) suppresses viral replication and promotes the recovery of peripheral CD4(+) T cells, HIV-infected patients fail to fully reconstitute the CD4(+) T-cell pool at mucosal sites. IL-15 has been shown to preferentially expand memory-phenotype T cells and promote their migration to nonlymphoid tissues. Here we examined IL-15 treatment in combination with highly active ART in chronically SIV-infected rhesus macaques and found that IL-15 delayed viral suppression and failed to enhance ART-induced total and antigen-specific CD4(+) T-cell reconstitution at mucosal and lymphoid sites. IL-15 was able to induce the transient proliferation of SIV-specific, CMV-specific, and total memory CD8(+) T cells, but not of SIV-specific or total CD4(+) T cells. Moreover, upon treatment interruption, macaques receiving combined IL-15+ART lost CD4(+) T cells faster than those receiving ART alone. These results suggest that the combination of IL-15 with highly active ART is not more efficient than ART alone in promoting CD4(+) T-cell recovery in HIV-infected individuals and may accelerate CD4+ T-cell loss after treatment interruption.


High-resolution three-dimensional structure of a single zinc finger from a human enhancer binding protein in solution.
The three-dimensional structure of a 30-residue synthetic peptide containing the carboxy-terminal "zinc finger" motif of a human enhancer binding protein has been determined by two-dimensional nuclear magnetic resonance (2D NMR) spectroscopy and hybrid distance geometry-dynamical simulated annealing calculations. The structure determination is based on 487 approximate interproton distance and 63 torsion angle (phi, psi, and chi 1) restraints. A total of 40 simulated annealing structures were calculated, and the atomic rms distribution about the mean coordinate positions (excluding residues 29 and 30 which are ill-defined) is 0.4 A for the backbone atoms, 0.8 A for all atoms, and 0.41 A for all atoms excluding the lysine and arginine side chains, which are disordered. The solution structure of the zinc finger consists of two irregular antiparallel beta-strands connected by an atypical turn (residues 3-12) and a classical alpha-helix (residues 14-24). The zinc is tetrahedrally coordinated to the sulfur atoms of two cysteines (Cys-5 and Cys-8) and to the N epsilon 2 atoms of two histidines (His-21 and His-27). The two cysteine residues are located in the turn connecting the two beta-strands (residues 5-8); one of the histidine ligands (His-21) is in the alpha-helix, while the second histidine (His-27) is at the end of a looplike structure (formed by the end of the alpha-helix and a turn). The general architecture is qualitatively similar to two previously determined low-resolution Cys2-His2 zinc finger structures, although distinct differences can be observed in the beta-strands and turn and in the region around the two histidines coordinated to zinc. Comparison of the overall polypeptide fold of the enhancer binding protein zinc finger with known structures in the crystallographic data base reveals a striking similarity to one region (residues 23-44) of the X-ray structure of proteinase inhibitor domain III of Japanese quail ovomucoid [Papamokos, E., Weber, E., Bode, W., Huber, R., Empie, M. W., Kato, I., & Laskowski, M. (1982) J. Mol. Biol. 158, 515-537], which could be superimposed with a backbone atomic rms difference of 0.95 A on residues 3-25 (excluding residue 6) of the zinc finger from the enhancer binding protein. The presence of structural homology between two proteins of very different function may indicate that the so-called zinc finger motif is not unique for a class of DNA binding proteins but may represent a general folding motif found in a variety of proteins irrespective of their function.


Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression.
Treatment with curcumin attenuated modeled microgravity-induced bone loss, possibly through abating oxidative stress and activating vitamin D receptor. Curcumin might be an effective countermeasure for microgravity-induced bone loss but remains to be tested in humans. Bone loss is one of the most important complications for human crewmembers who are exposed to long-term microgravity in space and also for bedridden people. The aim of the current study was to elucidate whether treatment with curcumin attenuated bone loss induced by microgravity. We used hind-limb suspension (HLS) and rotary wall vessel bioreactor (RWVB) to model microgravity in vivo and in vitro, respectively. We investigated the effects of curcumin consumption (40 mg kg(-1) body weight day(-1), via daily oral gavages) on Sprague-Dawley (SD) rats exposed to HLS for 6 weeks. Then, we investigated the effects of incubation with curcumin (4 μM) on MC3T3-E1 and RAW264.7 cells cultured in RWVB. Curcumin alleviated HLS-induced reduction of bone mineral density in tibiae and preserved bone structure in tibiae and mechanical strength in femurs. Curcumin alleviated HLS-induced oxidative stress marked by reduced malondialdehyde content and increased total sulfhydryl content in femurs. In cultured MC3T3-E1 cells, curcumin inhibited modeled microgravity-induced reactive oxygen species (ROS) formation and enhanced osteoblastic differentiation. In cultured RAW264.7 cells, curcumin reduced modeled microgravity-induced ROS formation and attenuated osteoclastogenesis. In addition, curcumin upregulated vitamin D receptor (VDR) expression in femurs of rats exposed to HLS and MC3T3-E1 cells exposed to modeled microgravity. Curcumin alleviated HLS-induced bone loss in rats, possibly via suppressing oxidative stress and upregulating VDR expression.


Acute systemic and lung inflammation in C57Bl/6J mice after intratracheal aspiration of particulate matter from small-scale biomass combustion appliances based on old and modern technologies.
Inflammation is regarded as an important mechanism behind mortality and morbidity experienced by cardiorespiratory patients exposed to urban air particulate matter (PM). Small-scale biomass combustion is an important source of particulate air pollution. In this study, we investigated association between inflammatory responses and chemical composition of PM(1) emissions from seven different small-scale wood combustion appliances representing old and modern technologies. Healthy C57Bl/6J mice were exposed by intratracheal aspiration to single dose (10 mg/kg) of particulate samples. At 4 and 18 h after the exposure, bronchoalveolar lavage fluid (BALF) as well as serum was collected for subsequent analyses of inflammatory indicators (interleukin (IL)-6, IL-1β, IL-12, and IL-10; tumor necrosis factor-α (TNF-α); keratinocyte-derived chemoattractant (KC), and interferon-γ (IFN-γ)) in multiplexing assay. When the responses to the PM(1) samples were compared on an equal mass basis, the PM from modern technology appliances increased IL-6, KC, and IL-1β levels significantly in BALF at 4 and 18 h after the exposure. In contrast, these responses were seen only at 4 h time point in serum. Increased cytokine concentrations correlated with metal-rich ash related compounds which were more predominant in the modern technology furnaces emissions. These particles induced both local and systemic inflammation. Instead, polycyclic hydrocarbon (PAH) rich PM(1) samples from old technology (OT) evoked only minor inflammatory responses. In conclusion, the combustion technology largely affects the toxicological and chemical characteristics of the emissions. The large mass emissions of old combustion technology should be considered, when evaluating the overall harmfulness between the appliances. However, even the small emissions from modern technologies may pose significant toxic risks.


Functions of SK channels in central neurons.
1. SK channels are small-conductance calcium-activated potassium channels that are widely expressed in neurons. The traditional view of the functional role of SK channels is in mediating one component of the after-hyperpolarization that follows action potentials. Calcium influx via voltage-gated calcium channels active during action potentials opens SK channels and the resultant hyperpolarization lowers the firing frequency of action potentials in many neurons. 2. Recent advances have shown that, in addition to controlling action potential firing frequency, SK channels are also important in regulating dendritic excitability, synaptic transmission and synaptic plasticity. 3. In accordance with their role in modulating synaptic plasticity, SK channels are also important in regulating several learning and memory tasks and may also play a role in a number of neurological disorders. 4. The present review discusses recent findings on the role of SK channels in central neurons.


