The RpoS sigma factor relieves H-NS-mediated transcriptional repression of csgA, the subunit gene of fibronectin-binding curli in Escherichia coli.
Curli encoded by the curlin subunit gene, csgA, are fibronectin- and laminin-binding fibres expressed by many natural Escherichia coli and E. coli K-12 strains in response to low temperature, low osmolarity and stationary-phase growth conditions. Curli expression is dependent on RpoS, a sigma factor that controls many stationary phase-inducible genes. Many commonly used K-12 strains carry an amber mutation in rpoS. Strains able to form curli carry an amber suppressor whereas curli-negative E. coli K-12 strains, in general, are sup0. Introduction of SupD, SupE, or supF suppressors into sup0 strains resulted in expression of temperature-regulated curli. In curli-deficient, RpoS- E. coli K-12 strains, csgA is transcriptionally activated by mutations in hns, which encodes the histone-like protein H-NS. Curli expression, fibronectin binding, and csgA transcription remain temperature- and osmoregulated in such double mutants. Our data suggest that RpoS+ strains, and hence curli-proficient strains of E. coli K-12, are relieved for the transcriptional repression mediated by the H-NS protein upon accumulating RpoS as cells reach stationary phase.


Association between dairy product intake and abdominal obesity in Azorean adolescents.
Some studies have reported an inverse association between dairy product (DP) consumption and weight or fat mass loss. The objective of our study was to assess the association between DP intake and abdominal obesity (AO) among Azorean adolescents. This study was a cross-sectional analysis. A total of 903 adolescents (370 boys) aged 15-16 years was evaluated. Anthropometric measurements were collected (weight, height and waist circumference (WC)) and McCarthy's cut-points were used to categorize WC. AO was defined when WC was ≥90th percentile. Adolescent food intake was assessed using a self-administered semiquantitative food frequency questionnaire and DP intake was categorized in <2 and ≥2 servings/day. Data were analyzed separately for girls and boys, and logistical regression was used to estimate the association between DPs and AO adjusting for potential confounders. The prevalence of AO was 54.9% (boys: 32.1% and girls: 70.7%, P<0.001). For boys and girls, DP consumption was 2.3±1.9 and 2.1±1.6 servings/day (P=0.185), respectively. In both genders, the proportion of adolescents with WC <90th percentile was higher among individuals who reported a dairy intake of <2 servings/day compared with those with an intake <2 servings/day (boys: 71% vs 65% and girls: 36% vs 24%, P<0.05). After adjustments for confounders, two or more DP servings per day were a negative predictor of AO (odds ratio, 0.217; 95% confidence interval, 0.075-0.633) only in boys. We found a protective association between DP intake and AO only in boys.


Localization of spermidine uptake in rabbit lung slices.
The lungs have a high polyamine transport capability, and the type II pneumocyte has recently been identified as a major site of putrescine uptake and localization (N. A. Saunders, P. J. Rigby, K. F. Ilett, and R. F. Minchin. Lab. Invest. 59: 380-386, 1988). However, recent evidence suggests that multiple polyamine transport systems exist. In the present study, localization of spermidine uptake in rabbit lung was investigated. Although [14C]spermidine was rapidly accumulated by lung slices, it was not significantly metabolized, and no efflux of the accumulated polyamine was apparent. Autoradiographs prepared after [3H]spermidine transport revealed a localization of uptake activity to cells identified by electron microscopy as type II pneumocytes. Spermidine uptake occurred in all type II cells examined and thus appeared to be a characteristic function of this cell type. In contrast, spermidine uptake was virtually absent in the major airways and blood vessels, whereas moderate uptake was associated with pulmonary alveolar macrophages and alveolar tissue. Subsequent purification and culture of type II pneumocytes showed these cells to have significant polyamine uptake activity. In addition, spermidine uptake activity was positively correlated with the proportion of type II cells present at the various stages of their purification. In other studies, cultured pulmonary alveolar macrophages possessed similar uptake activity to that of cultured type II cells. Combined, these data suggest that both type II cells and pulmonary alveolar macrophages may represent major sites of spermidine uptake in vivo. We also suggest that the transport of polyamines by type II cells may reflect a critical role for polyamines in a characteristic function of this cell type.


Memory for expectation-violating concepts: the effects of agents and cultural familiarity.
Previous research has shown that ideas which violate our expectations, such as schema-inconsistent concepts, enjoy privileged status in terms of memorability. In our study, memory for concepts that violate cultural (cultural schema-level) expectations (e.g., "illiterate teacher", "wooden bottle", or "thorny grass") versus domain-level (ontological) expectations (e.g., "speaking cat", "jumping maple", or "melting teacher") was examined. Concepts that violate cultural expectations, or counter-schematic, were remembered to a greater extent compared with concepts that violate ontological expectations and with intuitive concepts (e.g., "galloping pony", "drying orchid", or "convertible car"), in both immediate recall, and delayed recognition tests. Importantly, concepts related to agents showed a memory advantage over concepts not pertaining to agents, but this was true only for expectation-violating concepts. Our results imply that intuitive, everyday concepts are equally attractive and memorable regardless of the presence or absence of agents. However, concepts that violate our expectations (cultural-schema or domain-level) are more memorable when pertaining to agents (humans and animals) than to non-agents (plants or objects/artifacts). We conclude that due to their evolutionary salience, cultural ideas which combine expectancy violations and the involvement of an agent are especially memorable and thus have an enhanced probability of being successfully propagated.


