Effect of a computer-aided diagnosis system on radiologists' performance in grading gliomas with MRI.
The effects of a computer-aided diagnosis (CAD) system based on quantitative intensity features with magnetic resonance (MR) imaging (MRI) were evaluated by examining radiologists' performance in grading gliomas. The acquired MRI database included 71 lower-grade gliomas and 34 glioblastomas. Quantitative image features were extracted from the tumor area and combined in a CAD system to generate a prediction model. The effect of the CAD system was evaluated in a two-stage procedure. First, a radiologist performed a conventional reading. A sequential second reading was determined with a malignancy estimation by the CAD system. Each MR image was regularly read by one radiologist out of a group of three radiologists. The CAD system achieved an accuracy of 87% (91/105), a sensitivity of 79% (27/34), a specificity of 90% (64/71), and an area under the receiver operating characteristic curve (Az) of 0.89. In the evaluation, the radiologists' Az values significantly improved from 0.81, 0.87, and 0.84 to 0.90, 0.90, and 0.88 with p = 0.0011, 0.0076, and 0.0167, respectively. Based on the MR image features, the proposed CAD system not only performed well in distinguishing glioblastomas from lower-grade gliomas but also provided suggestions about glioma grading to reinforce radiologists' confidence rating.


Observations of sound-speed fluctuations on the New Jersey continental shelf in the summer of 2006.
Environmental sensors moored on the New Jersey continental shelf tracked constant density surfaces (isopycnals) for 35 days in the summer of 2006. Sound-speed fluctuations from internal-wave vertical isopycnal displacements and from temperature/salinity variability along isopycnals (spiciness) are analyzed using frequency spectra and vertical covariance functions. Three varieties of internal waves are studied: Diffuse broadband internal waves (akin to waves fitting the deep water Garrett/Munk spectrum), internal tides, and, to a lesser extent, nonlinear internal waves. These internal-wave contributions are approximately distinct in the frequency domain. It is found that in the main thermocline spicy thermohaline structure dominates the root mean square sound-speed variability, with smaller contributions coming from (in order) nonlinear internal waves, diffuse internal waves, and internal tides. The frequency spectra of internal-wave displacements and of spiciness have similar form, likely due to the advection of variable-spiciness water masses by horizontal internal-wave currents, although there are technical limitations to the observations at high frequency. In the low-frequency, internal-wave band the internal-wave spectrum follows frequency to the -1.81 power, whereas the spice spectrum shows a -1.73 power. Mode spectra estimated via covariance methods show that the diffuse internal-wave spectrum has a smaller mode bandwidth than Garrett/Munk and that the internal tide has significant energy in modes one through three.


Application of the American College of Cardiology (ACC/AHA) 2017 Guideline for the Management of Hypertension in Adults and Comparison with the 2014 Eighth Joint National Committee Guideline.
This study aims to compare the 2017-ACC/AHA hypertension guideline with 2014-JNC-8 guideline in regard to the number of patients who are eligible for treatment and to determine the physicians' adherence and the financial impact of implementing the new guideline. A cross-sectional observational study was conducted on adult patients who attended the hospital outpatient setting in UAE during January 1, 2018 till February 28, 2018. Adults who are diagnosed with hypertension and those with blood pressure (BP) levels based on two or more readings obtained on two or more different occasions were screened for inclusion into this study and cardiovascular diseases (CVD) risk was calculated. The two guidelines were compared with respect to the number of patients diagnosed with hypertension and eligible for treatment. Results were extrapolated to the UAE population. Financial impact of applying the 2017-ACC/AHA guideline was also evaluated. In comparison with the JNC-8, the 2017-ACC/AHA guideline would increase the proportion of patients diagnosed with hypertension among UAE adults from 40.8% to 76.3% and the number of UAE adults recommended for antihypertensive medications would rise from 2.42 million (32.1%) to 4.71 million (62.5%). Among UAE adults, almost 4.42 million (58.6%) and 0.76 million (10.1%) would have BP above the target according to the 2017-ACC/AHA and JNC-8 guidelines, respectively. The expected increase in the cost of anti-hypertension medications prescribed for the new labeled cases according to 2017-ACC/AHA but not JNC-8 would reach 1.8 billion AED/year. For those who were recommended for antihypertensive medications, who had BP above target, the additional cost would reach 3.5 billion AED/year. The current study reveals marked increase in the proportion of patients diagnosed with hypertension in concordance with the 2017-ACC/AHA guideline. This is also will be associated with almost double the number of UAE adults recommended for antihypertensive medications. The poor compliance with the 2017-ACC/AHA reflects the concern regarding the increase risk of adverse events.


Costs of newborn care in California: a population-based study.
We sought to describe the current costs of newborn care by using population-based data, which includes linked vital statistics and hospital records for both mothers and infants. These data allow costs to be reported by episode of care (birth), instead of by hospitalization. Data for this study were obtained from the linked 2000 California birth cohort data. These data (n = 518,704), provided by the California Office of Statewide Health Planning and Development (OSHPD), contain infant vital statistics data (birth and death certificate data) linked to infant and maternal hospital discharge summaries. In addition to the infant and maternal hospital discharge summaries associated with delivery, these data include discharge summaries for all infant hospital-to-hospital transfers and maternal prenatal hospitalizations. The linkage algorithm that is used by OSHPD in creating the linked cohort data file is highly accurate. More than 99% of the maternal and infant discharge abstracts were linked successfully with the birth certificates. These data were also linked successfully with the infant discharge abstracts from the receiving hospital for 99% of the infants who were transferred to another hospital. The hospital discharge records were the source of the hospital charges and length-of-stay information summarized in this study. Hospital costs were estimated by adjusting charges by hospital-specific ratios of costs to charges obtained from the OSHPD Hospital Financial Reporting data. Costs, lengths of stay, and mortality were summarized by birth weight groups, gestational age, cost categories, and types of admissions. Low birth weight (LBW) and very low birth weight (VLBW) infants had significantly longer hospital stays and accounted for a significantly higher proportion of total hospital costs. The average hospital stay for LBW infants ranged from 6.2 to 68.1 days, whereas the average hospital stay for infants who weighed >2500 g at birth was 2.3 days. Overall, VLBW infants accounted for 0.9% of cases but 35.7% of costs, whereas LBW infants accounted for 5.9% of cases but 56.6% of total hospital costs. Although total maternal and infant costs were similar (approximately 1.6 billion dollars), the distribution of maternal costs was much less skewed. For infants, 5% of infants accounted for 76% of total infant hospital costs. Conversely, the most expensive 3% of deliveries accounted for only 17% of total maternal costs. The very smallest infants make up a hugely disproportionate share of costs; more than half of all neonatal costs are incurred by LBW or premature infants. Maternal costs are similar in magnitude to newborn costs, but they are much less skewed than for infants. Preventing premature deliveries could yield very large cost savings, in addition to saving lives.


A cell-selective glutathione-responsive tris(phthalocyanine) as a smart photosensitiser for targeted photodynamic therapy.
A biotin-conjugated disulfide-linked tris(phthalocyanine) has been synthesised and characterised. As shown by electronic absorption and steady-state fluorescence spectroscopy methods, the compound remains non-aggregated in N,N-dimethylformamide, but is significantly aggregated in phosphate buffered saline with 1% Cremophor EL. The reduction in fluorescence intensity and singlet oxygen generation efficiency as compared with the monomeric counterpart suggests that the tris(phthalocyanine) exhibits an excellent self-quenching effect, particularly in an aqueous medium. Upon interaction with glutathione, both the fluorescence emission and singlet oxygen production can be restored as a result of the cleavage of the disulfide linkages, thereby releasing the phthalocyanine units and reducing their aggregation and self-quenching effects. With a biotin moiety, this tris(phthalocyanine) is preferentially taken up by the biotin-receptor-positive HeLa cells and activated by the intracellular glutathione, resulting in fluorescence recovery and photocytotoxicity with an IC50 value of 0.68 μM. This compound can therefore act as a dual functional photosensitiser.


Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study.
The aim of this study was to determine the prevalence of aortic sclerosis and stenosis in the elderly and to identify clinical factors associated with degenerative aortic valve disease. Several lines of evidence suggest that degenerative aortic valve disease is not an inevitable consequence of aging and may be associated with specific clinical factors. In 5,201 subjects > or = 65 years of age enrolled in the Cardiovascular Health Study, the relation between aortic sclerosis or stenosis identified on echocardiography and clinical risk factors for atherosclerosis was evaluated by using stepwise logistic regression analysis. Aortic valve sclerosis was present in 26% and aortic valve stenosis in 2% of the entire study cohort; in subjects > or = 75 years of age, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (twofold increased risk for each 10-year increase in age), male gender (twofold excess risk), present smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein(a) and low density lipoprotein cholesterol levels. Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.