Caffeinated coffee consumption and risk of atrial fibrillation in two Spanish cohorts.
The association between caffeinated coffee consumption and atrial fibrillation remains unclear. Recent studies suggest an inverse association only between a moderate caffeinated coffee consumption and atrial fibrillation, but others have reported no association. The aim of our study was to prospectively assess the association between caffeinated coffee consumption and atrial fibrillation in two Spanish cohorts, one of adults from a general population and another of elderly participants at high cardiovascular risk. We included 18,983 and 6479 participants from the 'Seguimiento Universidad de Navarra' (SUN) and 'Prevención con Dieta Mediterránea' (PREDIMED) cohorts, respectively. Participants were classified according to their caffeinated coffee consumption in three groups: ≤3 cups/month, 1-7 cups/week, and >1 cup/day. We identified 97 atrial fibrillation cases after a median follow-up of 10.3 years (interquartile range 6.5-13.5), in the SUN cohort and 250 cases after 4.4 years median follow-up (interquartile range 2.8-5.8) in the PREDIMED study. No significant associations were observed in the SUN cohort although a J-shaped association was suggested. A significant inverse association between the intermediate category of caffeinated coffee consumption (1-7 cups/week) and atrial fibrillation was observed in PREDIMED participants with a multivariable-adjusted hazard ratio = 0.53 (95% confidence interval 0.36-0.79) when compared with participants who did not consume caffeinated coffee or did it only occasionally. No association was found for higher levels of caffeinated coffee consumption (>1 cup per day), hazard ratio = 0.79 (95% confidence interval 0.49-1.28). In the meta-analysis of both PREDIMED and SUN studies, the hazard ratio for intermediate consumption of caffeinated coffee was 0.60 (95% confidence interval 0.44-0.82) without evidence of heterogeneity. Similar findings were found for the association between caffeine intake and atrial fibrillation risk. Intermediate levels of caffeinated coffee consumption (1-7 cups/week) were associated with a reduction in atrial fibrillation risk in two prospective Mediterranean cohorts.


Gender differences in sociodemographic and behavioral influences of physical activity in Mexican-origin adolescents.
Understanding the factors that contribute to physical activity (PA) in Mexican-origin adolescents is essential to the design of effective efforts to enhance PA participation in this population. Multivariable logistic regression was used to identify sociodemographic and behavioral correlates of self-reported PA in school and community settings in 1154 Mexican-origin adolescents aged 12-17 years in Houston, TX. The majority of adolescents were born in the US (74%), approximately half (51%) were overweight or obese, and nearly three-quarters (73%) watched more than 2 hours of weekday television. Similarities and differences by setting and gender were observed in the relationships between sociodemographic and behavioral characteristics and PA. In boys, parental education and attending physical education (PE) were positively associated with PA across multiple PA outcomes. Adolescent linguistic acculturation was inversely associated with participation in community sports, whereas parental linguistic acculturation was positively associated with PA at school. In girls, PA in school and community settings was inversely associated with TV viewing and positively associated with PE participation. These findings highlight similarities and differences in correlates of PA among boys and girls, and point toward potential sources of opportunities as well as disparities for PA behaviors in Mexican-origin adolescents.


An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo.
Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with wild-type IgA. In vitro, Fab- and Fc-mediated effector functions, such as inhibition of ligand binding, receptor modulation, and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity, were similar between wild-type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy because the novel IgA antibody demonstrated therapeutic activity also in non-FcαRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo.