Severe periodontitis is associated with low serum albumin among patients on maintenance hemodialysis therapy.
The relationship between periodontitis and two measures of systemic inflammation, serum albumin and C-reactive protein (CRP), were examined among patients who were receiving chronic outpatient hemodialysis. Adult patients at two locations, North Carolina and New York City, were evaluated by dentist examiners. Six sites per tooth (up to 32 teeth per patient) were examined. A periodontitis case was defined as > or = 60% of sites with attachment level > or = 4 mm. Multivariable logistic regression was used to determine the association of periodontitis with low serum albumin, defined as < 3.5 mg/dl, and with high CRP, defined as > 3.0 mg/dl. A total of 154 patients completed the study. The mean age was 54.6 yr (SD 13.3), and average duration of dialysis was 4.0 yr (3 mo to 16 yr). Eighty-six (54.6%) were men, and 89 (58.2%) were black. Common causes of end-stage kidney disease were hypertension (12.3%), diabetes (22.1%), glomerulonephritis (7.1%), and other (58.4%). The average number of teeth was 20.3 (SD 8.4). Thirty-five (23%) patients were periodontitis cases. Severe periodontitis was associated with low serum albumin (odds ratio 8.20; 95% confidence interval 1.61 to 41.82; P = 0.01) compared with individuals without severe periodontitis disease after adjustment for age, gender, race, diabetes, hypertension, body mass index, smoking, study site, total cholesterol, serum calcium, serum phosphorus, and normalized protein catabolic rate. There was no observed association of severe periodontitis with CRP. Investigation of the potential contribution of periodontitis to serum albumin and possibly to morbidity and mortality among patients with end-stage kidney disease seems warranted.


Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women.
The Klotho gene is a suppressor of the aging phenomena, and the secretion as well as the circulation of Klotho proteins decrease with aging. Although habitual exercise has antiaging effects (e.g., a decrease in arterial stiffness), the relationship between Klotho and habitual exercise remains unclear. In the present study, we investigated the effect of habitual exercise on Klotho, with a particular focus on arterial stiffness. First, we examined the correlation between plasma Klotho concentration and arterial stiffness (carotid artery compliance and β-stiffness index) or aerobic exercise capacity [oxygen uptake at ventilatory threshold (VT)] in 69 healthy, postmenopausal women (50-76 years old) by conducting a cross-sectional study. Second, we tested the effects of aerobic exercise training on plasma Klotho concentrations and arterial stiffness. A total of 19 healthy, postmenopausal women (50-76 years old) were divided into two groups: control group and exercise group. The exercise group completed 12 wk of moderate aerobic exercise training. In the cross-sectional study, plasma Klotho concentrations positively correlated with carotid artery compliance and VT and negatively correlated with the β-stiffness index. In the interventional study, aerobic exercise training increased plasma Klotho concentrations and carotid artery compliance and decreased the β-stiffness index. Moreover, the changes in plasma Klotho concentration and arterial stiffness were found to be correlated. These results suggest a possible role for secreted Klotho in the exercise-induced modulation of arterial stiffness.


Household perceptions of coastal hazards and climate change in the Central Philippines.
As a tropical archipelagic nation, the Philippines is particularly susceptible to coastal hazards, which are likely to be exacerbated by climate change. To improve coastal hazard management and adaptation planning, it is imperative that climate information be provided at relevant scales and that decision-makers understand the causes and nature of risk in their constituencies. Focusing on a municipality in the Central Philippines, this study examines local meteorological information and explores household perceptions of climate change and coastal hazard risk. First, meteorological data and local perceptions of changing climate conditions are assessed. Perceived changes in climate include an increase in rainfall and rainfall variability, an increase in intensity and frequency of storm events and sea level rise. Second, factors affecting climate change perceptions and perceived risk from coastal hazards are determined through statistical analysis. Factors tested include social status, economic standing, resource dependency and spatial location. Results indicate that perceived risk to coastal hazards is most affected by households' spatial location and resource dependency, rather than socio-economic conditions. However, important differences exist based on the type of hazard and nature of risk being measured. Resource dependency variables are more significant in determining perceived risk from coastal erosion and sea level rise than flood events. Spatial location is most significant in determining households' perceived risk to their household assets, but not perceived risk to their livelihood.


Micro-scaled topographies direct differentiation of human epidermal stem cells.
Human epidermal stem cells initiate terminal differentiation when spreading is restricted on ECM-coated micropatterned islands, soft hydrogels or hydrogel-nanoparticle composites with high nanoparticle spacing. The effect of substrate topography, however, is incompletely understood. To explore this, primary human keratinocytes enriched for stem cells were seeded on a topographical library with over 2000 different topographies in the micrometre range. Twenty-four hours later the proportion of cells expressing the differentiation marker transglutaminase-1 was determined by high content imaging. As predicted, topographies that prevented spreading promoted differentiation. However, we also identified topographies that supported differentiation of highly spread cells. Topographies supporting differentiation of spread cells were more irregular than those supporting differentiation of round cells. Low topography coverage promoted differentiation of spread cells, whereas high coverage promoted differentiation of round cells. Based on these observations we fabricated a topography in 6-well plate format that supported differentiation of spread cells, enabling us to examine cell responses at higher resolution. We found that differentiated spread cells did not assemble significant numbers of hemidesmosomes, focal adhesions, adherens junctions, desmosomes or tight junctions. They did, however, organise the actin cytoskeleton in response to the topographies. Rho kinase inhibition and blebbistatin treatment blocked the differentiation of spread cells, whereas SRF inhibition did not. These observations suggest a potential role for actin polymerization and actomyosin contraction in the topography-induced differentiation of spread cells. STATEMENT OF SIGNIFICANCE: The epidermis is the outer covering of the skin. It is formed by layers of cells called keratinocytes. The basal cell layer contains stem cells, which divide to replace cells in the outermost layers that are lost through a process known as differentiation. In this manuscript we have developed surfaces that promote the differentiation of epidermal stem cells in order to understand the signals that control differentiation. The experimental tools we have developed have the potential to help us to devise new treatments that control diseases such as psoriasis and eczema in which epidermal stem cell proliferation and differentiation are disturbed.