Dual function of thalamic low-vigilance state oscillations: rhythm-regulation and plasticity.
During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Ca2+ spikes. Recent evidence reveals that thalamic Ca2+ spikes are inextricably linked to global somatodendritic Ca2+ transients and are essential for several forms of thalamic plasticity. Thus, we propose herein that alongside their rhythm-regulation function, thalamic oscillations of low-vigilance states have a plasticity function that, through modifications of synaptic strength and cellular excitability in local neuronal assemblies, can shape ongoing oscillations during inattention and NREM sleep and may potentially reconfigure thalamic networks for faithful information processing during attentive wakefulness.


A pragmatic clinicopathobiological grouping/staging system for gliomas: proposal of the Indian TNM subcommittee on brain tumors.
There is no universally accepted staging system for primary brain tumors wherein prognostication is mainly based on complex composite indices. To develop a simple, pragmatic, and widely applicable grouping/staging system for gliomas, the most common primary brain tumor. An expert neurooncology panel with representation from radiation oncology, neurosurgery, pathology, radiology, and medical oncology had several rounds of discussion on issues pertinent to brain tumor staging. The trade off was between the accuracy of prognostic categorization and a pragmatic, widely applicable approach. The Tumor-Node-Metastasis staging was considered irrelevant for gliomas that seldom metastasize to lymphatics or outside the neuraxis. Instead, a 4-point staging/grouping system is proposed, using histological grade as the main prognostic variable and at least one stage migration based on other unfavorable features such as tumor location (brainstem); age (<5 years for all grades, >50 years for high-grade, and >40 years for low-grade gliomas); poor neurological performance status (NPS 2-4); multicentricity and/or gliomatosis; and adverse biological parameters (proliferative index, angiogenesis markers, apoptotic index, cytogenetic abnormalities, and molecular markers). In absence of a grouping/staging system for primary brain tumors, prognostification is mostly based on complex composite indices. The proposed clinicopathobiological grouping/staging system for gliomas is a simple, pragmatic, and user-friendly tool with a potential to fulfill the objectives of staging classification.


Creation of an Internal Teledermatology Store-and-Forward System in an Existing Electronic Health Record: A Pilot Study in a Safety-Net Public Health and Hospital System.
External store-and-forward (SAF) teledermatology systems operate separately from the primary health record and have many limitations, including care fragmentation, inadequate communication among clinicians, and privacy and security concerns, among others. Development of internal SAF workflows within existing electronic health records (EHRs) should be the standard for large health care organizations for delivering high-quality dermatologic care, improving access, and capturing other telemedicine benchmark data. Epic EHR software (Epic Systems Corporation) is currently one of the most widely used EHR system in the United States, and development of a successful SAF workflow within it is needed. To develop an SAF teledermatology workflow within the Epic system, the existing EHR system of Parkland Health and Hospital System (Dallas, Texas), assess its effectiveness in improving access to care, and validate its reliability; and to evaluate the system's ability to capture meaningful outcomes. Electronic consults were independently evaluated by 2 board-certified dermatologists, who provided diagnoses and treatment plans to primary care physicians (PCPs). Results were compared with in-person referrals from May to December 2013 from the same clinic (a community outpatient clinic in a safety-net public hospital system). Patients were those 18 years or older with dermatologic complaints who would have otherwise been referred to dermatology clinic. Median time to evaluation; percentage of patients evaluated by a dermatologist through either teledermatology or in-person compared with the previous year. Seventy-nine teledermatology consults were placed by 6 PCPs from an outpatient clinic between May and December 2014; 57 (74%) were female and their mean (SD) age was 47.0 (12.4) years. Teledermatology reduced median time to evaluation from 70.0 days (interquartile range [IQR], 33.25-83.0 days) to 0.5 days (IQR, 0.172-0.94 days) and median time to treatment from 73.5 to 3.0 days compared with in-person dermatology visits. Overall, a greater percentage of patients (120 of 144 [83.3%]) were evaluated by a dermatologist through either teledermatology or in-person during the 2014 study period compared with the previous year (111 of 173 [64.2%]). Primary care physicians followed management recommendations 93% of the time. Epic-based SAF teledermatology can improve access to dermatologic care in a public safety-net hospital setting. We hope that the system will serve as a model for other health care organizations wanting to create SAF teledermatology workflows within the Epic EHR system.


Antibiotic policies in acute English NHS trusts: implementation of 'Start Smart-Then Focus' and relationship with Clostridium difficile infection rates.
The objective of this study was to establish how antibiotic prescribing policies at National Health Service (NHS) hospitals match the England Department of Health 'Start Smart-Then Focus' recommendations and relate to Clostridium difficile infection (CDI) rates. Antibiotic pharmacists were surveyed regarding recommendations for empirical treatment of common syndromes ('Start Smart') and antimicrobial prescription reviews ('Focus') at their hospital trusts. If no response was provided, policy data were sought from trust websites and the MicroGuide app (Horizon Strategic Partners, UK). Empirical treatment recommendations were categorized as broad spectrum (a β-lactam penicillin/β-lactamase inhibitor, cephalosporin, quinolone or carbapenem) or narrow spectrum. CDI rates were gathered from the national mandatory surveillance system. Data were obtained for 105/145 English acute hospital trusts (72%). β-Lactam/β-lactamase inhibitor combinations were recommended extensively. Only for severe community-acquired pneumonia and pyelonephritis were narrow-spectrum agents recommended first line at a substantial number of trusts [42/105 (40%) and 50/105 (48%), respectively]. Policies commonly recommended dual therapy with aminoglycosides and β-lactams for abdominal sepsis [40/93 trusts (43%)] and undifferentiated severe sepsis [54/94 trusts (57%)]. Most policies recommended treating for ≥ 7 days for most indications. Nearly all policies [100/105 trusts (95%)] recommended antimicrobial prescription reviews, but only 46/96 respondents (48%) reported monitoring compliance. Independent predictors of higher CDI rates were recommending a broad-spectrum regimen for community-acquired pneumonia (P=0.06) and, counterintuitively, a recommended treatment duration of <48 h for nosocomial pneumonia (P=0.01). Hospital antibiotic policies in the NHS 'Start Smart' by recommending broad-spectrum antibiotics for empirical therapy, but this may have the unintended potential to increase the use of broad-spectrum antibiotics and risk of CDI unless better mechanisms are in place to improve 'Focus'.


Infrared Topological Plasmons in Graphene.
We propose a two-dimensional plasmonic platform-periodically patterned monolayer graphene-which hosts topological one-way edge states operable up to infrared frequencies. We classify the band topology of this plasmonic system under time-reversal-symmetry breaking induced by a static magnetic field. At finite doping, the system supports topologically nontrivial band gaps with mid-gap frequencies up to tens of terahertz. By the bulk-edge correspondence, these band gaps host topologically protected one-way edge plasmons, which are immune to backscattering from structural defects and subject only to intrinsic material and radiation loss. Our findings reveal a promising approach to engineer topologically robust chiral plasmonic devices and demonstrate a realistic example of high-frequency topological edge states.


Advancing exposure characterization for chemical evaluation and risk assessment.
A new generation of scientific tools has emerged to rapidly measure signals from cells, tissues, and organisms following exposure to chemicals. High-visibility efforts to apply these tools for efficient toxicity testing raise important research questions in exposure science. As vast quantities of data from high-throughput screening (HTS) in vitro toxicity assays become available, this new toxicity information must be translated to assess potential risks to human health from environmental exposures. Exposure information is required to link information on potential toxicity of environmental contaminants to real-world health outcomes. In the immediate term, tools are required to characterize and classify thousands of environmental chemicals in a rapid and efficient manner to prioritize testing and assess potential for risk to human health. Rapid risk assessment requires prioritization based on both hazard and exposure dimensions of the problem. To address these immediate needs within the context of longer term objectives for chemical evaluation and risk management, a translation framework is presented for incorporating toxicity and exposure information to inform public health decisions at both the individual and population levels. Examples of required exposure science contributions are presented with a focus on early advances in tools for modeling important links across the source-to-outcome paradigm. ExpoCast, a new U.S. Environmental Protection Agency (EPA) program aimed at developing novel approaches and metrics to screen and evaluate chemicals based on the potential for biologically relevant human exposures is introduced. The goal of ExpoCast is to advance characterization of exposure required to translate findings in computational toxicology to information that can be directly used to support exposure and risk assessment for decision making and improved public health.