Efficacy of guanidinoacetic acid on growth and muscle energy metabolism in broiler chicks receiving arginine-deficient diets.
Guanidinoacetic acid (GAA) is formed from arginine (Arg) and is the immediate precursor to creatine (Cr) and phosphocreatine (PCr), which are important compounds involved in muscle energy homeostasis. This study sought to determine whether GAA could spare Arg in broiler chicks fed an Arg-deficient practical diet. A basal [0.84% standardized ileal digestible (SID) Arg] was supplemented with combinations of L-Arg (0 or 0.16%) and GAA (0, 0.06, or 0.12%) to form a factorial arrangement of diets; the unsupplemented basal served as the negative control (NC). Additionally, the basal was supplemented with 0.32% Arg to generate an Arg-adequate positive control (PC). Mash diets were fed to 8 replicate pens of 5 chicks per treatment from d 8 to 22 posthatch, with measurements including growth performance, blood GAA metabolites, muscle cellular energy markers, and clinical outcomes. Supplementation of 0.16% Arg increased (P < 0.05) BW gain from d 15 to 22 posthatch, while graded addition of GAA tended to improve BW gain (P < 0.094). Supplementation of either Arg or GAA increased (P < 0.05) feed efficiency from d 15 to 22 and d 8 to 22 posthatch. Birds fed the PC diet had greater (P < 0.05) responses for nearly all blood and tissue outcomes compared with NC-fed birds. Serum GAA was more responsive to supplementation of GAA in the presence versus absence of supplemental Arg (interaction, P < 0.001). Interactions (P < 0.05) were also observed for concentrations of muscle total Cr, creatinine, and most serum essential amino acids, notably Arg. Serum Cr, as well as muscle PCr, total Cr, and glycogen were increased (P < 0.05) independently by Arg and GAA supplementation, with highest levels achieved via combined addition of 0.12% GAA and 0.16% Arg. Minimal effects were detected on hematological and clinical chemistry outcomes. Overall, we conclude that GAA supplementation can spare Arg in broiler chicks fed Arg-deficient practical diets as evidenced by improvements in growth performance and muscle energy stores.


The gingival biotype revisited: transparency of the periodontal probe through the gingival margin as a method to discriminate thin from thick gingiva.
To detect groups of subjects in a sample of 100 periodontally healthy volunteers with different combinations of morphometric data related to central maxillary incisors and surrounding soft tissues. Four clinical parameters were included in a cluster analysis: crown width/crown length ratio (CW/CL), gingival width (GW), papilla height (PH) and gingival thickness (GT). The latter was based on the transparency of the periodontal probe through the gingival margin while probing the buccal sulcus. Every first volunteer out of 10 was re-examined to evaluate intra-examiner repeatability for all variables. High agreement between duplicate recordings was found for all parameters, in particular for GT, pointing to 85% (kappa=0.70; p=0.002). The partitioning method identified three clusters with specific features. Cluster A1 (nine males, 28 females) displayed a slender tooth form (CW/CL=0.79), a GW of 4.92 mm, a PH of 4.29 mm and a thin gingiva (probe visible on one or both incisors in 100% of the subjects). Cluster A2 (29 males, five females) presented similar features (CW/CL=0.77; GW=5.2 mm; PH=4.54 mm), except for GT. These subjects showed a clear thick gingiva (probe concealed on both incisors in 97% of the subjects). The third group (cluster B: 12 males, 17 females) differed substantially from the other clusters in many parameters. These subjects showed a more quadratic tooth form (CW/CL=0.88), a broad zone of keratinized tissue (GW=5.84 mm), low papillae (PH=2.84 mm) and a thick gingiva (probe concealed on both incisors in 83% of the subjects). The present analysis, using a simple and reproducible method for GT assessment, confirmed the existence of gingival biotypes. A clear thin gingiva was found in about one-third of the sample in mainly female subjects with slender teeth, a narrow zone of keratinized tissue and a highly scalloped gingival margin corresponding to the features of the previously introduced "thin-scalloped biotype" (cluster A1). A clear thick gingiva was found in about two-thirds of the sample in mainly male subjects. About half of them showed quadratic teeth, a broad zone of keratinized tissue and a flat gingival margin corresponding to the features of the previously introduced "thick-flat biotype" (cluster B). The other half could not be classified as such. These subjects showed a clear thick gingiva with slender teeth, a narrow zone of keratinized tissue and a high gingival scallop (cluster A2).