Development and evaluation of a study design typology for human research.
A systematic classification of study designs would be useful for researchers, systematic reviewers, readers, and research administrators, among others. As part of the Human Studies Database Project, we developed the Study Design Typology to standardize the classification of study designs in human research. We then performed a multiple observer masked evaluation of active research protocols in four institutions according to a standardized protocol. Thirty-five protocols were classified by three reviewers each into one of nine high-level study designs for interventional and observational research (e.g., N-of-1, Parallel Group, Case Crossover). Rater classification agreement was moderately high for the 35 protocols (Fleiss' kappa = 0.442) and higher still for the 23 quantitative studies (Fleiss' kappa = 0.463). We conclude that our typology shows initial promise for reliably distinguishing study design types for quantitative human research.


Stakeholder perspectives about general practice pharmacists in the Australian Capital Territory: a qualitative pilot study.
Previous studies have found that integrating non-dispensing pharmacists in general practice may improve patient safety, improve patient outcomes, deliver health system efficiencies and generate savings. However, the employment of pharmacists in general practice is not common in Australia. A naturalistic study was conducted in the Australian Capital Territory with three general practices, each employing a part-time pharmacist for 12 months. This study reports on stakeholder perspectives of the benefits, barriers and enablers for integrating pharmacists into general practice. Patients, practice staff and community pharmacists that had interacted with a practice pharmacist were asked to complete a self-administered questionnaire. Patient questionnaire respondents (n=44) reported that a practice pharmacist was beneficial and wanted to see this continue. Practice pharmacists were also perceived beneficial by primary healthcare employees surveyed (n=42). Opinions were further explored by individual semi-structured interviews (n=20). The qualitative data explored five themes: perception of the practice pharmacist, collaboration with doctors, pharmacist roles, sustainability and community pharmacy aspects. Patients welcomed improved understanding about their medication, whereas general practice staff appreciated pharmaceutical advice about patients with chronic conditions. Participants discussed options to fund practice pharmacists longer term, which was identified as the main barrier to widespread roll out.


[Pediatric inflammatory bowel disease: is it still increasing?].
Crohn's disease (CD), Ulcerative Colitis (UC) and Indeterminate Colitis (IC), commonly known as Inflammatory Bowel Disease (IBD) represent a heterogeneous group of chronic diseases of unknown origin and varying course, diagnosed in pediatric age at 25 to 30% of cases. Epidemiological international studies studies show IBD incidence has increased exponentially in industrialized nations over the last 50 years. Characterization of the pediatric population diagnosed with IBD, followed at medical consultation in Gastroenterology at Hospital de Dona Estefânia (HDE). Descriptive and retrospective study by consulting the medical files of patients diagnosed with IBD followed between 1987 and 2009 (23 years). Clinical, radiological and histological criteria were used to define IBD. The following variables were studied: sex, family history, race, characterization of IBD, age at diagnosis, time from onset of symptoms to diagnosis and clinical presentation. Four different periods of time were compared: 1987-1992, 1993-1998, 1999-2004 and 2005-2009. 100 children were included (51 female), of which 59% are CD, 38% UC and 3% IC. Family history of IBD was present in 7 cases, with no sex difference between UC and CD. During the period of time between 2005-2009, it was registered the highest number of new cases (55 total, mean: 11 cases / year) and between 1987-1992 the lowest (9, 1.5 cases / year). Time from onset of symptoms to diagnosis was highly variable, ranging from 9 months (1987-1992) to 4 months (2005-2009). Children's age at the time of diagnosis varied from 14 months to 17 years, with a mean of 10.5 years. The most common symptoms at time of presentation were abdominal pain, diarrhea, and hematochezia. IBD are a heterogeneous group of diseases, not always easy to diagnose and difficult to classify as diagnostic criteria are not always uniform. The results show the number of IBD new cases has been rising during the last two decades, mainly CD, with no difference between gender. Time from onset of symptoms to diagnosis has been decreasing although age at time of diagnosis and clinical presentation has showed no difference in the last 20 years.


Introducing the Progesterone Vaginal Ring (PVR) as a New Option for Postpartum Family Planning in Sub-Saharan Africa: Insights from Engagements with Stakeholders.
The progesterone vaginal ring (PVR) is a ring-shaped device designed for use by women in the postpartum period to regulate fertility by complementing and extending the contraceptive effectiveness of lactational amenorrhea to suppress ovulation.1 It is available in eight Latin American countries for use by breastfeeding women who want more effective modern contraceptives in addition to contraceptive benefits provided by lactational amenorrhea alone.1 The PVR is a method that can be suitable to women in sub-Saharan Africa, given the near-universal practice of breastfeeding and the current level of unmet need for contraception in the postpartum period. Efforts are currently underway to introduce the PVR in Africa and south Asia. To ensure a seamless introduction, scale up and sustainability of the PVR in the region, the Population Council conducted pre-introductory activities with stakeholders in Kenya, Nigeria and Senegal to determine the level of interest in the ring, potential facilitating and mitigating factors and identify solutions to address challenges. The research team combined three approaches: in-depth interviews with family planning stakeholders; desk review of reports and policy guidelines; and in-group meetings. The stakeholders reached included public sector officials including policy makers and program managers, implementing partners, regulators, women and religious networks. All three countries had a promising policy and programmatic context that was supportive to PVR introduction. The exercise provided insights on socio-cultural and religious factors that could potentially impact how the PVR is perceived within communities and identified possible remedies to address misperceptions. It also paved the way for the conduct of an acceptability study of the PVR among breastfeeding women in these countries. The high acceptability rate in each country and the support expressed by government and other stakeholders have provided impetus for registration of the product in each country. Learning from this process could also direct how other family planning and reproductive health commodities would be introduced in the future.