Effects of music learning and piano practice on cognitive function, mood and quality of life in older adults.
Reading music and playing a musical instrument is a complex activity that comprises motor and multisensory (auditory, visual, and somatosensory) integration in a unique way. Music has also a well-known impact on the emotional state, while it can be a motivating activity. For those reasons, musical training has become a useful framework to study brain plasticity. Our aim was to study the specific effects of musical training vs. the effects of other leisure activities in elderly people. With that purpose we evaluated the impact of piano training on cognitive function, mood and quality of life (QOL) in older adults. A group of participants that received piano lessons and did daily training for 4-month (n = 13) was compared to an age-matched control group (n = 16) that participated in other types of leisure activities (physical exercise, computer lessons, painting lessons, among other). An exhaustive assessment that included neuropsychological tests as well as mood and QOL questionnaires was carried out before starting the piano program and immediately after finishing (4 months later) in the two groups. We found a significant improvement on the piano training group on the Stroop test that measures executive function, inhibitory control and divided attention. Furthermore, a trend indicating an enhancement of visual scanning and motor ability was also found (Trial Making Test part A). Finally, in our study piano lessons decreased depression, induced positive mood states, and improved the psychological and physical QOL of the elderly. Our results suggest that playing piano and learning to read music can be a useful intervention in older adults to promote cognitive reserve (CR) and improve subjective well-being.


Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.
Mutation of the VHL tumor suppressor is associated with the inherited von Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible proteins. The structure of the ternary complex at 2.7 angstrom resolution shows two interfaces, one between VHL and ElonginC and another between ElonginC and ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL responsible for ElonginC binding. A mutational patch on a separate domain of VHL indicates a second macromolecular binding site. The structure extends the similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins for degradation, supporting the hypothesis that VHL may function in an analogous pathway.


The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense.
Only humans and higher primates have high uric acid blood levels. Although high uric acid causes gout, it has been linked with human longevity because of its hypothetical antioxidant function. Recent studies reveal that p53 has significant roles in cellular metabolism. One example of this is an antioxidant function that potentially contributes to tumor suppression. Here, we reported a first beneficial link between p53 and uric acid. We identified the uric acid transporter SLC2A9 (also known as GLUT9) as a direct p53 target gene and a key downstream effector in the reduction of reactive oxygen species (ROS) through transporting uric acid as a source of antioxidant. Oxidative stress induced SLC2A9 expression in a p53-dependent manner, and inhibition of SLC2A9 by small interfering RNA (siRNA) or anti-gout drugs such as probenecid significantly increased ROS levels in an uric acid-dependent manner and greatly sensitized cancer cells to chemotherapeutic drugs. Conversely, expression of SLC2A9 reduced ROS and protected against DNA damage and cell death, suggesting its antioxidant function. The increased production of ROS because of p53 loss was rescued by SLC2A9 expression. Furthermore, decreased SLC2A9 expression was observed in several cancer types and was associated with a poorer prognosis. Our findings suggest that the p53-SLC2A9 pathway is a novel antioxidant mechanism that uses uric acid to maintain ROS homeostasis and prevent accumulation of ROS-associated damage that potentially contributes to cancer development.


Interventions for erythema nodosum leprosum.
Erythema nodosum leprosum (ENL) is a serious immunological complication of leprosy, causing inflammation of skin, nerves, other organs, and general malaise. Many different therapies exist for ENL, but it is unclear if they work or which therapy is optimal. To assess the effects of interventions for erythema nodosum leprosum. We searched the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2009), MEDLINE (from 2003), EMBASE (from 2005), LILACS and AMED (from inception), CINAHL (from 1981), and databases of ongoing trials, all in March 2009. We checked reference lists of articles and contacted the American Leprosy Missions in Brazil to locate studies. Randomised controlled trials (RCTs) of interventions for ENL in people with leprosy. Two authors performed study selection, assessed trial quality, and extracted data. We included 13 studies with a total of 445 participants. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant remission of skin lesions compared to acetylsalicylic acid (aspirin) (RR 2.43; 95% CI 1.28 to 4.59) (1 trial, 92 participants). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 1.36 to 9.91) (1 trial, 24 participants), and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01 to 0.56) (1 trial, 72 participants). We did not find any significant benefit for intravenous betamethasone compared to dextrose (1 trial, 10 participants), pentoxifylline compared to thalidomide (1 trial, 44 participants), indomethacin compared to prednisolone, aspirin or chloroquine treatments (2 trials, 80 participants), or levamisole compared to placebo (1 trial, 12 participants). Mild to moderate adverse events were significantly lower in participants taking 100 mg thalidomide compared to 300 mg thalidomide daily (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear evidence of benefit for interventions in the management of ENL. However, this does not mean they do not work, because the studies were small and poorly reported. Larger studies using clearly defined participants, outcome measures, and internationally recognised scales are urgently required.


[Reactive changes in psychological condition and behaviour in children of parents with cancer--results of an epidemiological survey].
Children of cancer patients are at risk for developing psychological symptoms. The parental appraisal of the child's psychological condition is a key variable for the utilization of child-centred psychosocial services. This study aimed at the systematic analysis of parental appraisals of changes in the emotional condition or behaviour of their children. We conducted an epidemiologic survey with a sample size of 1,809 patients with different cancer diagnoses, giving information about 2,581 children aged 21 years or younger at time of diagnosis. Quantitative information on children's distress during the disease and on changes in psychological condition or behaviour and qualitative information on the kind of changes were analysed. About half of the children were considered to be psychologically strongly affected during the disease. For about 25 % negative changes in psychological condition or behaviour are reported, positive changes are reported for 20 % of the children. Negative changes are most frequently described in young children (up to five years), positive changes are most frequently described in young adults (18 to 21 years). The results indicate that from the cancer parent's view many children are substantially distressed. Thus, the implementation of additional preventive psychosocial services seems reasonable and necessary.


Morphometric analyses of the body and the branches of the normal third interosseous muscle (suspensory ligament) in Standardbreds.
The third interosseous muscle (suspensory ligament, TIOM) is composed of connective tissue (CT) with a variable proportion of muscle (MT) and adipose tissue (AT). The aim of our study is to quantify the CT, MT and AT within the body and the branches of right thoracic and pelvic limbs TIOM in sound horses to determine whether there are differences in CT, MT and AT between age, sex, limbs and levels. Right limbs from 11 sound horses were collected. Samples from 6 levels of the TIOM were embedded in paraffin or in Tissue-Tek(®) . Most of the paraffin sections were shredded. Using the cryosection, some artefacts appeared. Cryoprotection was carried out, which produced the best results. Hematoxylin-phloxine-saffron and Hematoxylin-eosin gave a good contrast of colours between the tissues observed allowing the use of an image analysis programme to calculate percentage of each tissue within the TIOM. The percentage of MT and AT decreased significantly (P < 0.0001), whereas the percentage of CT increased significantly (P < 0.0001) with age and when descending from the proximal to the distal level of the TIOM. The percentage of MT was significantly higher (P < 0.0001) in females than males, while the percentage of CT was significantly higher (P < 0.0001) in males than females. The percentage of AT was significantly higher (P = 0.0278) in pelvic limbs than in thoracic limbs. These results confirm the variation in tissue composition within the TIOM of sound horses.


MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival.
The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.


Integrating motion, illumination, and structure in video sequences with applications in illumination-invariant tracking.
In this paper, we present a theory for combining the effects of motion, illumination, 3D structure, albedo, and camera parameters in a sequence of images obtained by a perspective camera. We show that the set of all Lambertian reflectance functions of a moving object, at any position, illuminated by arbitrarily distant light sources, lies "close" to a bilinear subspace consisting of nine illumination variables and six motion variables. This result implies that, given an arbitrary video sequence, it is possible to recover the 3D structure, motion, and illumination conditions simultaneously using the bilinear subspace formulation. The derivation builds upon existing work on linear subspace representations of reflectance by generalizing it to moving objects. Lighting can change slowly or suddenly, locally or globally, and can originate from a combination of point and extended sources. We experimentally compare the results of our theory with ground truth data and also provide results on real data by using video sequences of a 3D face and the entire human body with various combinations of motion and illumination directions. We also show results of our theory in estimating 3D motion and illumination model parameters from a video sequence.


Consumer Shell Egg Consumption and Handling Practices: Results from a National Survey.
Numerous cases and outbreaks of Salmonella infection are attributable to shell eggs each year in the United States. Safe handling and consumption of shell eggs at home can help reduce foodborne illness attributable to shell eggs. A nationally representative Web survey of 1,504 U.S. adult grocery shoppers was conducted to describe consumer handling practices and consumption of shell eggs at home. Based on self-reported survey data, most respondents purchase shell eggs from a grocery store (89.5%), and these eggs were kept refrigerated (not at room temperature; 98.5%). As recommended, most consumers stored shell eggs in the refrigerator (99%) for no more than 3 to 5 weeks (97.6%). After cracking eggs, 48.1% of respondents washed their hands with soap and water. More than half of respondents who fry and/or poach eggs cooked them so that the whites and/or the yolks were still soft or runny, a potentially unsafe practice. Among respondents who owned a food thermometer (62.0%), only 5.2% used it to check the doneness of baked egg dishes when they prepared such a dish. Consumers generally followed two of the four core "Safe Food Families" food safety messages ("separate" and "chill") when handling shell eggs at home. To prevent Salmonella infection associated with shell eggs, consumers should improve their practices related to the messages "clean" (i.e., wash hands after cracking eggs) and "cook" (i.e., cook until yolks and whites are firm and use a food thermometer to check doneness of baked egg dishes) when preparing shell eggs at home. These findings will be used to inform the development of science-based consumer education materials that can help reduce foodborne illness from Salmonella infection.


