Education research: case logs in the assessment of medical students in the neurology outpatient clinic.
Using outpatient neurology clinic case logs completed by medical students on neurology clerkships, we examined the impact of outpatient clinical encounter volume per student on outcomes of knowledge assessed by the National Board of Medical Examiners (NBME) Clinical Neurology Subject Examination and clinical skills assessed by the Objective Structured Clinical Examination (OSCE). Data from 394 medical students from July 2008 to June 2012, representing 9,791 patient encounters, were analyzed retrospectively. Pearson correlations were calculated examining the relationship between numbers of cases logged per student and performance on the NBME examination. Similarly, correlations between cases logged and performance on the OSCE, as well as on components of the OSCE (history, physical examination, clinical formulation), were evaluated. There was a correlation between the total number of cases logged per student and NBME examination scores (r = 0.142; p = 0.005) and OSCE scores (r = 0.136; p = 0.007). Total number of cases correlated with the clinical formulation component of the OSCE (r = 0.172; p = 0.001) but not the performance on history or physical examination components. The volume of cases logged by individual students in the outpatient clinic correlates with performance on measures of knowledge and clinical skill. In measurement of clinical skill, seeing a greater volume of patients in the outpatient clinic is related to improved clinical formulation on the OSCE. These findings may affect methods employed in assessment of medical students, residents, and fellows.


The presence of SARS-CoV-2 RNA in human sewage in Santa Catarina, Brazil, November 2019.
Human sewage from Florianopolis (Santa Catarina, Brazil) was analyzed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) from October 2019 until March 2020. Twenty five ml of sewage samples were clarified and viruses concentrated using a glycine buffer method coupled with polyethylene glycol precipitation, and viral RNA extracted using a commercial kit. SARS-CoV-2 RNA was detected by RT-qPCR using oligonucleotides targeting N1, S and two RdRp regions. The results of all positive samples were further confirmed by a different RT-qPCR system in an independent laboratory. S and RdRp amplicons were sequenced to confirm identity with SARS-CoV-2. Genome sequencing was performed using two strategies; a sequence-independent single-primer amplification (SISPA) approach, and by direct metagenomics using Illumina's NGS. SARS-CoV-2 RNA was detected on 27th November 2019 (5.49 ± 0.02 log10 SARS-CoV-2 genome copies (GC) L-1), detection being confirmed by an independent laboratory and genome sequencing analysis. The samples in the subsequent three events were positive by all RT-qPCR assays; these positive results were also confirmed by an independent laboratory. The average load was 5.83 ± 0.12 log10 SARS-CoV-2 GC L-1, ranging from 5.49 ± 0.02 log10 GC L-1 (27th November 2019) to 6.68 ± 0.02 log10 GC L-1 (4th March 2020). Our findings demonstrate that SARS-CoV-2 was likely circulating undetected in the community in Brazil since November 2019, earlier than the first reported case in the Americas (21st January 2020).


An Overview of the Potential of Food-Based Carbon Dots for Biomedical Applications.
Food-based carbon dots (CDs) hold significant importance across various fields, ranging from biomedical applications to environmental and food industries. These CDs offer unique advantages over traditional carbon nanomaterials, including affordability, biodegradability, ease of operation, and multiple bioactivities. This work aims to provide a comprehensive overview of recent developments in food-based CDs, focusing on their characteristics, properties, therapeutic applications in biomedicine, and safety assessment methods. The review highlights the potential of food-based CDs in biomedical applications, including antibacterial, antifungal, antivirus, anticancer, and anti-immune hyperactivity. Furthermore, current strategies employed for evaluating the safety of food-based CDs have also been reported. In conclusion, this review offers valuable insights into their potential across diverse sectors and underscores the significance of safety assessment measures to facilitate their continued advancement and application.


Patients With Concomitant Painful External Snapping Hip and Femoroacetabular Impingement Syndromes Reported Complete Snapping Resolution With Release of the Gluteus Maximus and Iliotibial Band, and Comparable Minimum 2-Year Outcomes to a Propensity-Matched Control Group.
To report minimum 2-year patient-reported outcome measures (PROMs) following primary hip arthroscopy for femoroacetabular impingement syndrome (FAIS) and painful external snapping hip (ESH) treatment and ESH resolution, and to compare these PROMs to a benchmark FAIS propensity-matched control group without ESH. Data were prospectively collected and retrospectively reviewed between November 2009 and April 2018. Patients were eligible if they were preoperatively diagnosed with FAIS and painful ESH and received primary hip arthroscopy to address these pathologies. ESH was treated with gluteus maximus and iliotibial band releases. Inclusion criteria were baseline and minimum two-year follow-up scores for the modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score-Sport Specific Subscale, and visual analog scale for pain. Exclusion criteria were Tönnis grade >1 and previous hip conditions. A secondary subanalysis was performed to benchmark these outcomes to a FAIS propensity-matched control group without ESH, according to age, sex, body mass index (BMI), Tönnis grade, and preoperative lateral center-edge and α-angles using a 1:3 ratio. The minimal clinically important difference (MCID) and the maximum outcome improvement (MOI) rates were reported. Twenty-two hips (21 patients) were included. The mean age, BMI, and follow-up were 31.3 years ± 14.0, 26 kg/m2 ± 5.0, and 31.4 months ± 4.4, respectively, with 68.2% being female. ESH was resolved in 100% of patients. Significant improvement for all PROMs at a minimum two-year (P < .001) was reported. The minimum two-year PROMs and the rate of achieving the MCID and MOI threshold were comparable to the control group. Following primary hip arthroscopy for FAIS and painful ESH, patients demonstrated significant improvement in all PROMs, and the rate of resolution of ESH was 100% at minimum two-year follow-up: with gluteus maximus and iliotibial band releases. Functional outcomes and rates of MCID and MOI achievement were comparable to a FAIS propensity-matched benchmark control group without ESH. Level III, retrospective comparative study.


The non-structural proteins of bluetongue virus are a dominant source of cytotoxic T cell peptide determinants.
Virus-specific, CD8+ cytotoxic T lymphocytes (CTLs) were generated in two strains of mice (BALB/c, CBA/Ca) against bluetongue virus serotype 10 (BTV-10). Recombinant vaccinia viruses (VV) expressing the individual structural and non-structural proteins of BTV were used to infect syngeneic target cells. We found that in both BALB/c (H-2d) and CBA/Ca (H-2k) mice, polyclonal CTL populations recognized target cells expressing the non-structural proteins better than those expressing the structural proteins. CTLs generated against other BTV serotypes also predominantly recognized the non-structural proteins. However, the extent of cross-reactivity was dependent on the H-2 background of the animals immunized. No CTLs cross-reactive to the BTV-10 heterotype were demonstrated with the panel of molecularly cloned recombinants in the H-2d haplotype. The outer capsid proteins VP2 and VP5 which vary considerably between serotypes were not recognized by heterotypic CTLs. Using this murine model we have determined which BTV proteins are the major targets of the CTL response. The implications for the design and development of subunit vaccines are discussed.


Cost-effectiveness of dapagliflozin in chronic heart failure: an analysis from the Australian healthcare perspective.
To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction. A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for heart failure' and 'dead'. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually. Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively. Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.


Explanation of dijet asymmetry in Pb-Pb collisions at the Large Hadron Collider.
We investigate the medium modification of a partonic jet shower traversing in a hot quark-gluon plasma. We derive and solve a differential equation that governs the evolution of the radiated gluon distribution as the jet propagates through the medium. Energy contained inside the jet cone is lost by dissipation through elastic collisions with the medium and by scattering of shower partons to larger angles. We find that the jet energy loss at early times is dominated by medium effects on the vacuum radiation, and by medium-induced radiation effects at late times. We compare our numerical results for the nuclear modification of the dijet asymmetry with that recently reported by the ATLAS Collaboration.


[18F]GE-180 PET Detects Reduced Microglia Activation After LM11A-31 Therapy in a Mouse Model of Alzheimer's Disease.
Microglial activation is a key pathological feature of Alzheimer's disease (AD). PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation in vivo. Here we assessed flutriciclamide ([18F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials. AD mice displaying pathology were treated orally with LM11A-31 for 3 months. Subsequent [18F]GE-180-PET imaging revealed significantly lower signal in cortex and hippocampus of LM11A-31-treated AD mice compared to those treated with vehicle, corresponding with decreased levels of TSPO immunostaining and microglial Iba1 immunostaining. In addition to detecting decreased microglial activation following LM11A-31 treatment, [18F]GE-180 identified activated microglia in AD mice with greater sensitivity than another second-generation TSPO radiotracer, [18F]PBR06. Together, these data demonstrate the promise of [18F]GE-180 as a potentially sensitive tool for tracking neuroinflammation in AD mice and for monitoring therapeutic modulation of microglial activation.


Alcoholic typologies. A review of empirical evaluations of common classification schemes.
This chapter reviews literature examining two typological classifications of alcoholism: typologies derived empirically by employing multivariate statistical techniques and typological classification schemes formulated from theoretical frameworks. Most of the empirical classifications were based on personality measures such as the MMPI, 16PF, and others. Examinations of theoretically based typologies included gender, psychopathology, and family history. The usefulness and limitations of these typological approaches are discussed.