The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103.
These revised Recommendations for a System of Radiological Protection formally replace the Commission's previous, 1990, Recommendations; and update, consolidate, and develop the additional guidance on the control of exposure from radiation sources issued since 1990. Thus, the present Recommendations update the radiation and tissue weighting factors in the quantities equivalent and effective dose and update the radiation detriment, based on the latest available scientific information of the biology and physics of radiation exposure. They maintain the Commission's three fundamental principles of radiological protection, namely justification, optimisation, and the application of dose limits, clarifying how they apply to radiation sources delivering exposure and to individuals receiving exposure. The Recommendations evolve from the previous process-based protection approach using practices and interventions by moving to an approach based on the exposure situation. They recognise planned, emergency, and existing exposure situations, and apply the fundamental principles of justification and optimisation of protection to all of these situations. They maintain the Commission's current individual dose limits for effective dose and equivalent dose from all regulated sources in planned exposure situations. They reinforce the principle of optimisation of protection, which should be applicable in a similar way to all exposure situations, subject to the following restrictions on individual doses and risks; dose and risk constraints for planned exposure situations, and reference levels for emergency and existing exposure situations. The Recommendations also include an approach for developing a framework to demonstrate radiological protection of the environment.


Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis.
Growing evidence suggests that microRNAs coordinate various biological processes in the liver. We describe experiments to address the physiologic roles of these new regulators of gene expression in the liver that are as of yet largely undefined. We disrupted Dicer, an enzyme essential for the processing of microRNAs, in hepatocytes using a conditional knockout mouse model to elucidate the consequences of loss of microRNAs. The conditional knockout mouse livers showed the efficient disruption of Dicer1 at 3 weeks after birth. This resulted in prominent steatosis and the depletion of glycogen storage. Dicer1-deficient liver exhibited increased growth-promoting gene expression and the robust expression of fetal stage-specific genes. The consequence of Dicer elimination included both increased hepatocyte proliferation and overwhelming apoptosis. Over time, Dicer1-expressing wild-type hepatocytes that had escaped Cre-mediated recombination progressively repopulated the entire liver. Unexpectedly, however, two thirds of the mutant mice spontaneously developed hepatocellular carcinomas derived from residual Dicer1-deficient hepatocytes at 1 year of age. Dicer and microRNAs have critical roles in hepatocyte survival, metabolism, developmental gene regulation, and tumor suppression in the liver. Loss of Dicer primarily impairs hepatocyte survival but can promote hepatocarcinogenesis in cooperation with additional oncogenic stimuli.


Quality of life and economic burdens of malocclusion in U.S. patients enrolled in Medicaid.
Patients enrolled in Medicaid have limited access to orthodontic services in the United States. No studies are available, to the authors' knowledge, regarding the clinical and psychosocial burdens of malocclusion on these patients from an economic perspective. The authors conducted a systematic review of the relevant economic literature. They identified issues from the perspectives of the various stakeholders (dentists, patients and parents, Medicaid programs) and developed a conceptual model for studying decision making focused on the strategy of providing early interceptive and preventive treatment rather than, or in addition to, comprehensive care in the patient's permanent dentition. Medicaid coverage and reimbursement amounts vary nationwide, and decision making associated with obtaining care can be complex. The perspectives of all relevant stakeholders deserve assessment. A conceptual framework of the cost-effectiveness of interceptive orthodontic treatment compared with comprehensive treatment illustrates the issues to be considered when evaluating these strategies. Policymakers and the dental community should identify creative solutions to addressing low-income families' limited access to orthodontic services and compare them from various perspectives with regard to their relative cost-effectiveness. Dentists should be aware of the multiple problems faced by low-income families in obtaining orthodontic services and the impact of stakeholder issues on access to care; they also should be proactive in helping low-income patients obtain needed orthodontic services.