Coffee, caffeine-related genes, and Parkinson's disease: a case-control study.
An inverse association between coffee and Parkinson's disease (PD) has been reported. However, it remains uncertain why some but not all coffee drinkers are less susceptible to PD. We considered the possibility of a pharmacogenetic effect. In our study, we included 1,208 subjects (446 case-unaffected sibling pairs and 158 case-unrelated control pairs) recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We collected information on lifetime coffee drinking and we studied two genes: ADORA2A, which encodes the major receptor activity of caffeine in the brain (variants rs5751876 and rs3032740), and CYP1A2, which encodes the major rate-limiting step of caffeine metabolism (variants rs35694136 and rs762551). We did not observe significant associations of coffee drinking or of the genetic variants with PD susceptibility, either independently or jointly, in the sample overall and in most strata. Our study neither supports the hypothesis that coffee protects against PD nor provides evidence for a pharmacogenetic effect.


Bilateral prophylactic mastectomy: issues and concerns.
At present, the care of women at increased risk of developing breast cancer poses a clinical dilemma and remains an area of controversy. A number of investigators have addressed the pros and cons of prophylactic mastectomy versus close follow-up, utilizing annual mammography, semiannual or even more frequent physical examinations of the breast, and proficient monthly breast self-examinations. Recent efforts to isolate a gene (BRCA1) on chromosome 17q12-21 raise additional concerns about the management of women testing positive for BRCA1 mutations. These women are estimated to have an 85% lifetime risk of developing breast cancer. Testing for BRCA1 mutation carriers may soon be available for population screening. This article describes preliminary studies investigating health care provider and patient perceptions of bilateral prophylactic mastectomy. In addition, a number of research questions remain regarding the efficacy and utilization of bilateral prophylactic mastectomy as a treatment option for women at increased risk of developing breast cancer. These women include those testing positive for BRCA1 mutations. In addition, women with a strong family history opting against testing for BRCA1 mutations may express interest in surgery.


Pulsed electromagnetic field therapy effectiveness in low back pain: A systematic review of randomized controlled trials.
Low back pain is a worldwide prevalent musculoskeletal condition in the general population. In this sense, the pulsed electromagnetic fields (PEMF) therapy has shown significant clinical benefits in several musculoskeletal conditions. To assess the effectiveness of the PEMF therapy in reducing pain and clinical symptomatology in patients with low back pathological conditions. It was performed a comprehensive database search using Pubmed, Scopus, Cochrane Library and PEDro databases to assess the effectiveness of the PEMF therapy in reducing pain and clinical symptomatology in patients with low back pathological conditions. The search was performed from January 2005 to August 2015 and conducted by two independent investigators, which scrutinize the reference list of most relevant studies. The methodological quality was assessed by the PEDro scale and the level of evidence was set according Oxford Center for Evidence-Based Medicine scale. Six studies were eligible inclusion on the qualitative analysis and five into the quantitative analysis, scoring an overall 6.8 points according the PEDro scale. The studies showed heterogeneity concerning the intervention protocols. Nevertheless, the effect sizes' indicated a clear tendency to reduction of the pain intensity favoring the PEMF groups, reaching a minimal clinically important difference. PEMF therapy seems to be able to relieve the pain intensity and improve functionality in individuals with low back pain conditions. Further research is needed regarding PEMF effects on the different conditions of low back pain, with standardized protocols, larger samples and adjustment for low back pain confounders in order to achieve stronger conclusions.


Optimizing the yield of recombinant pharmaceutical proteins in plants.
The production of recombinant pharmaceutical proteins in plants is entering a new phase with the recent approval of recombinant glucocerebrosidase produced in carrot cells and the successful production of clinical-grade proteins in diverse plant-based production platforms. In the long journey from concept to product, the field of molecular farming has faced technical and economic hurdles, many reflecting the initially limited productivity of plants compared to established platforms such as mammalian cells. This challenge has been met by innovative research aiming to increase recombinant protein yields and maximize the economic benefits of plants. Research has focused on increasing the intrinsic yield capability of plants by optimizing expression construct design, and also on novel strategies to avoid epigenetic silencing and environmental effects on protein accumulation. In this article, we discuss the diverse approaches that have been used to increase the productivity of plant-based platforms for the production of recombinant pharmaceutical proteins and consider future opportunities to maximize the potential of plants and increase their competitiveness outside niche markets.


Resting-state functional magnetic resonance imaging analysis with seed definition constrained by regional homogeneity.
Researchers have recently focused their attention on the intrinsic functional connectivity (FC) in the brain using resting-state functional magnetic resonance imaging. Seed-based correlation analysis (SCAC), which correlates a predefined seed region with other voxels in the brain, is a common index for FC. However, definition of seed sizes and locations was ambiguous in previous studies and this may lead to spurious results for people with a unique functional anatomy. To address this issue, this study proposes a novel method (SCAReHo) that provides a data-driven seed selection (including sizes and locations) method by incorporating regional homogeneity (ReHo) in the SCAC method. The disparities between SCAC and SCAReHo methods among 12 healthy participants were evaluated in the FC of default mode network (DMN), task-positive network (TPN), and amygdala network. The SCAReHo method bypasses the seed-selection ambiguity and enhances the sensitivity in detecting FC of the DMN, TPN, and amygdala network. This study suggests that the SCAReHo method improves the sensitivity of FC analysis and reduces the uncertainty of seed selection. Thus, this method may be particularly useful for psychiatric and neurological investigations.


A Graph theoretical approach to study the organization of the cortical networks during different mathematical tasks.
The two core systems of mathematical processing (subitizing and retrieval) as well as their functionality are already known and published. In this study we have used graph theory to compare the brain network organization of these two core systems in the cortical layer during difficult calculations. We have examined separately all the EEG frequency bands in healthy young individuals and we found that the network organization at rest, as well as during mathematical tasks has the characteristics of Small World Networks for all the bands, which is the optimum organization required for efficient information processing. The different mathematical stimuli provoked changes in the graph parameters of different frequency bands, especially the low frequency bands. More specific, in Delta band the induced network increases it's local and global efficiency during the transition from subitizing to retrieval system, while results suggest that difficult mathematics provoke networks with higher cliquish organization due to more specific demands. The network of the Theta band follows the same pattern as before, having high nodal and remote organization during difficult mathematics. Also the spatial distribution of the network's weights revealed more prominent connections in frontoparietal regions, revealing the working memory load due to the engagement of the retrieval system. The cortical networks of the alpha brainwaves were also more efficient, both locally and globally, during difficult mathematics, while the fact that alpha's network was more dense on the frontparietal regions as well, reveals the engagement of the retrieval system again. Concluding, this study gives more evidences regarding the interaction of the two core systems, exploiting the produced functional networks of the cerebral cortex, especially for the difficult mathematics.


Outcomes of Hip Arthroscopic Surgery in Adolescents With a Subanalysis on Return to Sport: A Systematic Review.
There is a plethora of literature on outcomes after hip arthroscopic surgery in the adult population; however, outcomes in the adolescent population have not been as widely reported. Additionally, as adolescents represent a very active population, it is imperative to understand their athletic activity and return to sport after hip arthroscopic surgery. To analyze patient-reported outcomes (PROs) after hip arthroscopic surgery in adolescents (aged 10-19 years) and present a return-to-sport analysis in the athletic adolescent subgroup. Systematic review; Level of evidence, 4. The PubMed, Embase, and Cochrane databases were searched according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to identify articles that reported PROs after hip arthroscopic surgery in adolescents. The standardized mean difference was calculated to compare the effect size of hip arthroscopic surgery on various PROs. For the athletic subgroup, a return-to-sport summary was also provided. Ten studies, with 618 adolescent hips and a collective study period of December 2004 to February 2015, were included in this systematic review. Across all studies, the mean age was 15.8 years (range, 11.0-19.9 years), and female patients composed approximately 56.7% of the entire cohort. The mean follow-up was 34.5 months (range, 12-120 months). The modified Harris Hip Score (mHHS) was reported in 9 studies, and at latest follow-up, scores were excellent in 4 studies (range, 90-95) and good in the remaining 5 studies (range, 82.1-89.6). All adolescents also showed significant improvement on the Non-Arthritic Hip Score (NAHS), the Hip Outcome Score-Activities of Daily Living (HOS-ADL), the HOS-Sport-Specific Subscale (HOS-SSS), the physical component of the 12-Item Short Form Health Survey (SF-12P), a visual analog scale for pain (VAS), and both versions of the International Hip Outcome Tool (iHOT-12 and iHOT-33) at latest follow-up (P < .05). Further, mean improvements reported in all studies surpassed reported values of the minimal clinically important difference and patient acceptable symptomatic state for the mHHS, HOS-ADL, HOS-SSS, and iHOT-33. Finally, the collective return-to-sport rate among athletic adolescents was 84.9%. In the setting of labral tears and femoroacetabular impingement, hip arthroscopic surgery can safely be performed in adolescents and leads to significant functional improvement. Furthermore, athletic adolescents return to sport at high levels after hip arthroscopic surgery.