Simulation guided design of silver nanostructures for plasmon-enhanced fluorescence, singlet oxygen generation and SERS applications.
Plasmonic nanostructures such as gold and silver could alter the intrinsic properties of fluorophores, photosensitizers or Raman reporters in their close vicinity. In this study, we have conducted systematic simulations to provide insight for the design of silver nanostructures with appropriate geometrical features for metal-enhanced fluorescence (MEF), metal-enhanced singlet oxygen generation (ME-SOG) and surface-enhanced Raman scattering (SERS) applications. The size-dependent optical properties and electric field enhancement of single and dimeric nanocubes were simulated. The extinction spectra of silver nanocubes were analysed by the multipole expansion method. Results show that a suitable size of Ag nanocubes for MEF and ME-SOG can be selected based on their maximum light scattering yield, the excitation and emission wavelengths of a particular fluorophore/photosensitizer and their maximum spectral overlap. Simulations of the 'hot-spot' or gap distance between two silver nanocubes with different configurations (i.e., face-to-face, edge-to-edge and corner-to-corner) were also performed. A direct correlation was found between the size and enhanced electric field around the Ag nanocubes simulated under 15 common Raman laser wavelengths from the UV to near-infrared region. The maximum SERS enhancement factor can be achieved by selecting the silver nanocubes with the right orientation, suitable edge length and gap distance that give the highest electric field at a specific Raman laser wavelength. It was also found that the higher order of silver nanostructures, e.g., trimer and tetramer, can lead to better enhancement effects. These simulation results can serve as generic guidelines to rationally design metal-enhancement systems including MEF, ME-SOG and SERS for different application needs without cumbersome optimization and tedious trial-and-error experimentation.


Dilatation balloons: polymer selection, balloon design and assembly.
The current status of coronary dilating instruments is presented from the designer's perspective. Catheter shaft design is considered by important features, common catheter materials and types of catheter construction. Among the seven companies manufacturing balloon dilating instruments, only three types of catheter and four materials are offered. Balloon design is presented by important features and by materials selected. Performance comparisons are made between the three materials used to fabricate dilating balloons: PVC, PE and PET.


Ethanol Solvation in Water Studied on a Molecular Scale by Photoelectron Spectroscopy.
Because of the amphiphilic properties of alcohols, hydrophobic hydration is important in the alcohol-water system. In the present paper we employ X-ray photoelectron spectroscopy (XPS) to investigate the bulk and surface molecular structure of ethanol-water mixtures from 0.2 to 95 mol %. The observed XPS binding energy splitting between the methyl C 1s and hydroxymethyl C 1s groups (BES_[CH3-CH2OH]) as a function of the ethanol molar percentage can be divided into different regions: one below 35 mol % with higher values (about 1.53 eV) and one starting at 60 mol % up to 95 mol % with 1.49 eV as an average value. The chemical shifts agree with previous quantum mechanics/molecular mechanics (QM/MM) calculations [ Löytynoja , T. ; J. Phys. Chem. B 2014 , 118 , 13217 ]. According to these calculations, the BES_[CH3-CH2OH] is related to the number of hydrogen bonds between the ethanol and the surrounding molecules. As the ethanol concentration increases, the average number of hydrogen bonds decreases from 2.5 for water-rich mixtures to 2 for pure ethanol. We give an interpretation for this behavior based on how the hydrogen bonds are distributed according to the mixing ratio. Since our experimental data are surface sensitive, we propose that this effect may also be manifested at the interface. From the ratio between the XPS C 1s core lines intensities we infer that below 20 mol % the ethanol molecules have their hydroxyl groups more hydrated and possibly facing the solution's bulk. Between 0.1 and 14 mol %, we show the formation of an ethanol monolayer at approximately 2 mol %. Several parameters are derived for the surface region at monolayer coverage.


Crosstalk between glial and glioblastoma cells triggers the "go-or-grow" phenotype of tumor cells.
Glioblastoma (GBM), the most malignant primary brain tumor, leads to poor and unpredictable clinical outcomes. Recent studies showed the tumor microenvironment has a critical role in regulating tumor growth by establishing a complex network of interactions with tumor cells. In this context, we investigated how GBM cells modulate resident glial cells, particularly their paracrine activity, and how this modulation can influence back on the malignant phenotype of GBM cells. Conditioned media (CM) of primary mouse glial cultures unexposed (unprimed) or exposed (primed) to the secretome of GL261 GBM cells were analyzed by proteomic analysis. Additionally, these CM were used in GBM cells to evaluate their impact in glioma cell viability, migration capacity and activation of tumor-related intracellular pathways. The proteomic analysis revealed that the pre-exposure of glial cells to CM from GBM cells led to the upregulation of several proteins related to inflammatory response, cell adhesion and extracellular structure organization within the secretome of primed glial cells. At the functional levels, CM derived from unprimed glial cells favored an increase in GBM cell migration capacity, while CM from primed glial cells promoted cells viability. These effects on GBM cells were accompanied by activation of particular intracellular cancer-related pathways, mainly the MAPK/ERK pathway, which is a known regulator of cell proliferation. Together, our results suggest that glial cells can impact on the pathophysiology of GBM tumors, and that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the "go-or-grow" phenotypic switch of GBM cells.


[Streptococcus gallolyticus infections in racing pigeons, a literature review].
S. gallolyticus, formerly known as S. bovis is known since 1988 as a facultative pathogen of racing pigeons. Important clinical signs include acute mortality, inability to fly, lameness, weight loss and slimy green diarrhea. A pathognomonic sign at post mortem examination is the presence of well circumscribed areas of necrosis in the pectoral muscle. Furthermore tenosynovitis of the supracoracoid muscle and arthritis of the knee, shoulder and hock can be observed. In one study S. gallolyticus septicaemia was diagnosed in 10% of necropsied pigeons. Since S. gallolyticus was also isolated from nearly 40% of clinical healthy pigeons it is regarded as a facultative pathogen. Various biotypes, serotypes and culture supernatant phenotypes can be distinguished. Supernatant phenotypes are identified on the basis of the presence of either a T1, T2 or T3 protein triplet and the presence or absence of an extracellular A protein. S. gallolyticus strains with A protein are highly virulent, while strains with only T3 or T2 protein are of moderately or low virulence respectively. Fimbriae are only seen in highly virulent and some of the moderately virulent strains. Possible virulence factors include survival in macrophages, adhesion to cells and toxin production. Infection with serotype 1 and 2 induces some degree of protection against re-infection with serotype 1, which offers perspectives for the development of a vaccine. Experimentally ampicillin, doxycycline and erythromycin have shown therapeutic effects. For the treatment of clinical cases the use of ampicillin is advocated, together with hygienic measures, such as the use of grid floors and avoiding overcrowding.


The role of dynamics in heterogeneous catalysis: Surface diffusivity and N2 decomposition on Fe(111).
Dynamics has long been recognized to play an important role in heterogeneous catalytic processes. However, until recently, it has been impossible to study their dynamical behavior at industry-relevant temperatures. Using a combination of machine learning potentials and advanced simulation techniques, we investigate the cleavage of the N[Formula: see text] triple bond on the Fe(111) surface. We find that at low temperatures our results agree with the well-established picture. However, if we increase the temperature to reach operando conditions, the surface undergoes a global dynamical change and the step structure of the Fe(111) surface is destabilized. The catalytic sites, traditionally associated with this surface, appear and disappear continuously. Our simulations illuminate the danger of extrapolating low-temperature results to operando conditions and indicate that the catalytic activity can only be inferred from calculations that take dynamics fully into account. More than that, they show that it is the transition to this highly fluctuating interfacial environment that drives the catalytic process.


Psychosocial work environment, stress factors and individual characteristics among nursing staff in psychiatric in-patient care.
The psychosocial work environment is an important factor in psychiatric in-patient care, and knowing more of its correlates might open up new paths for future workplace interventions. Thus, the aims of the present study were to investigate perceptions of the psychosocial work environment among nursing staff in psychiatric in-patient care and how individual characteristics--Mastery, Moral Sensitivity, Perceived Stress, and Stress of Conscience--are related to different aspects of the psychosocial work environment. A total of 93 nursing staff members filled out five questionnaires: the QPSNordic 34+, Perceived Stress Scale, Stress of Conscience Questionnaire, Moral Sensitivity Questionnaire, and Mastery scale. Multivariate analysis showed that Perceived Stress was important for Organisational Climate perceptions. The Stress of Conscience subscale Internal Demands and Experience in current units were indicators of Role Clarity. The other Stress of Conscience subscale, External Demands and Restrictions, was related to Control at Work. Two types of stress, Perceived Stress and Stress of Conscience, were particularly important for the nursing staff's perception of the psychosocial work environment. Efforts to prevent stress may also contribute to improvements in the psychosocial work environment.


[Myelodepression during antitumor therapy in hepatorenal insufficiency].
The hematotoxicity of cytostatics was found enhanced if these agents were used in therapy of oncologic patients with disordered functional activity of the hepatorenal system. Decreased absorption and excretory functions of the hepatocytes or renal abnormalities associated with impaired glomerular filtration and secretory-excretory function are the factors that contribute to the development of leukopenia by the middle or end of the treatment course. This permits a conclusion on the prognostic value of examinations of liver and kidney function in cases with the development of secondary hemodepression in chemotherapy of oncologic patients.


Misonidazole with small dose fractions in an experimental osteosarcoma.
The mouse osteosarcoma C22LR was irradiated with a single X-ray dose of 1000 or 1500 rad (to prevent rapid growth) and then with fractionated doses of 300 or 600 rad each. Half the mice were given 0.8 mg/g of misonidazole 1 h before irradiation. Tumour growth delay was determined. The radiosensitizer did enhance the effect of small (300 rad) doses per fraction, as well as that of 600 rad doses.