Universal polarization terahertz phase controllers using randomly aligned liquid crystal cells with graphene electrodes.
We present a universal polarization terahertz (THz) phase controller using a randomly aligned liquid crystal (LC) cell with graphene electrodes. The LC cell was fabricated using a nematic LC and two quartz substrates that were coated with a monolayer of graphene as the transparent electrode. The LC in the cell was prepared without any alignment treatments and was randomly aligned. The size of the random domains and the width of the disclination lines in the LC layer were several tens of microns. These textures disappeared when an alternating voltage was applied to the LC through the graphene layers. Using a THz time domain spectroscopic technique, we investigated the complex transmittance of the LC cell. The LC cell was highly transparent in the THz frequency range, and there was little change in the transmittance with the applied voltage. This indicated that the scattering loss originating in the randomly aligned LC molecules was small for the THz waves. We also demonstrated that the THz phase shift could be controlled by the applied voltage. The amplitude of the phase shift was explained by the ordinary and extraordinary refractive indices of the LC. These LC cells with graphene electrodes can be used to realize universal polarization THz phase controllers because of the random alignment.


Artificial Intelligence and Black-Box Medical Decisions: Accuracy versus Explainability.
Although decision-making algorithms are not new to medicine, the availability of vast stores of medical data, gains in computing power, and breakthroughs in machine learning are accelerating the pace of their development, expanding the range of questions they can address, and increasing their predictive power. In many cases, however, the most powerful machine learning techniques purchase diagnostic or predictive accuracy at the expense of our ability to access "the knowledge within the machine." Without an explanation in terms of reasons or a rationale for particular decisions in individual cases, some commentators regard ceding medical decision-making to black box systems as contravening the profound moral responsibilities of clinicians. I argue, however, that opaque decisions are more common in medicine than critics realize. Moreover, as Aristotle noted over two millennia ago, when our knowledge of causal systems is incomplete and precarious-as it often is in medicine-the ability to explain how results are produced can be less important than the ability to produce such results and empirically verify their accuracy.


Physiologically-based simulation modelling for the reduction of animal use in the discovery of novel pharmaceuticals.
The global pharmaceutical industry is estimated to use close to 20 million animals annually, in in vivo studies which apply the results of fundamental biomedical research to the discovery and development of novel pharmaceuticals, or to the application of existing pharmaceuticals to novel therapeutic indications. These applications of in vivo experimentation include: a) the use of animals as disease models against which the efficacy of therapeutics can be tested; b) the study of the toxicity of those therapeutics, before they are administered to humans for the first time; and c) the study of their pharmacokinetics - i.e. their distribution throughout, and elimination from, the body. In vivo pharmacokinetic (PK) studies are estimated to use several hundred thousand animals annually. The success of pharmaceutical research currently relies heavily on the ability to extrapolate from data obtained in such in vivo studies to predict therapeutic behaviour in humans. Physiologically-based modelling has the potential to reduce the number of in vivo animal studies that are performed by the pharmaceutical industry. In particular, the technique of physiologically-based pharmacokinetic (PBPK) modelling is sufficiently developed to serve as a replacement for many in vivo PK studies in animals during drug discovery. Extension of the technique to incorporate the prediction of in vivo therapeutic effects and/or toxicity is less well-developed, but has potential in the longer-term to effect a significant reduction in animal use, and also to lead to improvements in drug discovery via the increased rationalisation of lead optimisation.


Inhibition of CYP2B4 by the mechanism-based inhibitor 2-ethynylnaphthalene: inhibitory potential of 2EN is dependent on the size of the substrate.
2-Ethynylnaphthalene (2EN) is a mechanism-based inhibitor of CYP2B4 with two components to the inhibition, (1) enzyme inactivation, which requires covalent binding of the 2EN metabolite, and (2) reversible inhibition by 2EN itself. Both inhibitory components were examined using several different CYP2B4 substrates. Preincubation of CYP2B4 with 2EN led to a time-dependent inactivation of each of the CYP2B4-dependent activities examined; however, the ability of 2EN to reversibly inhibit CYP2B4 depended on the substrate employed, which is inconsistent with classical inhibition patterns. The degree 2EN's reversible inhibition was shown not to correlate with the substrate affinity for the active site, but with parameters related to the molecular size of the substrate. The results are consistent with 2EN and the smaller substrates simultaneously fitting in the CYP2B4 active site, leading to very little inhibition. Larger substrates exhibited greater degrees of inhibition because of their inability to co-bind with inhibitor in the active site.