The effects of psychotherapy, nefazodone, and their combination on subjective assessment of disturbed sleep in chronic depression.
The purpose of the study was to compare the effects of psychotherapy, nefazodone, and their combination on subjective measures of sleep in patients with chronic forms of major depression. Participants were randomized to receive 12 weeks of treatment with one of the three interventions. The study was conducted in parallel at 12 academic institutions and was approved by the Human Subjects Committee at each site. 484 adult outpatients (65.29% female) who met DSM-IV criteria for one of three chronic forms of major depression. Psychotherapy (16-20 sessions) was provided by certified therapists following a standardized treatment manual for Cognitive Behavioral Analysis System of Psychotherapy (CBASP), a variant of cognitive psychotherapy developed for chronic depression. Pharmacotherapy consisted of open-label nefazodone, 300-600 mg per day in two divided doses prescribed by psychiatrists. The clinical management visits were limited to 15-20 minutes and followed a standardized protocol. Combination treatment consisted of both therapies. Depression outcome was determined by the 24-item Hamilton Rating Scale for Depression and the 30-item Inventory of Depressive Symptomatology-Self Rating. Sleep outcome was measured prospectively with daily sleep diaries that were completed a week prior to HRSD assessments at baseline and after 1, 2, 3, 4, 8, and 12 weeks of treatment. Although nefazodone alone and CBASP alone had comparable impact on global measures of depression outcome, only monotherapy with nefazodone improved early morning awakening and total sleep time. Significant improvements in sleep quality, time awake after sleep onset, latency to sleep onset, and sleep efficiency were present in each of the three treatment groups. These improvements, however, occurred earlier in the course of treatment for participants receiving nefazodone, alone or in combination with CBASP. Nefazodone therapy may have a direct impact on disturbed sleep associated with depression beyond what would be expected if the improvements were all a consequence of improved depression.


Qualitative light-scattering angular correlations of conglomerate particles.
The scattering phase functions of micrometer-sized glycerol droplets containing spherical latex inclusions undergo random fluctuations with time. We measure scattering intensities in the near-forward and near-backward scattering directions and find them to have strong positive correlations during some time periods and strong negative correlations during other time periods. The characteristic time constants of these correlations are of the order of seconds. We calculate scattering correlations from two types of scattering system. Correlations from a two-sphere system generally are positive, whereas correlations from a sphere containing a single spherical inclusion may be both positive and negative. Calculations of correlations from our experimental data are consistent with diffusion of inclusions within the host droplet, rather than interference effects between the inclusions.


Capacity of a Bayesian model to detect infected herds using disease dynamics and risk factor information from surveillance programmes: A simulation study.
Control programmes against non-regulated infectious diseases of farm animals are widely implemented. Different control programmes have different definitions of "freedom from infection" which can lead to difficulties when trading animals between countries. When a disease is still present, in order to identify herds that are safe to trade with, estimating herd-level probabilities of being infected when classified "free from infection" using field data is of major interest. Our objective was to evaluate the capacity of a Bayesian Hidden Markov Model, which computes a herd-level probability of being infected, to detect infected herds compared to using test results only. Herd-level risk factors, infection dynamics and associated test results were simulated in a population of herds, for a wide range of realistic infection contexts and test characteristics. The model was used to predict the infection status of each herd from longitudinal data: a simulated risk factor and a simulated test result. Two different indexes were used to categorize herds from the probability of being infected into a herd predicted status. The model predictive performances were evaluated using the simulated herd status as the gold standard. The model detected more infected herds than a single final test in 85 % of the scenarios which converged. The proportion of infected herds additionally detected by the model, compared to test results alone, varied depending on the context. It was higher in a context of a low herd test sensitivity. On average, around 20 %, for high test sensitivity scenarios, and 40 %, for low test sensitivity scenarios, of infected herds that were undetected by the test were accurately classified as infected by the model. Model convergence did not occur for 39 % of the scenarios, mainly in association with low herd test sensitivity. Detection of additional newly infected herds was always associated with an increased number of false positive herds (except for one scenario). The number of false positive herds was lower for scenarios with low herd test sensitivity and moderate to high incidence and prevalence. These results highlight the benefit of the model, in particular for control programmes with infection present at an endemic level in a population and reliance on test(s) of low sensitivity.


[The subject's propriety, space, and place].
This article deals with the "scenery", "horizons", and perspectives constituting the subject's place and situation from the psychoanalyst's limited perspective. Moving away from the body and its "embodiments" and places, many of which are institutionalized, including language itself, we look into such matters as velocity and other "conjectures" associated with technique. In addition, we also consider the body and nature as a whole as sites of action and presentations, which in several scenes lead to representations of the world in view of the peculiarities in the subject's experiences. All virtualities, together with the "disembodiment of physical presence", add one more variable to our thoughts. Recent endeavors like the feminist and homeless movements have shed new light on our understanding of the desire to possess and govern a territory. Art (and here drama plays an essential role) seems to be the perfect system towards which perceptions and syntheses are directed in search of new concepts and directions for understanding (which, in turn, has recently undergone an unprecedented crisis). Still, we should point out that the latter issue, not dealt with in this article, will be discussed at a suitable opportunity.


Evaluation of Clearview and Magic Lite tests, polymerase chain reaction, and cell culture for detection of Chlamydia trachomatis in urogenital specimens.
The Clearview Chlamydia test (CV; Unipath Ltd., Bedford, United Kingdom), the Magic Lite Chlamydia test (ML; CIBA Corning, Medfield, Mass.), a polymerase chain reaction (PCR), and cell culture (CC) were evaluated for detection of Chlamydia trachomatis in urogenital specimens. Specimens were collected from 283 men and 724 women visiting the outpatient clinic for Sexually Transmitted Diseases at the University Hospital Rotterdam, Rotterdam, The Netherlands. ML, PCR, and CC were all performed on the same sample to prevent swab-to-swab variability. CV was performed on a separate sample. Analysis of discordant results was performed by application of the following confirmatory assays: first, PCR on the CC, second, ML was repeated, and third, PCR was repeated by using a different DNA extraction protocol. If more than one test was positive, the sample was considered true positive. If only one test was positive, which was confirmed by the confirmatory assay, the sample was also considered true positive. By using these interpretations, the following results were obtained. The sensitivity and specificity of CV for samples from men were 60.4 and 86.3%, respectively. For samples from women, these values were 62.3 and 99.7%, respectively. The low specificity for samples from men was caused by unidentified substances in the swab that was used. The use of CV on samples from men is not recommended by the manufacturer. For samples from women, the specificity of CV was high, but the low sensitivity of CV limits its use for diagnostic purposes. The sensitivities of ML were low for samples from both men and women (68.8% and 50.9% respectively), while specificities were excellent for samples from both groups (100 and 99.9%, respectively). The low sensitivity of ML limits its diagnostic value. The PCR technique was highly specific for samples from both men (99.6%) and women (99.9%). The sensitivity of PCR, however, was unexpectedly low for samples from both groups (men, 87.5%; women, 79.2%), most likely because of the sample treatment method used. The sensitivity and specificity values of CC for samples from men were 95.8 and 100%, respectively. For samples from women, these values were 100 and 99.9%, respectively. In the present study, CC was the most reliable technique for the detection of C. trachomatis.


Use of a novel colony assay to evaluate the cytotoxicity of an immunotoxin containing pokeweed antiviral protein against blast progenitor cells freshly obtained from patients with common B-lineage acute lymphoblastic leukemia.
We report a novel colony assay for B-lineage progenitor cells in acute lymphoblastic leukemia (ALL). The primary plating efficiency of blast progenitors freshly obtained from common B-lineage ALL patients varied between 0.09 and 2.63%. Morphological, cytochemical, and immunological analyses of cells from day 7 colonies provided the evidence that they are B-lineage lymphoblasts. Immunological marker analyses of cultured blasts using BA-2 (anti-CD9), BA-3 (anti-CD10), BA-1 (anti-CD24), and B43 mAb have allowed us to define two distinct immunological groups. The first group had BA-2+, BA-3+, BA-1+, B43+ marker profiles, consistent with the phenotype of uncultured bone marrow blasts. The second group differed in that the cells in the blast colonies were BA-3 (anti-CD10)-negative, although many of the cells in the bulk population were BA-3+ before culture. Blasts from both groups were able to proliferate and form secondary colonies when recultured. A pan-B immunotoxin was synthesized by linking B43, a human B cell-specific mAb, to pokeweed antiviral protein (PAP). This study showed that B43-PAP can effectively eradicate leukemic progenitor cells freshly obtained from patients with common B-lineage ALL. B43-PAP eliminated greater than 99.96% of blast progenitors under conditions in which only minimal inhibition of normal bone marrow progenitor cells (CFU-GM, CFU-E, CFU-MK, CFU-GEMM) was observed. Our results establish that the surface determinant recognized by B43 is expressed on B-lineage progenitor cells in ALL, and that these cells are sensitive to PAP at the ribosomal level. To our knowledge, B43-PAP is the first IT to prove effective against common B-lineage ALL cells.