Colon cancer information as a source of exercise motivation for relatives of patients with colon cancer.
Using a Protection Motivation Theory (PMT) framework, this study examined whether factual colon cancer information is a meaningful source of exercise motivation for relatives of patients with colon cancer. One hundred sixty-six inactive relatives were randomly assigned to one of two treatment conditions: PMT group (intervention); and non-PMT group (attention control). At baseline (T1) participants completed demographic information, a questionnaire designed to assess their beliefs toward exercise and colon cancer as well as their exercise intentions. At T2 (one week following T1) participants watched one of two DVD videos that were created for the study. The intervention DVD contained exercise and colon cancer information that was yoked within the four major components of PMT: perceived vulnerability (PV); perceived severity (PS); response efficacy (RE); and self-efficacy (SE), while the attention control DVD contained general diet and cancer information. Immediately following watching the DVD, participants completed the same measures as in T1. Participants assigned to the PMT intervention group showed significant improvement in PV, RE, SE and exercise intentions, whereas participants assigned to the attention control group showed significant improvement only in RE. RE, SE, and PS made significant and unique contributions to prediction of exercise intention. Overall, the results of the present study demonstrate that a single exposure media intervention grounded in a PMT framework can change individuals' exercise and colon cancer beliefs, as well as change their exercise intentions. Implications of these findings and direction for future research are discussed.


The role of a palliative care intervention in moderating the relationship between depression and survival among individuals with advanced cancer.
Randomized controlled trials (RCTs) of early palliative care interventions in advanced cancer have positively impacted patient survival, yet the mechanisms remain unknown. This secondary analysis of 2 RCTs assessed whether an early palliative care intervention moderates the relationship between depressive symptoms and survival. The relationships among mood, survival, and early palliative care intervention were studied among 529 advanced cancer patients who participated in 2 RCTs. The first (N = 322) compared intervention versus usual care. The second (N = 207) compared early versus delayed intervention (12 weeks after enrollment). The interventions included an in-person consultation, weekly nurse coach-facilitated phone sessions, and monthly follow-up. Mood was measured using the Center for Epidemiologic Studies-Depression (CES-D) scale. Cox proportional hazard analyses were used to examine the effects of baseline CES-D scores, the intervention, and their interaction on mortality risk while controlling for demographic variables, cancer site, and illness severity. The combined sample was 56% male (M = 64.7 years). Higher baseline CES-D scores were significantly associated with greater mortality risk (hazard ratio [HR] = 1.042, 95% confidence interval [CI] [1.017, 1.067], p = .001). However, participants with higher CES-D scores who received the intervention had a lower mortality risk (HR = .963, CI [0.933, 0.993], p = .018) even when controlling for demographics, cancer site, and illness-related variables. This study is the first to demonstrate that patients with advanced cancer who also have depressive symptoms benefit the most from early palliative care. Future research should be devoted to exploring the mechanisms responsible for these relationships. (PsycINFO Database Record


Trends in Pediatric Private Insurance and Medicaid Spending: A Repeated Cross-Sectional Analysis of Data from 2002 to 2014.
Given increased focus on health spending, this investigation aims to compare trends in pediatric Medicaid and private insurance spending on type of service from 2002 to 2014 in order to inform policy and research. A repeated cross-sectional analysis of 2002 to 2014 National Health Expenditure Accounts data was conducted. Total spending, per capita spending, and compounded annual growth rates for type of service were determined for children ages 0 to 18 at the national level. Per capita spending growth was higher for private insurance than for Medicaid, and the areas of high per capita spending growth differed for private insurance and Medicaid. While Medicaid spent more per capita on hospital care than private insurance, private insurance demonstrated greater per capita spending growth on hospital care than Medicaid (8.49% vs 1.99%, respectively). Conversely, per capita spending on home health care grew more for Medicaid (6.79%) than for private insurance (3.18%). Trends in private insurance and Medicaid overall and per capita spending differ. Medicaid experienced higher annual growth in total spending than per capita spending, while private insurance had greater annual growth in per capita spending than total spending. Growth in private insurance per capita spending was higher than growth in Medicaid per capita spending, but growth in Medicaid total spending was higher than growth in private insurance total spending. These data suggest that Medicaid and private insurance may have different drivers of spending growth, highlighting the need for policy makers to examine spending patterns by payer. Further research to determine why such differences in spending growth exist will better inform efforts to increase health care value.


Functional capacity of people with early osteoarthritis: a comparison between subjects from the cohort hip and cohort knee (CHECK) and healthy ageing workers.
The prevalence of osteoarthritis (OA) increases, but the impact of the disorder on peoples' functional capacity is not known. Therefore, the objective of this study was to compare self-reported health status and functional capacity of subjects with early OA of hip and/or knee to reference data of healthy working subjects and to assess whether this capacity is sufficient to meet physical job demands. Self-reported health status and functional capacity of 93 subjects from the Cohort Hip and Cohort Knee (CHECK) were measured using the Short-Form 36 Health Survey and 6 tests of the Work Well Systems Functional Capacity Evaluation. Results were compared with reference data from 275 healthy workers, using t-tests. To compare the functional capacity with job demands, the proportions of subjects with OA performing lower than the p(5) of reference data were calculated. Compared to healthy workers, the subjects (mean age 56) from CHECK at baseline reported a significantly worse physical health status, whereas the women (n = 78) also reported a worse mental health status. On the FCE female OA subjects performed significantly lower than their healthy working counterparts on all 6 tests. Male OA subjects performed lower than male workers on 3 tests. A substantial proportion of women demonstrated functional capacities that could be considered insufficient to perform jobs with low physical demands. Functional capacity and self-reported health of subjects with early OA of the hips and knees were worse compared to healthy ageing workers. A substantial proportion of female subjects did not meet physical job demands.


Silicon Supplementation Alters the Composition of Herbivore Induced Plant Volatiles and Enhances Attraction of Parasitoids to Infested Rice Plants.
Silicon (Si) is important in plant defenses that operate in a direct manner against herbivores, and work in rice (Oryza sativa) has established that this is mediated by the jasmonate signaling pathway. Plant defenses also operate indirectly, by the production of herbivore induced plant volatiles (HIPVs) that attract predators and parasitoids of herbivores. These indirect defenses too are mediated by the jasmonate pathway but no earlier work has demonstrated an effect of Si on HIPVs. In this study, we tested the effect of Si supplementation versus Si deprivation to rice plants on subsequent HIPV production following feeding by the important pest, rice leaffolder (Cnaphalocrocis medinalis). Gas chromatography-mass spectrometry analyses showed lower production of α-bergamotene, β-sesquiohellandrene, hexanal 2-ethyl, and cedrol from +Si herbivore-infested plants compared with -Si infested plants. These changes in plant chemistry were ecologically significant in altering the extent to which parasitoids were attracted to infested plants. Adult females of Trathala flavo-orbitalis and Microplitis mediator both exhibited greater attraction to the HIPV blend of +Si plants infested with their respective insect hosts compared to -Si infested plants. In equivalent studies using RNAi rice plants in which jasmonate perception was silenced there was no equivalent change to the HIPV blend associated with Si treatment; indicating that the effects of Si on HIPVs are modulated by the jasmonate pathway. Further, this work demonstrates that silicon alters the HIPV blend of herbivore-infested rice plants. The significance of this finding is that there are no earlier-published studies of this phenomenon in rice or any other plant species. Si treatment to crops offers scope for enhancing induced, indirect defenses and associated biological control of pests because parasitoids are more strongly attracted by the HIPVs produced by +Si plants.


Distribution of dopamine transporter immunoreactive fibers in the human amygdaloid complex.
The nuclei of the human amygdaloid complex can be distinguished from each other on the basis of their cytoarchitecture, chemistry and connections, all of which process the information needed for the different functions (ranging from attention to memory and emotion) of the amygdala. This complex receives dopaminergic input that exerts modulatory effects over its intrinsic network and is critical for reward-related learning and fear conditioning. To determine the specific distribution of the dopaminergic input through the different nuclei and nuclear subdivisions of this structure we used stereological tools to quantify the fibers containing the dopamine transporter (used to signal the dopaminergic phenotype) in post-mortem samples from control individuals. Dopaminergic axons targeted every nucleus of the amygdaloid complex, and the density of dopamine transporter-containing axons varied considerably among its nuclear groups. The central group showed the greatest density of dopamine transporter-positive fibers, more than double the density of the basolateral group, the second most densely innervated structure. The dopamine transporter-positive innervation is very scant in the corticomedial group. The density of dopamine transporter-positive fibers did not vary among the nuclei of the basolateral group - i.e. basal, lateral and accessory basal nuclei - although there were significant density gradients among the subdivisions of these nuclei. These detailed quantitative data on dopamine transporter-positive innervation in the human amygdaloid complex can offer a useful reference in future studies aimed at analysing putative dysfunctions of this system in diseases involving brain dopamine, such as certain anxiety disorders, Parkinson's disease and schizophrenia.


Health and Demographic Surveillance Systems Within the Child Health and Mortality Prevention Surveillance Network.
Health and demographic surveillance systems (HDSSs) provide a foundation for characterizing and defining priorities and strategies for improving population health. The Child Health and Mortality Prevention Surveillance (CHAMPS) project aims to inform policy to prevent child deaths through generating causes of death from surveillance data combined with innovative diagnostic and laboratory methods. Six of the 7 sites that constitute the CHAMPS network have active HDSSs: Mozambique, Mali, Ethiopia, Kenya, Bangladesh, and South Africa; the seventh, in Sierra Leone, is in the early planning stages. This article describes the network of CHAMPS HDSSs and their role in the CHAMPS project. To generate actionable health and demographic data to prevent child deaths, the network depends on reliable demographic surveillance, and the HDSSs play this crucial role.