Gonadotropin-releasing hormone analogue as sole luteal support in antagonist-based assisted reproductive technology cycles.
To evaluate the efficacy of GnRH agonists (GnRH-a) as sole luteal phase support in patients undergoing IVF in antagonist-based cycles compared with standard vaginal P preparations. Retrospective cohort. Private fertility clinic. Patients who underwent antagonist-based cycles performed at our clinic between 2009 and 2015. Intranasal GnRH-a or vaginal P as luteal support. Live birth rates. A total of 2,529 antagonist-based cycles from 1,479 women were available for analysis, in which GnRH-a were used in 1,436 cycles (56.7%) and P supplementation in 1,093 cycles (43.2%). Significantly higher live birth rates were demonstrated for the entire GnRH-a group compared with the P group. This result was even more prominent when women older than 35 years were considered separately. Furthermore, after adjustment for age, body mass index (BMI), past obstetric history, number of IVF cycles, oocyte retrieved and embryos transferred, GnRH-a was still associated with a higher rate of live birth (odds ratio 1.46, 95% confidence interval 1.10-1.94). Once a positive β-hCG was achieved, chemical pregnancy rates (PRs) and miscarriage rates were not statistically different between the GnRH-a and the P supplementation group, and GnRH-a was associated with a higher rate of live births (odds ratio 1.59, 95% confidence interval 1.07-2.36). This large retrospective study suggests that repeated intranasal GnRH-a for luteal phase support is associated with a higher live birth rate compared with standard P supplementations.


Complete relief of pain in acute painful diabetic neuropathy of rapid glycaemic control (insulin neuritis) with venlafaxine HCL.
This article reports a case of a diabetic patient who suffered from acute painful diabetic neuropathy, following an intensive insulin treatment after a poor glycaemic control period of 8 yr. On the 15th day of the insulin treatment, which enabled rapid successful glycaemic control, the patient began complaining of pain and a burning sensation in the lower extremities, especially during the night. Venlafaxine HCL was initiated and the patient was completely free of pain on the third day of the treatment. As insulin neuritis is infrequent among diabetic patients we consider it is worth reporting the dramatic effect of the venlafaxine HCL treatment.


A systematic review of special events to promote breast, cervical and colorectal cancer screening in the United States.
Special events are common community-based strategies for health promotion. This paper presents findings from a systematic literature review on the impact of special events to promote breast, cervical or colorectal cancer education and screening. Articles in English that focused on special events involving breast, cervical, and/or colorectal cancer conducted in the U.S. and published between January 1990 and December 2011 were identified from seven databases: Ovid, Web of Science, CINAHL, PsycINFO, Sociological Abstract, Cochrane Libraries, and EconLit. Study inclusion and data extraction were independently validated by two researchers. Of the 20 articles selected for screening out of 1,409, ten articles on special events reported outcome data. Five types of special events were found: health fairs, parties, cultural events, special days, and plays. Many focused on breast cancer only, or in combination with other cancers. Reach ranged from 50-1732 participants. All special events used at least one evidence-based strategy suggested by the Community Guide to Preventive Services, such as small media, one-on-one education, and reducing structural barriers. For cancer screening as an outcome of the events, mammography screening rates ranged from 4.8% to 88%, Pap testing was 3.9%, and clinical breast exams ranged from 9.1% to 100%. For colorectal screening, FOBT ranged from 29.4% to 76%, and sigmoidoscopy was 100% at one event. Outcome measures included intentions to get screened, scheduled appointments, uptake of clinical exams, and participation in cancer screening. Special events found in the review varied and used evidence-based strategies. Screening data suggest that some special events can lead to increases in cancer screening, especially if they provide onsite screening services. However, there is insufficient evidence to demonstrate that special events are effective in increasing cancer screening. The heterogeneity of populations served, event activities, outcome variables assessed, and the reliance on self-report to measure screening limit conclusions. This study highlights the need for further research to determine the effectiveness of special events to increase cancer screening.


Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension.
Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear. To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI. A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15). Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group. In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae.


Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level.
The Food and Nutrition Board of the National Academy of Sciences states that 95 microg vitamin D/d is the lowest observed adverse effect level (LOAEL). Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 microg (1000 and 4000 IU)/d. Efficacy was based on the lowest serum 25-hydroxyvitamin D [25(OH)D] concentration achieved by subjects taking vitamin D3; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios. Healthy men and women (n = 61) aged 41 +/- 9 y (mean +/- SD) were randomly assigned to receive either 25 or 100 microg vitamin D3/d for 2-5 mo, starting between January and February. Serum 25(OH)D was measured by radioimmunoassay. Baseline serum 25(OH)D was 40.7 +/- 15.4 nmol/L (mean +/- SD). From 3 mo on, serum 25(OH)D plateaued at 68.7 +/- 16.9 nmol/L in the 25-microg/d group and at 96.4 +/- 14.6 nmol/L in the 100-microg/d group. Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 +/- 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 microg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L, respectively. Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study. The 100-microg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range; therefore, we consider 100 microg vitamin D3/d to be a safe intake.