Eco-friendly non-biocide-release coatings for marine biofouling prevention.
Environmental concerns have been changing the way of looking for solutions to problems. The hydrosphere, together with its biosphere, has been feeling the impact of many pollutants, used for instance in the marine industry for economic reasons or lack of knowledge of their effects. In particular biocides, applied as coatings in paints, are released into the waters becoming toxic and persistent extending their action to an area far beyond the initial coated surface they should protect. In order to minimize these side effects, two biocides, Irgarol (I) and Econea (E), were covalently attached to polyurethane (PU) and foul-release silicone based (PDMS) marine paints through an isocyanate linker. Their antifouling bioactivity was better in PDMS coatings, both for single (Econea) and combined biocides (E/I ratio = 1.5) with contents lower than 0.6 wt%. The treated samples remained almost clean after more than one year immersion in the Portuguese shore of the Atlantic Ocean, and after about 24 weeks under the tropical conditions of Singapore (Fouling rate < 1%). Complementary biofilm adhesion susceptibility tests against Pseudoalteromonas tunicata D2 showed adhesion reduction higher than 90% for PU formulations containing single biocides and close to 100% for PDMS with combined biocides. The eco-toxicity assessment evidenced a low environmental impact, in accordance with the European standards. In addition, shipping field trial tests showed the best antifouling performance for the Econea-based PDMS formulations (E = 0.6 wt%), which remained clean for about nine months in open seawaters, proving the efficacy of this non-release strategy, when applied under dynamic conditions.


Mechanical properties of plasma membrane vesicles correlate with lipid order, viscosity and cell density.
Regulation of plasma membrane curvature and composition governs essential cellular processes. The material property of bending rigidity describes the energetic cost of membrane deformations and depends on the plasma membrane molecular composition. Because of compositional fluctuations and active processes, it is challenging to measure it in intact cells. Here, we study the plasma membrane using giant plasma membrane vesicles (GPMVs), which largely preserve the plasma membrane lipidome and proteome. We show that the bending rigidity of plasma membranes under varied conditions is correlated to readout from environment-sensitive dyes, which are indicative of membrane order and microviscosity. This correlation holds across different cell lines, upon cholesterol depletion or enrichment of the plasma membrane, and variations in cell density. Thus, polarity- and viscosity-sensitive probes represent a promising indicator of membrane mechanical properties. Additionally, our results allow for identifying synthetic membranes with a few well defined lipids as optimal plasma membrane mimetics.


Combined Effects of Time Spent in Physical Activity, Sedentary Behaviors and Sleep on Obesity and Cardio-Metabolic Health Markers: A Novel Compositional Data Analysis Approach.
The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005-6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.


Failure of colonoscopic surveillance in ulcerative colitis.
A prospective surveillance programme for patients with longstanding (> = 8 years), extensive (> = splenic flexure) ulcerative colitis was undertaken between 1978 and 1990. It comprised annual colonoscopy with pancolonic biopsy. One hundred and sixty patients were entered into the programme and had 739 colonoscopies (4.6 colonoscopies per patient; 709 patient years follow up). Eight eight per cent of examinations reached the right colon. There was no procedure related death. One Dukes's A cancer was detected. Forty one patients (25%) defaulted. Of these 25 remain well; 13 are unaccounted for, and one died from colonic cancer. One patient had colectomy for medical reasons, and another died of carcinoma of the pancreas. Retrospectively an additional 16 eligible patients were identified who had not been recruited. Of these, 14 remain well, two are unaccounted for. None developed colonic cancer. Four patients refused colonoscopy. All remain well. Over the same period seven other cases of colonic cancer were found in association with ulcerative colitis, two in patients who had erroneously been diagnosed as having only proctitis and were therefore not entered into the programme, but were found at operation to have total colitis, one in a patient with colitis of seven years duration, and four patients who had previously attended the clinic but had been lost to follow up before 1978 and then had represented with new symptoms during the surveillance period. Thus, of the nine colitis related cancers diagnosed in this centre during the study period only one was detected by the surveillance programme. The results of this large study, a a review of published works, cast doubts on the effectiveness of colonoscopic surveillance programmes in detecting colorectal cancer in patients with ulcerative colitis.


Pregnenolone stimulates LNCaP prostate cancer cell growth via the mutated androgen receptor.
Pregnenolone (P(5)), a common precursor of many steroids, is present in the blood of normal adult men at concentrations of 1-3 nM. In vitro, P(5) was found to stimulate LNCaP-cell proliferation 7-8-fold at a physiological concentration (2 nM), and 3-4-fold at a subphysiological concentration (0.2 nM). Growth stimulation at the 2-nM concentration was comparable with that of the androgen, dihydrotestosterone at its physiological concentration (0.5 nM; 9-10-fold increase in cell number). To determine whether P(5) or its metabolites were mediating this growth response, LNCaP cells were incubated with [3H]P(5) and high-performance liquid chromatography (HPLC) was performed. After a 48-h exposure, two unidentified metabolites were detected. Although, the P(5) metabolites slightly increased LNCaP-cell growth in vitro, their effect was significantly less than P(5) alone, suggesting that the growth stimulation was mediated by P(5) itself. We further showed that P(5) sustained its proliferative activity in vivo and stimulated the growth of LNCaP-tumor xenografts in intact male SCID mice as well as in castrated animals. In order to determine whether P(5) was binding to a specific site in LNCaP cells, receptor binding studies were performed. Scatchard analysis predicted for a single class of binding sites with K(d)=1.4 nM. Studies were performed to determine the effects of P(5) on transcription mediated by wild-type and LNCaP androgen receptors. P(5) was shown to activate transcription through the LNCaP androgen receptor (AR), but not the wild-type AR. This implies that P(5) most likely stimulates LNCaP-cell proliferation through binding to the cellular mutated AR present in LNCaP cells. We have also demonstrated that drugs designed to be antagonists of the androgen, progesterone and estrogen receptors, and one of our novel compounds designed to be an inhibitor of androgen synthesis, were potent inhibitors of the AR-mediated transcriptional activity induced by P(5), and were able to inhibit LNCaP-cell proliferation. These findings suggest that some prostate cancer patients who appear to become hormone-independent may have tumors which are stimulated by P(5) via a mutated AR and that these patients could benefit from treatment with antiestrogens, antiprogestins, or with some of our novel androgen synthesis inhibitors.


Neutrophils Kill Reactive Oxygen Species-Resistant Pseudomonas aeruginosa by Sphingosine.
Cystic fibrosis (CF) is dominated by chronic inflammation and infection of the lung resulting in lung destruction and early death of patients. The lungs of CF patients are characterized by a massive accumulation of neutrophils. It requires definition why these massive numbers of neutrophils fail to eliminate typical CF pathogens like Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa) in CF lungs. We determined ceramide, sphingosine and reactive oxygen species (ROS) in neutrophils from wildtype and CF mice and determined the effect of sphingosine and ROS alone or in combination on killing of different P. aeruginosa strains. We demonstrate that wildtype neutrophils are able to kill non-mucoid and mucoid clinical P. aeruginosa strains, while neutrophils from CF mice are insufficient to kill these P. aeruginosa strains, although both types of neutrophils infected with P. aeruginosa produce comparable levels of superoxide. All three analyzed P. aeruginosa strains are resistant to reactive oxygen species. The inability of CF neutrophils to kill P. aeruginosa is caused by a marked decrease of surface sphingosine levels in CF neutrophils. Wildtype neutrophils contain much higher concentrations of surface sphingosine than CF neutrophils. Further, wildtype neutrophils, but not CF neutrophils, release sphingosine, most likely as microparticles, upon infection. Sphingosine kills P. aeruginosa in vitro at low micromolar concentrations. Reconstitution of sphingosine in CF neutrophils restores their ability to kill these pathogens, demonstrating the significance of sphingosine for bacterial killing. The data provide evidence for a new paradigm explaining how neutrophils kill ROS-resistant P. aeruginosa, i.e. by sphingosine that kills P. aeruginosa at low concentrations. This mechanism is defective in CF neutrophils.