Local accumulation of extracellular matrix regulates global morphogenetic patterning in the developing mammary gland.
The tree-like pattern of the mammary epithelium is formed during puberty through a process known as branching morphogenesis. Although mammary epithelial branching is stochastic and generates an epithelial tree with a random pattern of branches, the global orientation of the developing epithelium is predictably biased along the long axis of the gland. Here, we combine analysis of pubertal mouse mammary glands, a three-dimensional (3D)-printed engineered tissue model, and computational models of morphogenesis to investigate the origin and the dynamics of the global bias in epithelial orientation during pubertal mammary development. Confocal microscopy analysis revealed that a global bias emerges in the absence of pre-aligned networks of type I collagen in the fat pad and is maintained throughout pubertal development until the widespread formation of lateral branches. Using branching and annihilating random walk simulations, we found that the angle of bifurcation of terminal end buds (TEBs) dictates both the dynamics and the extent of the global bias in epithelial orientation. Our experimental and computational data demonstrate that a local increase in stiffness from the accumulation of extracellular matrix, which constrains the angle of bifurcation of TEBs, is sufficient to pattern the global orientation of the developing mammary epithelium. These data reveal that local mechanical properties regulate the global pattern of mammary epithelial branching and may provide new insight into the global patterning of other branched epithelia.


Oxidative stress-mediated myocardiotoxicity of ciprofloxacin and ofloxacin in juvenile rats.
In this study, evaluation of the myocardiotoxic effect potential of ciprofloxacin and ofloxacin in juvenile rats and the role of oxidative stress in heart toxicity was conducted. Doses (25 and 50 mg/kg) of each drug were administered to the rats for 1 week. Serum biochemical cardiotoxicity parameters and tissue malondialdehyde and nitric oxide levels were measured. All measured parameters were found elevated in the drug-treated rats, being the highest in the 50-mg/kg ofloxacin-treated rats. Ciprofloxacin and ofloxacin may cause myocardiotoxicity by inducing the oxidative stress in the heart, and nitric oxide is partly responsible for this toxicity.


Costs of adverse events in intensive care units.
Iatrogenic injuries are very common in critically ill adults. However, the financial implications of these events are incompletely understood. To determine the costs of adverse events in patients in the medical intensive care unit and in the cardiac intensive care unit. We performed a matched case-control analysis on data collected during a prospective 1-yr observation study (July 2002 to June 2003) of medical intensive care unit and cardiac intensive care unit patients at an academic, tertiary care urban hospital. A total of 108 cases were matched with 375 controls in our study. Costs of care and lengths of stay were determined from hospital billing systems for patients in the medical and cardiac intensive care units. We then determined the incremental costs and lengths of stay for patients with adverse events compared with patients without events while in the intensive care unit. Costs were truncated for patients with a second adverse event on a subsequent day during the intensive care unit stay. For 56 medical intensive care unit patients, the cost of an adverse event was $3,961 (p = .010) and the increase in length of stay was 0.77 days (p = .048). This extrapolated to annual costs of $853,000 for adverse events in the medical intensive care unit. Similarly, for 52 cardiac intensive care unit patients, the cost of an adverse event was $3,857 (p = .023), corresponding to $630,000 in annual costs. On average, patients with events in the cardiac intensive care unit had an increase of 1.08 days in length of stay (p = .003). Patients who require intensive care are especially at risk for adverse events, and the associated costs with such events are substantial. The costs of adverse events may justify further investment in prevention strategies.


FDG PET imaging in sarcoidosis.
The objective of this review is to highlight the clinical utility of FDG-PET/CT for evaluation of patients with chronic sarcoidosis. The emphasis was on the potential advantages and disadvantages of this technique in these patients based on which recommendations were made. The advantage of FDG-PET/CT technique is that it can visualize FDG accumulation in activated inflammatory cells and simultaneously provide PET and CT images. Of particular interest is the use of FDG-PET/CT for the staging and identification of occult sites and sites suitable for biopsy and for the assessment of inflammatory active sarcoidosis in patients with prolonged symptoms, especially when other markers of the disease are within normal values. FDG-PET/CT also provides a better visualization of extrathoracic sites of active sarcoidosis, such as in the bones, liver, spleen, and retroperitoneal lymph nodes. The use of FDG-PET/CT is of special interest in cardiac sarcoidosis because this potentially life-threatening disease is sometimes present in asymptomatic patients. FDG-PET/CT also has a role in the clinical management of patients with chronic persistent sarcoidosis, such as for planning treatment, monitoring response, and long-term follow-up. The limitations of FDG-PET/CT in patients with sarcoidosis are discussed in the context of a "sarcoidosis-lymphoma syndrome" and potentially excessive radiation exposure. Further prospective multicentre studies are needed to refine the clinical applications of FDG-PET/CT in patients with sarcoidosis and drive the field forward.


Isolation and characterization of Viviparous-1 genes in wheat cultivars with distinct ABA sensitivity and pre-harvest sprouting tolerance.
Pre-harvest sprouting (PHS) of wheat reduces the quality and economic value of grain, and increasing PHS tolerance is one of the most important traits in wheat breeding. Two new Vp-1B alleles related to PHS tolerance were identified on the 3BL chromosome of bread wheat and were designated Vp-1Bb and Vp-1Bc. Sequence analysis showed that Vp-1Bb has a 193 bp insertion and Vp-1Bc has a 83 bp deletion located in the third intron region of the Vp-1B gene, and that they shared 95.43% and 97.89% similarity, respectively, with the sequence of AJ400713 (Vp-1Ba) at the nucleotide level. Their sequences were deposited in the GenBank under the accession numbers DQ517493 and DQ517494. Semi-quantitative RT-PCR analysis showed that alternatively spliced transcripts of the Vp-1A, Vp-1B, and Vp-1D homologues were present and there were no differences in the splicing patterns or abundances of Vp-1A and Vp-1D from embryos 35 d after pollination between PHS-tolerant and -susceptible cultivars. Although Vp-1Ba, Vp-1Bb, and Vp-1Bc could each produce a set of transcripts, only one was correctly spliced and had the capacity to encode the full-length VP1 protein and was more highly expressed with Vp-1Bb and Vp-1Bc than with Vp-1Ba. Comparison of the expression patterns of Vp-1Ba, Vp-1Bb, and Vp-1Bc on different days after pollination also revealed that the expression of these genes was developmentally regulated. Furthermore, genotypes with different levels of tolerance to PHS respond differently to ABA exposure and differences in transcript levels of Vp-1Ba, Vp-1Bb, and Vp-1Bc were observed after ABA treatment. The results indicated that insertion or deletion in the third intron region might affect the expression of the Vp-1B gene and its sensitivity to ABA, and thus resistance to PHS.


Regulation of methyl group metabolism in lactating ewes.
The effect of lactation on a number of enzymes involved in transmethylation reactions and the secretion of major methyl compounds into milk have been examined in sheep. The activities of hepatic phospholipid methyltransferase and 5-methyltetrahydrofolate-homocysteine methyltransferase were significantly higher in lactating ewes, compared with those in non-lactating ewes, while the activity of both hepatic and pancreatic glycine methyltransferase was significantly lower in the lactating state. No differences were observed in the activities of hepatic guanidoacetate methyltransferase, betaine-homocysteine methyltransferase and cystathionine beta-synthase on lactation. These results suggest that the extra demand for methyl groups for the secretion of methyl compounds in the milk is facilitated by enhancing the rate of de novo methyl group synthesis and lowering the rate of physiologically nonessential methylation.


Novel Approach to Intradialytic Progressive Resistance Exercise Training.
Physical activity levels are typically undesirably low in chronic kidney disease patients, especially in those undergoing haemodialysis, and particularly on dialysis days. Intradialytic exercise programmes could be a solution to this issue and have been reported to be safe and relatively easily implemented in dialysis clinics. Nevertheless, such implementation has been failing in part due to barriers such as the lack of funding, qualified personnel, equipment, and patient motivation. Intradialytic aerobic exercise has been the most used type of intervention in dialysis clinics. However, resistance exercise may be superior in eliciting potential benefits on indicators of muscle strength and mass. Yet, few intradialytic exercise programmes have focused on this type of intervention, and the ones which have report inconsistent benefits, diverging on prescribed exercise intensity, absent or subjective load progression, equipment availability, or exercise supervision. Commonly, intradialytic resistance exercise interventions use free weights, ankle cuffs, or elastic bands which hinder load progression and exercise intensity monitoring. Here, we introduce a recently developed intradialytic resistance exercise device and propose an accompanying innovative resistance exercise training protocol which aims to improve the quality of resistance exercise interventions within dialysis treatment sessions.


Nonelectrochemical synthesis, crystal structure, and physical properties of the radical salt [ET]2[CuCl4] (ET = bis(ethylenedithio)tetrathiafulvalene).
The radical salt [ET]2[CuCl4] was obtained by chemical oxidation of bis(ethylenedithio)tetrathiafulvalene (ET) with the tetranuclear copper(II) halide cluster [Cu4OCl10](4-). Although a complex mixture of anions forms in solution during the redox reaction, only this product is obtained as large (>3 mm) single crystals. X-ray diffraction analysis determined that the ET molecules stack in the solid state forming dimerized 1D chains along the a axis, interleaved by [CuCl4](2-) anions. The ET dimers show very short S···S contacts (<3.41 Å). The physical properties are dominated by these intradimer ET interactions. The magnetic behavior shows antiferromagnetic coupling with a singlet-triplet gap >620 K (430 cm(-1)). The Cu(2+) (S = 1/2) centers are magnetically isolated and yield a narrow EPR line in the X-band at g = 2.01. The ET moieties are EPR silent.