Point matching under large image deformations and illumination changes.
To solve the general point correspondence problem in which the underlying transformation between image patches is represented by a homography, a solution based on extensive use of first order differential techniques is proposed. We integrate in a single robust M-estimation framework the traditional optical flow method and matching of local color distributions. These distributions are computed with spatially oriented kernels in the 5D joint spatial/color space. The estimation process is initiated at the third level of a Gaussian pyramid, uses only local information, and the illumination changes between the two images are also taken into account. Subpixel matching accuracy is achieved under large projective distortions significantly exceeding the performance of any of the two components alone. As an application, the correspondence algorithm is employed in oriented tracking of objects.


Beta+-thalassemia in cis of a sickle cell gene: occurrence of a promoter mutation on a beta s chromosome.
An atypical sickle cell trait with a very low level of hemoglobin S and features of heterozygous beta-thalassemia was recently described. In vitro globin chain synthesis strongly suggested the presence of the two abnormalities on the same chromosome. We report the corresponding beta S-thal gene. DNA sequence revealed a C----T base substitution in the distal promoter element CACCC, at position-88 from the cap site, in addition to the expected GAG----GTG mutation responsible for the structural variant (beta 6 Glu----Val). Reticulocyte mRNA titration and transient assay of the mutant gene in COS cells showed a defect in beta-mRNA production. Restriction haplotype and DNA sequence analyses revealed that the doubly mutated gene is associated with haplotype 19 (or Benin/Algeria haplotype). In particular, we found the (AT)9(T)4 repeated sequences specifically encountered 5' to the beta S gene of Benin Algeria type. These results support the view that the beta S-thal gene resulted from an independent thalassemic mutation having occurred on a beta S chromosome rather than (a) from a beta S mutation having altered a beta-thalassemic gene or (b) from a recombination event between two chromosomes, each carrying one of the mutations.


Adaptive nonlocal means filtering based on local noise level for CT denoising.
To develop and evaluate an image-domain noise reduction method based on a modified nonlocal means (NLM) algorithm that is adaptive to local noise level of CT images and to implement this method in a time frame consistent with clinical workflow. A computationally efficient technique for local noise estimation directly from CT images was developed. A forward projection, based on a 2D fan-beam approximation, was used to generate the projection data, with a noise model incorporating the effects of the bowtie filter and automatic exposure control. The noise propagation from projection data to images was analytically derived. The analytical noise map was validated using repeated scans of a phantom. A 3D NLM denoising algorithm was modified to adapt its denoising strength locally based on this noise map. The performance of this adaptive NLM filter was evaluated in phantom studies in terms of in-plane and cross-plane high-contrast spatial resolution, noise power spectrum (NPS), subjective low-contrast spatial resolution using the American College of Radiology (ACR) accreditation phantom, and objective low-contrast spatial resolution using a channelized Hotelling model observer (CHO). Graphical processing units (GPU) implementation of this noise map calculation and the adaptive NLM filtering were developed to meet demands of clinical workflow. Adaptive NLM was piloted on lower dose scans in clinical practice. The local noise level estimation matches the noise distribution determined from multiple repetitive scans of a phantom, demonstrated by small variations in the ratio map between the analytical noise map and the one calculated from repeated scans. The phantom studies demonstrated that the adaptive NLM filter can reduce noise substantially without degrading the high-contrast spatial resolution, as illustrated by modulation transfer function and slice sensitivity profile results. The NPS results show that adaptive NLM denoising preserves the shape and peak frequency of the noise power spectrum better than commercial smoothing kernels, and indicate that the spatial resolution at low contrast levels is not significantly degraded. Both the subjective evaluation using the ACR phantom and the objective evaluation on a low-contrast detection task using a CHO model observer demonstrate an improvement on low-contrast performance. The GPU implementation can process and transfer 300 slice images within 5 min. On patient data, the adaptive NLM algorithm provides more effective denoising of CT data throughout a volume than standard NLM, and may allow significant lowering of radiation dose. After a two week pilot study of lower dose CT urography and CT enterography exams, both GI and GU radiology groups elected to proceed with permanent implementation of adaptive NLM in their GI and GU CT practices. This work describes and validates a computationally efficient technique for noise map estimation directly from CT images, and an adaptive NLM filtering based on this noise map, on phantom and patient data. Both the noise map calculation and the adaptive NLM filtering can be performed in times that allow integration with clinical workflow. The adaptive NLM algorithm provides effective denoising of CT data throughout a volume, and may allow significant lowering of radiation dose.