Atmospheric observation-based estimation of fossil fuel CO2 emissions from regions of central and southern California.
Combustion of fossil fuel is the dominant source of greenhouse gas emissions to the atmosphere in California. Here, we describe radiocarbon (14CO2) measurements and atmospheric inverse modeling to estimate fossil fuel CO2 (ffCO2) emissions for 2009-2012 from a site in central California, and for June 2013-May 2014 from two sites in southern California. A priori predicted ffCO2 mixing ratios are computed based on regional atmospheric transport model (WRF-STILT) footprints and an hourly ffCO2 prior emission map (Vulcan 2.2). Regional inversions using observations from the central California site suggest that emissions from the San Francisco Bay Area (SFBA) are higher in winter and lower in summer. Taking all years together, the average of a total of fifteen 3-month inversions from 2009 to 2012 suggests ffCO2 emissions from SFBA were within 6 ± 35% of the a priori estimate for that region, where posterior emission uncertainties are reported as 95% confidence intervals. Results for four 3-month inversions using measurements in Los Angeles South Coast Air Basin (SoCAB) during June 2013-May 2014 suggest that emissions in SoCAB are within 13 ± 28% of the a priori estimate for that region, with marginal detection of any seasonality. While emissions from the SFBA and SoCAB urban regions (containing ~50% of prior emissions from California) are constrained by the observations, emissions from the remaining regions are less constrained, suggesting that additional observations will be valuable to more accurately estimate total ffCO2 emissions from California as a whole.


[Prognosis of symptomatic epilepsies in relation to their age of onset, monitored at a neuropediatric section of regional reference over a period of three years].
To analyze the factors involved in the prognosis of symptomatic epilepsies in relation to their age at onset, monitored at a neuropediatric section of regional reference over a period of three years. Children diagnosed with symptomatic epilepsy, supervised from January 1, 2008 to December 31, 2010, collecting epidemiological, clinical and developmental data. Of the 4595 children attended during the period, the diagnosis of epilepsy was established at 605 (13.17%): 277 (45.79%) symptomatic epilepsies. Symptomatic etiology predomininates in epileptic patients that started below one year of age, 67.72%, and between 1-3 years, 61.39%. 37.54% of symptomatic epilepsy is refractory, 72.92% have cognitive impairment, 55.23% have motor impairment and 17.32% have autism spectrum disorder. The younger the patient, the higher the percentage of refractoriness and display of any neurological or associated development impact. Some etiologies have higher rates of refractoriness. A useful classification would be etiological, with two groups: a large group with established etiology or very likely genetic syndromes and another with no established cause. The age of onset of epilepsy in each etiological group adds prognostic orientation. Prognosis of epilepsy is overshadowed by refractoriness and associated neurodevelopmental disorders, which are generally worse at an earlier onset and in certain etiologies.


One Sensor for Multiple Colors: Fluorescence Analysis of Microdroplets in Microbiological Screenings by Frequency-Division Multiplexing.
High-speed multiwavelength fluorescence measurements are of paramount importance in microfluidic analytics. However, multicolor detection requires an intricate arrangement of multiple detectors and meticulously aligned filters and dichroic beamsplitters that counteract the simplicity, versatility, and low cost of microfluidic approaches. To break free from the restrictions of optical setup complexity, we introduce a simpler single-sensor setup based on laser-frequency modulation and frequency-division multiplexing (FDM). We modulate lasers to excite the sample with four non-overlapping frequency signals. A single photomultiplier tube detects all the modulated emitted light collected by an optical fiber in the microfluidic chip. Signal demodulation is performed with a lock-in amplifier separating the emitted light into four color channels in real time. This approach not only reduces complexity and provides setup flexibility but also results in improved signal quality and, thus, higher signal-to-noise ratios that translate into increased sensitivity. To validate the setup for high-throughput biological applications, we measured multiple signals from different microorganisms and fluorescently encoded droplet populations for exploring beneficial or antagonistic roles in microbial cocultivation systems, as is the case for antibiotic screening assays.


Osseous regeneration in compromised extraction sites: a ten-year case study.
One of the many problems facing surgeons is finding adequate bone sites for implant support. Without adequate bone, there can be implant failure or poor esthetic results. By using guided tissue regeneration (GTR) membranes and bone grafting materials, implants may be placed into immediate extraction sites and areas with large osseous defects with an expectation of long-term positive results. These concepts are illustrated by comparing the results of a ten-year follow-up evaluation of a patient lacking healthy bone at the implant site with another case in which the implant site had bone of acceptable morphology and density, with both cases showing similarly good results.


Necator americanus secretory acetylcholinesterase and its purification from excretory-secretory products by affinity chromatography.
Acetylcholinesterase (AChE) secretion by adult N. americanus was enhanced in vitro by incorporating insoluble collagen rafts into culture dishes. Enzyme produced in this way had preferential substrate specificity for acetylthiocholine iodide (ATC), and its activity was inhibited by eserine (1.1 x 10(-8) M). Ancylostoma ceylanicum, another hookworm species, failed to produce comparable amounts of AChE in culture. AChE was efficiently purified from culture medium by affinity chromatography on edrophonium sepharose; 81% of the AChE activity was retained by the affinity matrix, although this fraction contained only 4.3% of the protein loaded. Antisera raised against purified AChE in rabbits immunohistochemically stained the oesophageal glands of the parasite, and reacted with molecules of 32, 60, 80, 140 and 220 kDa in reduced adult ES products on Western blotting, although differential activity was observed against worm homogenates and earlier developmental stages. On IEF, purified AChE resolved predominantly with a pl of 3.55; proteins with a similar pl were recognized by rabbit anti-AChE. IgG preparations of this antiserum inhibited AChE activity in ES products, and inhibited AChE secretion by adult worms in culture. The availability of this immunological probe will allow definitive experiments to be conducted on the role of this enigmatic enzyme in the host-parasite relationship.


Periostin, a matrix specific protein, is associated with proliferation and invasion of pancreatic cancer.
Overexpression of periostin is present in various malignant tumors and correlates with disease progression. However, its clinicopathological significance in pancreatic cancer is currently not known. Expression of periostin was analyzed by RT-PCR and western blotting in pancreatic cancers and cell lines. Using immunohistochemistry, expression of periostin in pancreatic cancers was evaluated according to factors influencing overall survival with Kaplan-Meier analysis. Ectopic expression of periostin was used to examine the effects of periostin on proliferation and invasiveness of pancreatic cancer cells in vitro. There was no detectable periostin mRNA and protein expression in the 4 pancreatic cell lines. Expression of periostin was found to be up-regulated in pancreatic cancer compared to the adjacent tumor free (TF) tissues by western blotting. The positive ratio of periostin expression in the neoplastic stroma was significantly correlated with the depth of invasion (p=0.007) and lymph node metastasis (p=0.027). Survival analysis showed that stromal or epithelium expression of periostin was associated with poor survival (p=0.035, p=0.022, log-rank test, respectively). In vitro studies showed that periostin was able to promote proliferation and invasiveness of pancreatic cancer cells. These results suggest that periostin may be involved in the progression and invasion of pancreatic cancer.


Chemical modulation of transcription factors.
Transcription factors (TFs) constitute a diverse class of sequence-specific DNA-binding proteins, which are key to the modulation of gene expression. TFs have been associated with human diseases, including cancer, Alzheimer's and other neurodegenerative diseases, which makes this class of proteins attractive targets for chemical biology and medicinal chemistry research. Since TFs lack a common binding site or structural similarity, the development of small molecules to efficiently modulate TF biology in cells and in vivo is a challenging task. This review highlights various strategies that are currently being explored for the identification and development of modulators of Myc, p53, Stat, Nrf2, CREB, ER, AR, HIF, NF-κB, and BET proteins.


The development and testing of a survey to measure patient and family experiences with injury care.
To deliver patient-centered trauma care, we must capture patient and family experiences with the services they receive. We developed and pilot tested a survey to measure patient and family experiences with major injury care. We conducted a structured literature review and focus groups to generate survey items. We pilot tested the survey at a Level I trauma center and assessed feasibility of implementation and construct validity with Spearman's correlation coefficients. Open ended questions were qualitatively analyzed to explore whether responses corroborated survey content. We developed a survey with two parts: acute care component (46 items) and post-acute care component (27 items) with nine domains. We offered the survey (acute care component offered before hospital discharge, post-acute care component offered 1-7 months after discharge) to 170 patients/families, of whom 134 (79%) responded. Patients were primarily male (73%) with major injuries (median Injury Severity Score, 18; interquartile range, 16-25). Overall, respondents for both the acute care and post-acute care components of the survey reported being completely (47% vs. 26%), very (37% vs. 38%), or mostly (16% vs. 21%) satisfied with their injury care, whereas a minority reported being slightly (0% vs. 9%) or very (0% vs. 6%) dissatisfied (p = 0.002 Fischer's exact test). Most survey items were significantly correlated with overall satisfaction (46 of 60 items). Almost all qualitatively identified themes matched survey domains, adding support to the survey content. This pilot study demonstrates the feasibility of implementing a survey to capture patient and family experiences associated with major injury care and provides preliminary evidence of the instrument's content and construct validity. Epidemiologic study, level III.