Resveratrol induces vascular smooth muscle cell differentiation through stimulation of SirT1 and AMPK.
Phenotypic plasticity in vascular smooth muscle cells (VSMC) is necessary for vessel maintenance, repair and adaptation to vascular changes associated with aging. De-differentiated VSMC contribute to pathologies including atherosclerosis and intimal hyperplasia. As resveratrol has been reported to have cardio- protective effects, we investigated its role in VSMC phenotypic modulation. We demonstrated the novel finding that resveratrol promoted VSMC differentiation as measured by contractile protein expression, contractile morphology and contraction in collagen gels. Resveratrol induced VSMC differentiation through stimulation of SirT1 and AMPK. We made the novel finding that low or high dose resveratrol had an initially different mechanism on induction of differentiation. We found that low dose resveratrol stimulated differentiation through SirT1-mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK-mediated inhibition of the mTORC1 pathway, allowing activation of AKT. The health effects of resveratrol in cardiovascular diseases, cancer and longevity are an area of active research. We have demonstrated a supplemental avenue where-by resveratrol may promote health by maintaining and enhancing plasticity of the vasculature.


Three-Dimensional Transperineal Ultrasonography for Diagnosis of Female Occult Stress Urinary Incontinence.
BACKGROUND We evaluated the utility of three-dimensional transperineal ultrasonography in detecting occult stress urinary incontinence in women undergoing anterior pelvic floor reconstruction surgery for severe cystocele. MATERIAL AND METHODS We enrolled 207 women with stage III-IV cystocele without urinary stress incontinence. One week before the operation, the patients underwent pelvic floor ultrasonography. We measured the vertical distance between the bladder neck and posterior margin of the pubic symphysis, the posterior vesicourethral angle, the urethral rotation angle, the formation of funnel shape, the hiatus area, and the length of the urethra and the funnel shape. Postoperatively, the patients were evaluated for symptoms of stress urinary incontinence and with the 20-minute pad test. RESULTS The posterior vesicourethral angle with Valsalva maneuver, the difference in the posterior vesicourethral angle between the resting state and with the Valsalva state, and the angle of the proximal urethra were larger in the incontinence-positive group than in the incontinence-negative group (P<0.05). Funnel shape urethra was longer in the incontinence-positive group than in the incontinence-negative group (P<0.05). The cutoff value was 137.5° for the posterior vesicourethral angle with Valsalva maneuver, 39.5° for the difference in the posterior vesicourethral angle, 44.5° for the angle of the proximal urethra, and 0.35 cm for the length of the funnel shape. Multivariate analysis revealed that the difference between the posterior vesicourethral angle in the resting state and with Valsalva, the angle of the proximal urethra, and the length of funnel shape were strongly correlated with occult stress urinary incontinence. CONCLUSIONS Ultrasonography is an effective method for identifying occult stress urinary incontinence.


Using protection motivation theory to predict intention to adhere to official MMR vaccination recommendations in Switzerland.
Switzerland has not yet reached the measles vaccination coverage of 95 percent that is recommended by the World Health Organization to achieve herd immunity. Within the overall objective of informing effective ways to promote the combined Measles, Mumps, Rubella (MMR) vaccination in Switzerland, the aim of this study was to identify predictors of parents' intention to adhere to official MMR vaccination recommendations. Between October 2012 and January 2013, we surveyed 554 parents of middle school students aged 13 to 15 in Ticino, Switzerland. Guided by Protection Motivation Theory (PMT), the survey covered predictors related to threat and coping appraisal with regards to measles and the MMR vaccine, MMR-related social attitudes and social norms, past experience with the disease and the vaccine, and information sources in the MMR vaccine context. Data were analyzed using Structural Equation Modelling. Among central PMT concepts describing people's threat and coping appraisal, only response (vaccination) efficacy showed to be directly related to parents' intention to adhere to MMR vaccination recommendations (B = .39, p < .001). In addition, social attitudes (B = .38, p < .001) were a direct predictor. Furthermore, social attitudes, social norms, knowing somebody who experienced MMR vaccination side effects, and having sought MMR information from public health institutions, all indirectly predicted parents' intention to adhere to MMR recommendations by activating different threat and coping appraisal mechanisms. To conclude, future communication measures from public health institutions should highlight the altruistic aspect (herd immunity) of the immunization practice as well as present evidence on the high effectiveness of the vaccination in reducing the risk at both the individual and collective levels of getting infected with measles.


Risks and benefits of menopausal hormone therapy in postmenopausal Chinese women.
The aim of this study was to assess risks and benefits of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal Chinese women. A retrospective cohort study was undertaken using the Taiwan National Health Insurance Research Database, a population-based healthcare claims dataset. Eligible women aged 50 to 79 years were classified as exposed to CEE 0.625 mg/day with MPA 5.0 mg/day (estrogen [E] + progestin [P], n = 4,712) or CEE 0.625 mg/day only (E-only, n = 1,208) and were age-matched to unexposed women (n = 10,125). Follow-up was complete in 96% of the participants. The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. The global index summarized risks of primary outcomes, stroke, pulmonary embolism, colon and endometrial cancers, hip fractures, and death. Time-to-event analyses were performed. Median durations of exposure in the E + P and E-only groups were 6.9 and 9 months, respectively. Median follow-up was 110 months. Hazard ratios (95% CI) for E + P exposure were as follows: myocardial infarction, 0.78 (0.51-1.19); CHD death, 1.21 (0.53-2.70); breast cancer, 1.48 (1.20-1.83); global index, 0.79 (0.72-0.87). Hazard ratios for E-only exposure were as follows: myocardial infarction, 0.76 (0.35-1.68); CHD death, 0.57 (0.11-2.80); breast cancer, 1.44 (0.99-2.10); global index, 1.09 (0.92-1.28). Per 10,000 person-years, there were 12 excess breast cancer cases with E + P exposure; there were 39 fewer global index events with E + P exposure. Adjusting for age, statin and aspirin use, hypercholesterolemia, diabetes, and hypertension did not significantly change estimates. In postmenopausal Chinese women, CEE with or without MPA was not associated with increased rates of CHD, but CEE with MPA may be associated with a higher breast cancer rate. E + P exposure conferred lower global index event rates.


Sub-nanosecond time-resolved radiation measurement using x-ray focusing crystal spectrometers.
In this paper, we describe a technique using a crystal spectrometer, a silicon-diode detector, and a filtered photoconductive detector to monitor photon energies in the L-shell (0.9-1 keV) and K-shell regimes for nickel and copper hybrid X-pinch x-ray sources. The detectors, system cabling, and an 8 GHz digital oscilloscope in combination enable time resolution better than 200 ps for photoconductive detectors and 700 ps for silicon-diode detectors of the K- and L-shell radiation signals, respectively. We substantially improve the relative timing of signals obtained using the oscilloscope by using an x-ray streak camera with a crystal spectrometer to monitor the L-shell line spectra and, separately, the K-shell line spectra relative to the continuum burst to better than 17 ps time resolution. This combination of instruments enabled and validated a new method by which plasma conditions in nickel and copper X-pinches can be assessed immediately before and after the ∼30 ps continuum x-ray burst produced by 370 kA hybrid X-pinches. In general, the method described here can be applied to observe otherwise highly filter-absorbed radiation in the presence of a broad spectrum of higher energy radiation by combining x-ray crystals and detectors.


A single urban center experience with adult pedestrians struck by motor vehicles.
Pedestrian-vehicle crashes are a significant problem in public health. Understanding contributing factors within a specific community helps recognize and target key intervention points. Trauma registry analysis included all of the patients treated at a Level I trauma center following pedestrian-motor vehicle collisions from January 1, 2000 to December 31, 2010. Variables examined included patient demographics, timing of collision, abbreviated injury scale score, injury severity score (ISS), hospital and intensive care unit (ICU) length of stay (LOS), and emergency department and hospital disposition. A total of 945 pedestrians were reviewed within the study period. Average age was 46.4+/-19.4 years. One hundred seventy-seven (18.7%) patients were elderly and of the elderly group, 69 (39%) were 80 years of age or greater. The median ISS score was 12, average hospital LOS was 10.8 days and average ICU length of stay was 6.0+/-7.5 days. More elderly patients required admission to the ICU than the nonelderly (61.6% vs 40.2%; P<0.001), and more elderly patients required admission to a skilled nursing facility than nonelderly (42.1% vs. 9%; P< 0.001). The mortality rate for elderly patients was more than double that of nonelderly patients (20.9% vs 9.1%; P<0.001). Pedestrian-motor vehicle collisions occurred disproportionately between the hours of 6 PM and midnight (P< 0.0001). Elderly patients struck by a motor vehicle have a mortality rate twice that of the nonelderly and a higher rate of discharge to a skilled nursing facility, despite having a similar injury severity score on admission. This highlights the need for aggressive prevention efforts targeted at the elderly population.