Combining resources to obtain a comprehensive survey of the bovine embryo transcriptome through deep sequencing and microarrays.
While most assisted reproductive technologies (ART) are considered routine for the reproduction of species of economical importance, such as the bovine, the impact of these manipulations on the developing embryo remains largely unknown. In an effort to obtain a comprehensive survey of the bovine embryo transcriptome and how it is modified by ART, resources were combined to design an embryo-specific microarray. Close to one million high-quality reads were produced from subtracted bovine embryo libraries using Roche 454 Titanium deep sequencing technology, which enabled the creation of an augmented bovine genome catalog. This catalog was enriched with bovine embryo transcripts, and included newly discovered indel type and 3'UTR variants. Using this augmented bovine genome catalog, the EmbryoGENE Bovine Microarray was designed and is composed of a total of 42,242 probes, including 21,139 known reference genes; 9,322 probes for novel transcribed regions (NTRs); 3,677 alternatively spliced exons; 3,353 3'-tiling probes; and 3,723 controls. A suite of bioinformatics tools was also developed to facilitate microrarray data analysis and database creation; it includes a quality control module, a Laboratory Information Management System (LIMS) and microarray analysis software. Results obtained during this study have already led to the identification of differentially expressed blastocyst targets, NTRs, splice variants of the indel type, and 3'UTR variants. We were able to confirm microarray results by real-time PCR, indicating that the EmbryoGENE bovine microarray has the power to detect physiologically relevant changes in gene expression.


Candidaemia in special care nurseries: comparison of albicans and parapsilosis infection.
Candidaemia caused by Candida parapsilosis (CP) is being increasingly reported among infants in neonatal intensive care units (NICU). To assess relative severity, clinical manifestations of candidaemia caused by C. albicans (CA) and CP in a NICU were compared. Between January 1994 and July 1997, episodes of candidaemia occurring among infants hospitalized in the NICU were identified in a children's hospital. The demographic characteristics, associated risk factors, clinical manifestations and outcome of the infants with CP fungaemia were collected and compared with those of the infants with CA fungaemia. Twenty-four episodes caused by CA and 22 episodes caused by CP were included in this study. No significant differences were found between the two groups for gestational age, birth weight, male gender, post-natal age at onset of candidaemia, frequency of antecedent neonatal events, prior duration of antibiotic therapy and hyperalimentation, as well as presence of central venous catheter (CVC). Infants with CA fungaemia were significantly more likely than those with CP fungaemia to present with hypoxaemia, bradycardia and respiratory distress requiring intubation, and have a longer prior duration of indwelling CVC and a higher dissemination rate. The eradication rate of candidaemia and overall case fatality rate were comparable in both groups. but CP fungaemia did not appear to cause acute lethal events. The presenting signs of CP fungaemia are relatively not so severe, but CP fungaemia, which is relatively difficult to eradicate, increases the morbidity and mortality of the infants.


Contradictory subject response in longitudinal research.
This study investigated the prevalence of logical and estimation errors in a 4-year longitudinal survey of substance abuse for elementary and junior high school students. Logical errors occur when a subject reports having used a substance on one measurement occasion, but reports never having used the substance on a second measurement occasion. Estimation errors occur when a subject reports a lifetime frequency of use on a later survey that is less than the lifetime frequency of use reported for an earlier survey. Substance abuse surveys were completed every year for four years by predominantly black District of Columbia students, beginning when the students were in 4th/5th grade, and ending when they were in 7th/8th grade. (Ns ranged from 5,671 to 6,421). Errors for alcohol, cigarette and marijuana use were calculated for every pair of years. Background characteristics such as demographic and academic performance variables were also assessed for each of the four years. Logical errors decreased for all substances as student got older, whereas estimation errors remained stable. Marijuana had the highest frequency of logical errors in every pair of years except one, and had the lowest frequency of estimation errors. Students who made errors in Years 1-2 were 1.64 times more likely to make errors again in Years 3-4. For some of the years, students who made any kind of error had lower school grades, were judged untrustworthy by their peers and were more likely to be males. The alarming prevalence of errors should be considered when conducting longitudinal substance abuse research. Several methods of dealing with these errors are reviewed. In most cases, the best a researcher can do is assess the error rates and report them.


Technical report--racial and ethnic disparities in the health and health care of children.
This technical report reviews and synthesizes the published literature on racial/ethnic disparities in children's health and health care. A systematic review of the literature was conducted for articles published between 1950 and March 2007. Inclusion criteria were peer-reviewed, original research articles in English on racial/ethnic disparities in the health and health care of US children. Search terms used included "child," "disparities," and the Index Medicus terms for each racial/ethnic minority group. Of 781 articles initially reviewed, 111 met inclusion criteria and constituted the final database. Review of the literature revealed that racial/ethnic disparities in children's health and health care are quite extensive, pervasive, and persistent. Disparities were noted across the spectrum of health and health care, including in mortality rates, access to care and use of services, prevention and population health, health status, adolescent health, chronic diseases, special health care needs, quality of care, and organ transplantation. Mortality-rate disparities were noted for children in all 4 major US racial/ethnic minority groups, including substantially greater risks than white children of all-cause mortality; death from drowning, from acute lymphoblastic leukemia, and after congenital heart defect surgery; and an earlier median age at death for those with Down syndrome and congenital heart defects. Certain methodologic flaws were commonly observed among excluded studies, including failure to evaluate children separately from adults (22%), combining all nonwhite children into 1 group (9%), and failure to provide a white comparison group (8%). Among studies in the final database, 22% did not perform multivariable or stratified analyses to ensure that disparities persisted after adjustment for potential confounders. Racial/ethnic disparities in children's health and health care are extensive, pervasive, and persistent, and occur across the spectrum of health and health care. Methodologic flaws were identified in how such disparities are sometimes documented and analyzed. Optimal health and health care for all children will require recognition of disparities as pervasive problems, methodologically sound disparities studies, and rigorous evaluation of disparities interventions.