Incidence of and risk factors for HIV-associated distal sensory polyneuropathy.
To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects. We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported. At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan-Meier estimate of the 1-year incidence of SDSP was 36%. Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.


Monolayer freeze-fracture autoradiography: quantitative analysis of the transmembrane distribution of radioiodinated concanavalin A.
The technique of monolayer freeze-fracture autoradiography (MONOFARG) has been developed and the principles, quantitation, and application of the method are described. Cell monolayers attached to polylysine-treated glass were freeze-fractured, shadowed, and coated with dry, Parlodion-supported Ilford L4 photographic emulsion at room temperature. Quantitative aspects of MONOFARG were examined using radioiodinated test systems. Background was routinely less than 2.5 X 10(-4) grains/microns 2/day, the highest overall efficiency was between 25% and 45%, and grain density and efficiency were dependent on radiation dose for iodine-125 and D-19 development. Corrected grain densities were linearly proportional to iodine-125 concentration. The method was applied to an examination of the transmembrane distribution of radioiodinated and fluoresceinated concanavalin A (125I-FITC-Con-A). Human erythrocytes were labeled, column-purified, freeze-dried or freeze-fractured, autoradiographed, and examined by electron microscopy. The number of silver grains per square micrometer of unsplit single membrane was essentially identical to that of split extracellular membrane "halves." These data demonstrate that 125I-FITC-Con-A partitions exclusively with the extracellular "half" of the membrane upon freeze-fracturing and can be used as a quantitative marker for the fraction of extracellular split membrane "halves." This method should be able to provide new information about certain transmembrane properties of biological membrane molecules and probes, as well as about the process of freeze-fracture per se.


Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.
In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.


Morphometric evaluation of the contractile apparatus in primary cultures of rabbit cardiac myocytes.
Rabbit cardiac myocytes remain quiescent for more than 1 month when cultured at low density. During this period, myofibrillar volume density declines sixfold as myofibrils are disassembled or degraded and are replaced by actin and alpha-actinin-positive, myosin-negative structures that resemble myofibrils but lack thick filaments. Such structures are termed minute myofibrils. The length of the sarcomeres in these altered myofibrils is significantly less than length values obtained from freshly isolated heart cells or from contracting myocytes. A number of high density cultures develop spontaneous, synchronous contraction during the second week of culture. Myofibrillar volume density is stabilized when beating begins, and no further decline is observed in the succeeding weeks of culture. Such contracting myocytes display myofibrils typical of normal heart with no visible evidence of minute myofibrils. The volume density of the transverse tubular system also declines significantly in both beating and nonbeating myocytes, and its reduction appears more closely correlated with cell spreading than with beating per se. No quantitative changes in volume density of mitochondria or sarcoplasmic reticulum could be documented, but the structural organization of the sarcoplasmic reticulum seems to be greatly influenced by the physiological state of the heart cell. The present observations document the importance of mechanical factors in regulating the integrity of the contractile apparatus in cardiac myocytes and emphasize the utility of the cultured heart cell to directly investigate structure-function relations in individual myocytes.


Adaptive interferometry of protein on a BioCD.
Adaptive spinning-disk interferometry is capable of measuring surface profiles of a thin biolayer with subnanometer longitudinal resolution. High-speed phase modulation in the signal beam arises from the moving surface height profile on the spinning disk and is detected as a homodyne signal via dynamic two-wave mixing. A photorefractive quantum-well device performs as an adaptive mixer that compensates disk wobble and vibration while it phase-locks the signal and reference waves in the phase quadrature condition (pi/2 relative phase between the signal and local oscillator). We performed biosensing of immobilized monolayers of antibodies on the disk in both transmission and reflection detection modes. Single- and dual-analyte adaptive spinning-disk immunoassays were demonstrated with good specificity and without observable cross-reactivity. Reflection-mode detection enhances the biosensing sensitivity to one-twentieth of a protein monolayer, creates a topographic map of the protein layer, and can differentiate monolayers of different species by their effective optical thicknesses.


Quantitative magnetic resonance imaging volumetry distinguishes delusional disorder from late-onset schizophrenia.
Late paraphrenia is recognised as a heterogeneous disorder. This is reflected by the division of such patients into schizophrenia and delusional disorder in ICD-10. Earlier imaging studies have suggested that major structural abnormalities may be associated with the onset of psychosis in later life. Fifty late paraphrenics and 35 age-matched healthy controls underwent structural magnetic resonance imaging of the whole brain in the coronal plane. Measurements were made of intracranial and brain volumes and the volumes of the intracerebral and extracerebral cerebrospinal fluid spaces. No differences in intracranial, brain or extracerebral cerebrospinal fluid volumes between patients and controls were found. Late paraphrenic patients had greater lateral and third ventricle volumes than controls and the left lateral ventricle was larger than the right. When the patients were divided into appropriate ICD-10 diagnoses: paranoid schizophrenia (n = 31) and delusional disorder (n = 16), lateral ventricle volumes in the delusional disorder patients were much greater than those of the schizophrenics and almost twice those of controls. Structural brain differences underly diagnostic heterogeneity within late paraphrenia. The brains of late onset schizophrenics are only subtly different from those of healthy elderly individuals.


Bifidobacterium-Rich Fecal Donor May Be a Positive Predictor for Successful Fecal Microbiota Transplantation in Patients with Irritable Bowel Syndrome.
Dysbiosis is associated with various systemic disorders including irritable bowel syndrome (IBS). Fecal microbiota transplantation (FMT) might restore intestinal microbial balance. The study aimed to determine the safety and efficacy of FMT in IBS patients, as well as also positive predictors for FMT. This was a single-arm, open-label study. Eligible patients were diagnosed based on Rome III Diagnostic Criteria. Fecal materials were administered to the patient via colonoscopy. The primary end point was a change in the Bristol stool form scale at 4 weeks after FMT. Recovery to types 3-4 was considered a clinical response. The secondary end point was a change in intestinal microbiota and psychological status using the Hamilton Rating Scale. Ten patients were enrolled. Six patients achieved a clinical response. The diversity of patients 4 weeks after FMT increased significantly compared with patients before FMT, and that of responding patients was significantly higher than non-responder patients. The abundance of Bifidobacterium in effective donors was significantly higher than in ineffective donors and patients. Psychological status of all patients was significantly improved after FMT. FMT for patients with IBS is safe, and relatively effective. Bifidobacterium-rich fecal donor may be a positive predictor for successful FMT. Key Summary: (1) Dysbiosis is associated with various gastrointestinal disorders including IBS. (2) FMT has potential to restore intestinal microbial balance. (3) We showed that FMT improved stool form and psychological status of IBS patients. (4) Bifidobacterium-rich donor efficiently induced symbiosis in IBS patients.


Human brain organoids assemble functionally integrated bilateral optic vesicles.
During embryogenesis, optic vesicles develop from the diencephalon via a multistep process of organogenesis. Using induced pluripotent stem cell (iPSC)-derived human brain organoids, we attempted to simplify the complexities and demonstrate formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day 30, brain organoids attempt to assemble optic vesicles, which develop progressively as visible structures within 60 days. These optic vesicle-containing brain organoids (OVB-organoids) constitute a developing optic vesicle's cellular components, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. OVB-organoids also display synapsin-1, CTIP-positive myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photosensitive activity of OVB-organoids, and light sensitivities could be reset after transient photobleaching. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow interorgan interaction studies within a single organoid.


Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor.
The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier.


Researchers of chronic obstructive pulmonary disease gathered at the 2017 Japan-China Joint Medical Workshop on Aging and Health.
As the number of elderly and the size of the total population increase, population aging will become a major problem because of an increase in diseases associated with aging, such as chronic obstructive pulmonary disease (COPD). The 2017 Japan-China Joint Medical Workshop on Aging and Health was held at The University of Tokyo on December 2, 2017 with a focus on management of COPD. More than 50 experts in the fields of respiratory medicine, emergency medicine, traditional Chinese medicine, and Kampo (traditional Japanese medicine) from Japan and China presented the results of their research and shared their experiences treating COPD from different perspectives. Guidelines for diagnosis and management of COPD in different countries were described at the workshop, and advances in recent research into the treatment of COPD with Kampo and traditional Chinese medicine were fully discussed. The results of the workshop should help to improve GOLD guidelines and they should greatly help to optimize COPD treatment.


Does the vagus nerve inform the brain about preclinical tumours and modulate them?
The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.