Philosophizing social justice in rural palliative care: Hayek's moral stone?
Increasingly, palliative care is being referred to as an essential programme and in some cases as a human right. Once it is recognized as such, it becomes part of the lexicon of social justice in that it can be argued that all members of society should have access to such care. However, this begs the question of how that care should be enacted, particularly in rural and remote areas. This question illustrates some of Friedrich Hayek's critiques of social justice. Hayek has likened social justice to a 'moral stone' arguing that social justice is meaningless to the extent that society is impersonal and as such cannot be just, only those individuals who make up that society can be just. When responsibility for justice is assigned to an impersonal society, ideas of social justice can become a clarion call for whom no one is directly accountable. This opens the door for questionable macro-level political agendas that have no capacity to enact the ideal, and worse, may suppress individual moral acts towards the desired end. Further, acts of interference at the macro level with the ideal of equal opportunity run the risk of disadvantaging other members of society. Instead, he has argued that a better approach lies in finding ways to induce and support individual moral acts that promote the human good. Hayek's arguments are particularly compelling for rural palliative care. In this paper we draw upon data from an ethnographic study in rural palliative care to illustrate the potential misfit between the ethical ideal of palliative care as expressed by rural participants and the narratives of social justice.


P53-dependent suppression of the human calcyclin gene (S100A6): the role of Sp1 and of NFkappaB.
Calcyclin (S100A6) is believed to participate in cell cycle control. It was, however, unclear if its expression depends on p53, a key regulator of apoptosis and cell cycle. We therefore performed transcription regulation assays in HeLa cells and found that wild type p53 suppressed the S100A6 promoter up to 12-fold in a dose-dependent manner. In contrast, the well-characterized V143A, R175H, R249S, and L344A p53 mutants cloned from human cancers suppressed this promoter with a 6 to 9-fold lower efficiency. All the sites mediating the p53-dependent suppression were contained in the -167 to +134 fragment of the S100A6 promoter. Separate overexpression of either Sp1 or of NFkappaB only partially counteracted the p53 inhibitory effect on the S100A6 promoter, while simultaneous overexpression of both these transactivators resulted in a complete abolishment of the p53 inhibitory effect on this promoter. Sp1 and NFkappaB binding to the probes resembling their putative binding sites present in the S100A6 promoter was decreased in the presence of wild type p53. We propose that the suppression of S100A6 is yet another mechanism by which p53 inhibits proliferation. Insufficient suppression of this gene by p53 mutants could well be responsible for calcyclin overexpression and cell cycle deregulation observed in cancer tissues.


Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging.
Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that the spermidine level was reduced in ovaries of aged mice and that supplementation with spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By microtranscriptomic analysis, we further discovered that spermidine-induced recovery of oocyte quality was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this mechanism of action was conserved in porcine oocytes under oxidative stress. Altogether, our findings suggest that spermidine supplementation could represent a therapeutic strategy to ameliorate oocyte quality and reproductive outcome in cis-gender women and other persons trying to conceive at an advanced age. Future work is needed to test whether this approach can be safely and effectively translated to humans.


The rise and rise of drug delivery.
Drug delivery has typically focused on optimizing marketed compounds, improving their effectiveness or tolerability, and simplifying their administration. This role now includes the first biopharmaceuticals as well as more conventional drugs. As drug-delivery technologies come into play earlier in the development cycle, however, they can also enhance the screening and evaluation of new compounds and 'rescue' failed compounds, such as those with low solubility. In this article, we look back at how the burgeoning field of drug delivery came into being and describe approaches for future discovery and development.


Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study.
It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis. BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression. MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration. Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.


Potent 5-Cyano-6-phenyl-pyrimidin-Based Derivatives Targeting DCN1-UBE2M Interaction.
Neddylation of the Cullin-RING E3 ligases (CRLs) regulates the homeostasis of approximately 20% of cellular proteins. Defective in cullin neddylation 1 (DCN1), as a co-E3 ligase, interacts with UBE2M to enhance the activation of CRLs, and this interaction is emerging as a therapeutic target for human diseases. Here, we present a series of pyrimidin-based small molecular inhibitors targeting DCN1-UBE2M interaction. After finding a novel inhibitor DC-1 with IC50 = 1.2 μM, we performed a series of chemical optimizations, which finally led to the discovery of a potent thiazole containing 5-cyano-6-phenylpyrimidin-based inhibitor DC-2 (IC50 = 15 nM). Next, using protein and cellular thermal shift assays, coimmunoprecipitation, molecular docking, and site-specific mutation experiments, we further proved that DC-2 specifically inhibited the interaction of UBE2M and DCN1 at molecule and cellular levels, resulting in the decrease of cullin3 neddylation and accumulation of its substrate, NRF2. Our findings indicate that DC-2 may serve as a novel lead compound for specific derivatives targeting DCN1-UBE2M interaction.


The Role of Bcl-2 and Bax as Markers of Disease Progression in Hepatitis C Virus Infected Patients.
Many apoptotic markers have been linked to hepatic cell injury in HCV-related liver diseases, and hence could be used as potential markers for early detection of the disease. The present study aimed to assess the role of apoptotic markers Bcl-2 and Bax in the pathogenesis of chronic HCV-related liver diseases. A total of 85 participants were enrolled into the study; 70 chronic HCV patients (35 non-cirrhotic and 35 cirrhotic), and 15 healthy controls. The serum levels of Bcl-2 and Bax were assayed in all participants by ELISA. Bcl-2 and Bcl-2/Bax ratio were significantly higher in non-cirrhotic patients than the cirrhotic and controls (P < 0.001). Bax was significantly higher in cirrhotic patients compared to the other groups (P < 0.001). Positive and negative correlations were found between serum Bcl-2, Bax, Bcl-2/Bax ratio and HCV viral load in non-cirrhotic and cirrhotic patients respectively. These findings provide an evidence that apoptosis is dysregulated in patients with chronic HCV.


[Blood viscosity in ischemic heart disease].
Through a capillary viscometer we measured venous and arterial blood viscosity (BV) in 25 patients with the diagnosis of ischemic heart disease (IHD); 10 of them with unstable angor pectoris (UA) and 15 with acute myocardial infarction (MI). The control group consisted of 100 normal individuals in whom the normal values were 2.70 +/- 0.10 centipoises, where as in patients with AU the values were 4.03 +/- 1.40 centipoises and in the group with MI was 3.65 +/- 1.20 centipoises. Statistically, we correlated the BV obtained in both groups with the following parameters: coronary risk factors, cell blood count; serum glucose, cholesterol and triglycerides as well as the number of coronary arteries involved. The levels of venous and arterial BV were elevated in both groups of patients in comparison with the control group. We concluded that arterial and venous BV is elevated in patients with IHD independently of the hematocrit. This suggest the probability of some other factors such as plasmatic viscosity and platelets aggregation could play a role in the BV elevation of this group of patients.


Point mutations and deletions in the znfn1a1/ikaros gene in chemically induced murine lymphomas.
The Znfn1a1 gene encodes a zinc finger protein called Ikaros, which is criticalfor T-cell development and differentiation. The execution of normal function of Ikaros requires sequence-specific DNA binding, transactivation, and dimerization domains. In this study, exons 3-5 and exon 7 of the Znfn1a1 gene that encode the functional domains of Ikaros were analyzed for point mutations and deletions in murine lymphomas induced by 1,3-butadiene, 2',3'-dideoxycytidine, or phenolphthalein. Missense and frameshift mutations were identified in 11% (11 of 104) of the tumors. Interestingly, 8 of the mutations were identified in the NH2-terminal zinc finger motifs, which are crucial for the DNA-binding function of Ikaros. The other 3 samples carried frameshift mutations in exon 7 that resulted in truncations and abrogation of both transactivation and dimerization domains. One tumor with a missense mutation in the DNA-binding domain also displayed a 45-bp deletion in the dimerization domain. Southern analysis disclosed interstitial homozygous deletions in the functional domains of Ikaros in 4% (3 of 68) of the lymphomas examined. Allelic losses on markers surrounding the Znfn1a1 gene were detected in 27% (12 of 45) of the tumors analyzed. However, only 2 tumors with allelic losses also showed mutations in the Znfn1a1 gene, indicating that other tumor suppressor genes located on this region might be involved as well. Our results suggest inactivation of Ikaros in a subset of chemically induced lymphomas and additionally support the contention of tumor-suppressor activity for Ikaros.


Effect of the Molecular Weight of Polyelectrolyte and Surfactant Chain Length on the Solid-Phase Molecular Self-Assembly.
Solid-phase molecular self-assembly (SPMSA) is emerging as an efficient approach, leading to scale-span self-assembled supramolecular films. With SPMSA, freestanding macroscopic supramolecular films can be formed upon mechanically pressing the precipitates formed with polyelectrolytes and oppositely charged surfactants. Herein, we report that the film formation ability and the mechanical strength of the resultant film depend highly on the surfactant chain lengths and the molecular weight of polyelectrolytes. A coarse-grained molecular dynamics study revealed that the longer surfactant chains are beneficial for the ordered assembly of surfactant bilayers in the film, whereas the larger molecular weight of PE favors the enhanced mechanical strength of the film by promoting the long-range order of the surfactant bilayers. The current results disclosed the physical insight of the surfactant chain length and the molecular weight of polyelectrolytes into the film structure and mechanical strength, which is of practical importance in guiding the creation of SPMSA materials.


Not all anxious individuals get lost: Trait anxiety and mental rotation ability interact to explain performance in map-based route learning in men.
Navigation through an environment is a fundamental human activity. Although group differences in navigational ability are documented (e.g., gender), little is known about traits that predict these abilities. Apart from a well-established link between mental rotational abilities and navigational learning abilities, recent studies point to an influence of trait anxiety on the formation of internal cognitive spatial representations. However, it is unknown whether trait anxiety affects the processing of information obtained through externalized representations such as maps. Here, we addressed this question by taking into account emerging evidence indicating impaired performance in executive tasks by high trait anxiety specifically in individuals with lower executive capacities. For this purpose, we tested 104 male participants, previously characterised on trait anxiety and mental rotation ability, on a newly-designed map-based route learning task, where participants matched routes presented dynamically on a city map to one presented immediately before (same/different judgments). We predicted an interaction between trait anxiety and mental rotation ability, specifically that performance in the route learning task would be negatively affected by anxiety in participants with low mental rotation ability. Importantly, and as predicted, an interaction between anxiety and mental rotation ability was observed: trait anxiety negatively affected participants with low-but not high-mental rotation ability. Our study reveals a detrimental role of trait anxiety in map-based route learning and specifies a disadvantage in the processing of map representations for high-anxious individuals with low mental rotation abilities.