Spectral embedded clustering: a framework for in-sample and out-of-sample spectral clustering.
Spectral clustering (SC) methods have been successfully applied to many real-world applications. The success of these SC methods is largely based on the manifold assumption, namely, that two nearby data points in the high-density region of a low-dimensional data manifold have the same cluster label. However, such an assumption might not always hold on high-dimensional data. When the data do not exhibit a clear low-dimensional manifold structure (e.g., high-dimensional and sparse data), the clustering performance of SC will be degraded and become even worse than K -means clustering. In this paper, motivated by the observation that the true cluster assignment matrix for high-dimensional data can be always embedded in a linear space spanned by the data, we propose the spectral embedded clustering (SEC) framework, in which a linearity regularization is explicitly added into the objective function of SC methods. More importantly, the proposed SEC framework can naturally deal with out-of-sample data. We also present a new Laplacian matrix constructed from a local regression of each pattern and incorporate it into our SEC framework to capture both local and global discriminative information for clustering. Comprehensive experiments on eight real-world high-dimensional datasets demonstrate the effectiveness and advantages of our SEC framework over existing SC methods and K-means-based clustering methods. Our SEC framework significantly outperforms SC using the Nyström algorithm on unseen data.


Effect of Fas and Fas ligand deficiency in resistance of C57BL/6 mice to HSV-1 keratitis and chorioretinitis.
To investigate the effect of Fas and Fas ligand (FasL) deficiency on the development of herpes stromal keratitis and on the von Szily model of herpes retinitis in C57BL/6 mice, which are ordinarily resistant to development of both of these herpetic diseases. Anterior chamber inoculation of the right eye of each mouse with various titers of HSV-1 (KOS strain) was performed. Both eyes of each mouse were enucleated on postinoculation day 15 and processed for histopathologic examination. HSV-1 was inoculated into one cornea of other mice, and the severity of stromal keratitis was scored. Contralateral destructive chorioretinitis developed in susceptible Balb/cByj mice (19/23); ipsilateral chorioretinitis did not occur (0/23). Stromal keratitis developed in susceptible C.AL-20 mice (15/16). None of the C57BL/6 (0/10 for keratitis or 0/20 for retinitis) developed inflammation. Neither did B6.SMN.C3H.gld (FasL deficient; 0/12 or 0/28) or B6.MRL.lpr (Fas deficient; 0/11 or 0/34) mice (keratitis or contralateral chorioretinitis). Minimal scattering of inflammatory cells in the contralateral retina but not destructive chorioretinitis was observed in two C57BL/6, three B6.SMN.C3H.gld, and five B6.MRL.lpr mice. Few inflammatory cells were also found in the ipsilateral vitreous and vitreoretinal interface (but not destructive chorioretinitis) of all C57BL/6, two gld, and three lpr mice. Immune dysregulation secondary to deficiency in Fas or FasL system does not influence the resistance of the C57BL/6 mice to develop herpes simplex keratitis or destructive herpes simplex chorioretinitis.


Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice.
Neuroligin-3 is a member of the class of cell adhesion proteins that mediate synapse development and have been implicated in autism. Mice with the human R451C mutation (NL3), identical to the point mutation found in two brothers with autism spectrum disorders, were generated and phenotyped in multiple behavioral assays with face validity to the diagnostic symptoms of autism. No differences between NL3 and their wildtype (WT) littermate controls were detected on measures of juvenile reciprocal social interaction, adult social approach, cognitive abilities, and resistance to change in a spatial habit, findings which were replicated in several cohorts of males and females. Physical and procedural abilities were similar across genotypes on measures of general health, sensory abilities, sensorimotor gating, motor functions, and anxiety-related traits. Minor developmental differences were detected between NL3 and WT, including slightly different rates of somatic growth, slower righting reflexes at postnatal days 2-6, faster homing reflexes in females, and less vocalizations on postnatal day 8 in males. Significant differences in NL3 adults included somewhat longer latencies to fall from the rotarod, less vertical activity in the open field, and less acoustic startle to high decibel tones. The humanized R451C mutation in mice did not result in apparent autism-like phenotypes, but produced detectable functional consequences that may be interpreted in terms of physical development and/or reduced sensitivity to stimuli.


Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.
The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.


Molecular epidemiology, evolution, and ecology of Francisella.
Tularemia is a disease caused by several subspecies of Francisella tularensis, although the severity of the disease varies greatly from subspecies to subspecies. Currently, there are four recognized subspecies (tularensis, holarctica, mediasiatica, and novicida), in addition to a second Francisella species, F. philomiragia. It is clear from molecular sampling of the environment that these human pathogens are a mere fraction of the Francisella diversity. Taxonomic nomenclature is now being based upon several DNA-sequence-based approaches and this advance provides for robust phylogenetic models that are guiding the systematics of this genus. This in turn allows for better molecular epidemiological investigations and more precise ecological analysis. Tularemia ecology is still only partially understood, with many knowledge gaps about the disease reservoir and vectors. Molecular analysis has identified a major population split within F. tularensis subsp. tularensis that points toward distinctive ecological adaptations, vectors, and host species. Current medical practice does not rely upon subspecies or subpopulation identification, although this information may have predictive value for clinical outcome, especially in the United States. Combined molecular and epidemiological analyses suggest that the population split in F. tularensis subsp. tularensis matches two distinct human diseases in the United States with different mortality rates. DNA-sequence-based typing of F. tularensis subsp. holarctica from tularemia outbreaks in Europe and the United States proves regional identity among isolates and also demonstrates that this subspecies successfully disseminated worldwide in recent evolutionary time.