Structural components and morphogenetic mechanics of the zebrafish yolk extension, a developmental module.
The yolk extension (YE) appears to be a novel developmental module that has been inserted into the phylotypic period of teleostean development, specifically in the order Cypriniformes. The zebrafish YE informs the study of morphogenetic movements reshaping ventral tissues because (1) this trait is easily visible, so disruptions are easy to score; (2) its ontogenesis occurs quickly; and (3) the yolk cell isolates the tissues elongating the ventrum from the rest of the embryo, serving as a three-dimensional in vivo "tissue culture." We determined that three histological compartments comprise the structural components of the YE: (1) the internal yolk cell; (2) the mesendodermal mantle external to the yolk cell; and (3) the external embryonic integument, consisting of an embryonic epidermis plus enveloping layer cells. These structural components interact with one another in a hierarchical manner, resulting in the morphogenesis of the elongated and tubular embryonic zebrafish ventrum as the cylindrical YE forms. Time-lapse videomicroscopy and experimental manipulation show that the yolk mass is a cohesive, viscoelastic foam, which resists compression. Moreover, as the mesodermal mantle participates in tubulation of the posterior trunk, Kupffer's Vesicle, the organ of laterality in teleosts, separates from the posterior pole of the yolk syncytial layer. Additionally, the embryonic integument becomes contractile over the posterior yolk cell, constricting the yolk mass to form the YE. These findings constitute an initial assessment of the morphogenetic mechanics underlying formation of the YE developmental module in zebrafish.


Clustering malignant cell states using universally variable genes.
Single-cell RNA sequencing (scRNA-seq) has revealed important insights into the heterogeneity of malignant cells. However, sample-specific genomic alterations often confound such analysis, resulting in patient-specific clusters that are difficult to interpret. Here, we present a novel approach to address the issue. By normalizing gene expression variances to identify universally variable genes (UVGs), we were able to reduce the formation of sample-specific clusters and identify underlying molecular hallmarks in malignant cells. In contrast to highly variable genes vulnerable to a specific sample bias, UVGs led to better detection of clusters corresponding to distinct malignant cell states. Our results demonstrate the utility of this approach for analyzing scRNA-seq data and suggest avenues for further exploration of malignant cell heterogeneity.


The C(-260)>T gene polymorphism in the promoter of the CD14 monocyte receptor gene is not associated with acute myocardial infarction.
CD surface molecules mediates cell activation and signaling. In particular, CD14 on blood monocytes mediate monocyte/macrophage activation by lipopolysaccharide. Lipopolysaccharide and its receptor, CD14, have been implicated in atherogenesis. It has been recently shown that a C(-260)T polymorphism in the promoter of the CD14 receptor may be a risk factor for coronary artery disease. Recently this association has been questioned because no increased risk was found with the T allele, even in the homozygous state. In the present study we investigated a possible association between the C(-260)T polymorphism in the CD14 promoter and acute myocardial infarction. Two hundred and thrteen patients with and acute myocardial infarction 213 healthy controls were included in the study. Genotype frequencies of the C(-260)T polymorphism in the CD14 promoter were determined by polimerase chain reaction and the amplified product was cleaved with HaeIII. The frequency of the T allele was not significantly different in patients compared with controls. In this study we were not able to detect differences of frequency of the allele T (-260) in the promoter of the CD14 receptor gene in survivors of myocardial infarction and controls.


[Neuroendocrinology of the stomach and aging].
The survey contains information about basic stomach endocrine cells in normal condition and their changes in chronic atrophic gastritis and ageing. The data of modern research devoted to endocrine cells age-related changes are represented here and analyzed. The reasons that influence on endocrine cells age-related changes and the ways of their possible correction are described.


The horizontal breast reduction: Surgical tips for maintaining projection.
Reduction mammoplasty is one of the most common procedures performed by plastic surgeons in Canada. The Wise and vertical scar techniques are two of the most commonly published and performed. Although the horizontal breast reduction is a less commonly used technique, it offers added benefits over other procedures. These include elimination of the vertical scar and a consistently round nipple. However, one of the criticisms of the horizontal technique is the loss of projection of the breast mound. The present article outlines several important points that can aid in achieving an optimal aesthetic result when performing a horizontal breast reduction.


Genotyping performance between saliva and blood-derived genomic DNAs on the DMET array: a comparison.
The Affymetrix Drug Metabolism Enzymes and Transporters (DMET) microarray is the first assay to offer a large representation of SNPs conferring genetic diversity across known pharmacokinetic markers. As a convenient and painless alternative to blood, saliva samples have been reported to work well for genotyping on the high density SNP arrays, but no reports to date have examined this application for saliva-derived DNA on the DMET platform. Genomic DNA extractions from saliva samples produced an ample quantity of genomic DNA for DMET arrays, however when human amplifiable DNA was measured, it was determined that a large percentage of this DNA was from bacteria or fungi. A mean of 37.3% human amplifiable DNA was determined for saliva-derived DNAs, which results in a significant decrease in the genotyping call rate (88.8%) when compared with blood-derived DNAs (99.1%). More interestingly, the percentage of human amplifiable DNA correlated with a higher genotyping call rate, and almost all samples with more than 31.3% human DNA produced a genotyping call rate of at least 96%. SNP genotyping results for saliva derived DNA (n = 39) illustrated a 98.7% concordance when compared with blood DNA. In conclusion, when compared with blood DNA and tested on the DMET array, saliva-derived DNA provided adequate genotyping quality with a significant lower number of SNP calls. Saliva-derived DNA does perform very well if it contains greater than 31.3% human amplifiable DNA.


Soluble LDL-immune complexes in type 2 diabetes and vascular disease.
The oxidative modification of LDL has been shown to affect its clearance and to exert cytotoxic and immunogenic effects. The objective of our study was to analyse markers of LDL oxidation-soluble LDL containing immune complexes (LDL-ICs) in type 2 diabetes with micro- and macrovascular disease. The study included 69 diabetic patients with coronary artery disease (DM + CAD), 78 non-diabetics with CAD, 47 controls, and 27 diabetics with nephropathy and 36 free from complications. OxLDL antibodies and advanced glycated end-products were measured by ELISA, and LDL-IC apo B content after PEG precipitation. Determination of a broad range of oxLDL antibody activity in all study groups showed no significant differences. In contrast, the content of apo B, a component of the antigen moiety of oxLDL-ICs, was higher in CAD and diabetes (+ CAD) than in LDL-ICs isolated from controls (p < 0.001). LDL-ICs did not differ between patients with CAD + DM and CAD patients free from diabetes. LDL-IC levels in diabetic patients with or without microangiopathy were significantly higher than in healthy volunteers (PEG-apo B 0.278 +/- 0.107 vs. 0.165 +/- 105 g/l, p < 0.002; PEG-IgG 151.7 +/- 76 vs. 115.4 +/- 62 g/l, p < 0.05). However, there was no significant difference in the level of circulating LDL-ICs between the subgroup of diabetic patients with nephropathy/retinopathy and patients free of microvascular disease (Ab-oxLDL 27.7 +/- 10.4 vs. 27.1 +/- 9.3 AU, NS; PEG-apo B 0.324 +/- 0.111 vs. 0.287 +/- 0.124 g/l, NS; PEG-IgG 1.68 +/- 0.68 vs. 1.42 +/- 0.80 g/l, NS). There was a statistically significant positive correlation between AGE content and LDL-ICs (r = 0.35, p < 0.009). A significant but inverse correlation was recorded between triglyceride concentration and level of LDL-ICs in DM + CAD (r = - 0.32, p < 0.016) and CAD patients (r = - 0.35, p < 0.002). A highly significant negative correlation between triglycerides and circulating LDL-ICs (r = - 0.54, p < 0.039) was observed in patients with early nephropathy, but not in those with physiological proteinuria. It is known that at a high triglyceride level in type 2 diabetes, the majority of LDL are small and dense, thus being more susceptible to oxidative modification. This could be a possible mechanism explaining why more LDL-ICs, with a level inversely correlating with triglyceride concentration, are generated in diabetes. The increased level of circulating LDL-ICs is a risk factor for the general population, including those with diabetes. Our results suggested the contribution of LDL-ICs to the development of atherosclerosis to probably be more significant than the direct contribution of oxLDLAb itself.


Development of N-(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase.
Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of the main endocannabinoid anandamide; thus, the simultaneous CB2R activation and FAAH inhibition may be a synergistic anti-inflammatory strategy. Encouraged by principal component analysis (PCA) data identifying a wide chemical space shared by CB2R and FAAH ligands, we designed a small library of adamantyl-benzamides, as potential dual agents, CB2R agonists, and FAAH inhibitors. The new compounds were tested for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best pharmacodynamic profile as CB2R full agonists and FAAH inhibitors, decreased pro-inflammatory and increased anti-inflammatory cytokines production. Molecular docking simulations complemented the experimental findings by providing a molecular rationale behind the observed activities. These multitarget ligands constitute promising anti-inflammatory agents.


Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression.
Members of the Forkhead box a (Foxa) transcription factor family are expressed in the liver, pancreatic islets and intestine and both Foxa1 and Foxa2 regulate proglucagon gene transcription. As Foxa proteins exhibit overlapping DNA-binding specificities, we examined the role of Foxa3 [hepatocyte nuclear factor (HNF)-3gamma] in control of proglucagon gene expression. Foxa3 was detected by reverse transcriptase PCR in glucagon-producing cell lines and binds to the rat proglucagon gene G2 promoter element in GLUTag enteroendocrine cells. Although Foxa3 increased rat proglucagon promoter activity in BHK fibroblasts, augmentation of Foxa3 expression did not increase proglucagon promoter activity in GLUTag cells. Furthermore, adenoviral Foxa3 expression did not affect endogenous proglucagon gene expression in islet or intestinal endocrine cell lines. Although Foxa3(-/-) mice exhibit mild hypoglycaemia during a prolonged fast, the levels of proglucagon-derived peptides and proglucagon mRNA transcripts were comparable in tissues from wild-type and Foxa3(-/-) mice. These findings identify Foxa3 as a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo.


Evidence of African horse sickness virus infection of Equus zebra hartmannae in the south-western Khomas Region, Namibia.
Equine mortalities suspected to be due to African horse sickness (AHS) were reported from the arid Khomas Region, Namibia, in 2008. The area was previously considered a localized AHS-free area. Hartmann's mountain zebra (Equus zebra hartmannae), a potential but unconfirmed reservoir host of African horse sickness virus (AHSV), occurs in the region. Between 2009 and 2010 serum, blood and tissue samples from 31 culled E. z. hartmannae were analysed by reverse transcription-polymerase chain reaction (RT-PCR) (n = 31) and enzyme-linked immunosorbent assay (ELISA) (n = 18) to determine the presence of AHSV and/or antibodies against AHSV. The presence of antibodies against AHSV was demonstrated in all 18 samples assayed, and AHSV double stranded RNA was detected in 26% of the animals. This is evidence that E. z. hartmannae can become infected with AHSV.


A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041.


Mechanics of biofilms formed of bacteria with fimbriae appendages.
Gram-negative bacteria, as well as some Gram-positive bacteria, possess hair-like appendages known as fimbriae, which play an important role in adhesion of the bacteria to surfaces or to other bacteria. Unlike the sex pili or flagellum, the fimbriae are quite numerous, with of order 1000 fimbriae appendages per bacterial cell. In this paper, a recently developed hybrid model for bacterial biofilms is used to examine the role of fimbriae tension force on the mechanics of bacterial biofilms. Each bacterial cell is represented in this model by a spherocylindrical particle, which interact with each other through collision, adhesion, lubrication force, and fimbrial force. The bacterial cells absorb water and nutrients and produce extracellular polymeric substance (EPS). The flow of water and EPS, and nutrient diffusion within these substances, is computed using a continuum model that accounts for important effects such as osmotic pressure gradient, drag force on the bacterial cells, and viscous shear. The fimbrial force is modeled using an outer spherocylinder capsule around each cell, which can transmit tensile forces to neighboring cells with which the fimbriae capsule collides. We find that the biofilm structure during the growth process is dominated by a balance between outward drag force on the cells due to the EPS flow away from the bacterial colony and the inward tensile fimbrial force acting on chains of cells connected by adhesive fimbriae appendages. The fimbrial force also introduces a large rotational motion of the cells and disrupts cell alignment caused by viscous torque imposed by the EPS flow. The current paper characterizes the competing effects of EPS drag and fimbrial force using a series of computations with different values of the ratio of EPS to bacterial cell production rate and different numbers of fimbriae per cell.


A closer look at the discrimination outcomes in the IAT literature.
To what extent the IAT (Implicit Association Test, Greenwald et al., 1998) predicts racial and ethnic discrimination is a heavily debated issue. The latest meta-analysis by Oswald et al. (2013) suggests a very weak association. In the present meta-analysis, we switched the focus from the predictor to the criterion, by taking a closer look at the discrimination outcomes. We discovered that many of these outcomes were not actually operationalizations of discrimination, but rather of other related, but distinct, concepts, such as brain activity and voting preferences. When we meta-analyzed the main effects of discrimination among the remaining discrimination outcomes, the overall effect was close to zero and highly inconsistent across studies. Taken together, it is doubtful whether the amalgamation of these outcomes is relevant criteria for assessing the IAT's predictive validity of discrimination. Accordingly, there is also little evidence that the IAT can meaningfully predict discrimination, and we thus strongly caution against any practical applications of the IAT that rest on this assumption. However, provided that the application is thoroughly informed by the current state of the literature, we believe the IAT can still be a useful tool for researchers, educators, managers, and students who are interested in attitudes, prejudices, stereotypes, and discrimination.


Six Years of Disease-free Survival After a Second Cord Blood Transplantation for Recurrent Acute Lymphocytic Leukemia in a Child With Down Syndrome.
Outcomes are extremely poor in Down syndrome-associated acute lymphocytic leukemia, particularly in recurrent cases. A 2-year-old boy with Down syndrome-associated acute lymphocytic leukemia achieved complete remission after standard chemotherapy. However, he experienced recurrence twice in the bone marrow and central nervous system. Salvage treatments included whole-brain/whole-spine irradiation. Thereafter, the patient received a second cord blood transplantation after the reduced-intensity conditioning. The graft was characterized by killer cell immunoglobulin-like receptor ligands mismatch. The patient has subsequently survived for 6.5 years without recurrence. We speculate that killer cell immunoglobulin-like receptor ligand-mismatched cord blood transplantation enhanced the graft-versus-leukemia effect through natural killer cells, and conferred long-term remission.


The Uganda version of the Pediatric Evaluation of Disability Inventory (PEDI). Part I: Cross-cultural adaptation.
The Pediatric Evaluation of Disability Inventory (PEDI) was developed and standardized to measure functional performance in American children. So far, no published study has examined the use of the PEDI in sub-Saharan Africa. This study describes the adaptation, translation, and validation process undertaken to develop a culturally relevant PEDI for Uganda (PEDI-UG). The cross-cultural adaptation and translation of the PEDI was performed in a series of steps. A project manager and a technical advisory group were involved in all steps of adaptation, translation, cognitive debriefing, and revision. Translation and back-translation between English and Luganda were performed by professional translators. Cognitive debriefing of two subsequent adapted revisions was performed by a field-testing team on a total of 75 caregivers of children aged 6 months to 7.5 years. The PEDI-UG was established in both English (the official language) and Luganda (a local language) and comprises 185 items. Revisions entailed deleting irrelevant items, modifying wording, inserting new items, and incorporating local examples while retaining the meaning of the original PEDI. Item statements were rephrased as questions. Seven new items were inserted and 19 items deleted. To accommodate major differences in living conditions between rural and urban areas, 10 alternative items were provided. The PEDI-UG is to be used to measure functional limitations in both clinical practice and research, in order to assess and evaluate rehabilitative procedures in children with developmental delay and disability in Uganda. In this study, we take the first step by translating and adapting the original PEDI version to the culture and life conditions in both rural and urban Uganda. In subsequent studies, the tool's psychometric properties will be examined, and the tool will be tested in children with developmental delay and disability.


Potential involvement of nicotinamide N-methyltransferase in the pathogenesis of metabolic syndrome.
Metabolic syndrome is a complex disorder characterized by the presence of insulin resistance (IR), type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), or impaired fasting glucose (IFG), plus at least two of the following conditions--hypertension, hyperlipidemia, obesity, and microalbuminuria. Metabolic syndrome exposes patients to a greater risk of developing cardiovascular disease (CVD) and is often associated with elevated levels of homocysteine (Hcy). In the current work, we analyzed the expression of nicotinamide N-methyltransferase (NNMT). Because NNMT is involved in Hcy metabolism and participates in the regulation of the cellular and plasma levels of this compound, we explored the role played by the enzyme in metabolic syndrome. Real-time PCR, immunohistochemistry, western blot analysis, and catalytic activity assay were performed to evaluate NNMT expression levels in adipose tissue from 10 Wistar Ottawa Karlsburg W (WOKW) rats, which are an animal model for metabolic syndrome, and from 10 Dark Agouti (DA) rats as the disease-resistant control strain. NNMT mRNA, protein, and activity levels were significantly higher in adipose tissue obtained from WOKW rats compared with those observed in adipose tissue of DA rats. Data reported in this study represent the first evidence supporting the hypothesis that NNMT could play an important role in the pathogenesis of metabolic syndrome and could have a potential for the development of a targeted therapy.


Time-gating improves the spatial resolution of STED microscopy.
Stimulated-emission depletion (STED) microscopy improves image resolution by encoding additional spatial information in a second stimulated-decay channel with a spatially-varying strength. Here we demonstrate that spatial information is also encoded in the fluorophore lifetime and that this information can be used to improve the spatial resolution of STED microscopy. By solving a kinetic model for emission in the presence of a time-varying STED pulse, we derive the effective resolution as a function of fluorophore lifetime and pulse duration. We find that the best resolution for a given pulse power is achieved with a pulse of infinitesimally short duration; however, the maximum resolution can be restored for pulses of finite duration by time-gating the fluorescence signal. In parallel, we consider time-gating in the presence of a continuous-wave (CW) STED beam and find that time-gating produces theoretically unbounded resolution with finite laser power. In both cases, the cost of this improved resolution is a reduction in the brightness of the final image. We conclude by discussing situations in which time-gated STED microscopy (T-STED) may provide improved microscope performance beyond an increase in resolution.