A contextually relevant approach to assessing health risk behavior in a rural sub-Saharan Africa setting: the Kilifi health risk behavior questionnaire.
Health risk behavior (HRB) is of concern during adolescence. In sub-Saharan Africa, reliable, valid and culturally appropriate measures of HRB are urgently needed. This study aims at assembling and psychometrically evaluating a comprehensive questionnaire on HRB of adolescents in Kilifi County at the coast of Kenya. The Kilifi Health Risk Behavior Questionnaire (KRIBE-Q) was assembled using items on HRB identified from a systematic review and by consulting 85 young people through 11 focus group discussions and in-depth interviews with 10 key informants like teachers and employees of organizations providing various services to young people in Kilifi County. The assembled list of HRB items were back and forward translated from English to Swahili and harmonized by a panel of experts. A total of 164 adolescents completed the assembled Swahili questionnaire at baseline and two weeks later 85 of them completed the questionnaire again. A classical test theory approach was utilized for psychometric evaluation. We computed the amount of missing data at item-level to verify data quality. Scaling evaluation was assessed by spread of responses across options at an item-level. Using Gwet's AC1 coefficient, test-retest reliability was assessed using data from the 85 adolescents who answered the questionnaire twice. Observations and completion of a brief questionnaire were done for non-psychometric evaluation of the KRIBE-Q administered via audio-computer assisted self-interview (ACASI) in Swahili language to 40 adolescents. The KRIBE-Q showed high data quality, good spread of responses across options and a very good test-retest reliability (Gwet's AC1 = 0.82). It comprised 8 components with acceptable test-retest reliability: behavior resulting in unintentional injury and violence (0.85); tobacco use (0.85); alcohol and drug use (0.96); sexual behaviors (0.94); dietary behaviors (0.60); physical activity (0.74); gambling (0.73); and hygiene behavior (0.89). About 96% of the adolescents found the ACASI private and easy to use. Prevalence of bullying (32%), physical fights (40%) and engagement in gambling (26%) was high. The KRIBE-Q assembled in this study is a psychometrically sound instrument for adolescents in rural coastal Kenya and feasible to administer via ACASI. This measure may be useful for surveys and planning interventions in similar settings.


Global analysis of trans-splicing in Drosophila.
Precursor mRNA (pre-mRNA) splicing can join exons contained on either a single pre-mRNA (cis) or on separate pre-mRNAs (trans). It is exceedingly rare to have trans-splicing between protein-coding exons and has been demonstrated for only two Drosophila genes: mod(mdg4) and lola. It has also been suggested that trans-splicing is a mechanism for the generation of chimeric RNA products containing sequence from multiple distant genomic sites. Because most high-throughput approaches cannot distinguish cis- and trans-splicing events, the extent to which trans-splicing occurs between protein-coding exons in any organism is unknown. Here, we used paired-end deep sequencing of mRNA to identify genes that undergo trans-splicing in Drosophila interspecies hybrids. We did not observe credible evidence for the existence of chimeric RNAs generated by trans-splicing of RNAs transcribed from distant genomic loci. Rather, our data suggest that experimental artifacts are the source of most, if not all, apparent chimeric RNA products. We did, however, identify 80 genes that appear to undergo trans-splicing between homologous alleles and can be classified into three categories based on their organization: (i) genes with multiple 3' terminal exons, (ii) genes with multiple first exons, and (iii) genes with very large introns, often containing other genes. Our results suggest that trans-splicing between homologous alleles occurs more commonly in Drosophila than previously believed and may facilitate expression of architecturally complex genes.


Influence of macronutrient intake and anthropometric characteristics on plasma insulin after eccentric exercise.
To increase understanding of the interaction between macronutrients and insulin resistance (IR), this study sought to determine the influence of macronutrient intake and anthropometric differences on IR and inflammation responses to eccentric resistance exercise. Men and women (n = 12, 19-36 years old) participated in a crossover study and completed 6 sets of 10 unilateral maximal eccentric contractions of the elbow flexors and extensors followed by controlled diet conditions for the first 8 hours postexercise of carbohydrate/fat/protein proportions of either 75%/15%/10% (CHO) or 6%/70%/24% (FAT/PRO). Fasting glucose, insulin, homeostatic model assessment (HOMA) variables, and interleukin (IL)-1β were measured preexercise and 23 hours postexercise (additional measures of glucose and insulin 1 hour after meals consumed 0.5, 3, and 7 hours postexercise). Insulin increased more (P < .01) in the CHO compared with the FAT/PRO condition at 1.5, 4, and 8 hours postexercise. Insulin, HOMA-IR, and HOMA-β-cell function increased 23 hours postexercise in both conditions, whereas IL-1β increased 23 hours postexercise only in the CHO condition. Magnitude of change (Δ) for these variables associated positively with body mass index (BMI) and waist to hip ratio (WHR) in the CHO and inversely in the FAT/PRO condition; that is, r = 0.53 (P = .10) and r = -0.82 (P < .01) for BMI vs Δ insulin in CHO and FAT/PRO conditions, respectively. The Δ IL-1β associated with BMI (r = 0.62, P < .05) and WHR (r = 0.84, P < .01) in the CHO condition. The CHO enhanced IR and inflammation as BMI and WHR increased, whereas fat and protein enhanced IR as BMI and WHR decreased. Thus, BMI and WHR may need to be taken into account in the development of nutritional strategies to prevent IR.


Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis.
The HIV pandemic affects 36·9 million people worldwide, of whom 1·5 million are pregnant women. 91% of HIV-positive pregnant women reside in sub-Saharan Africa, a region that also has very poor perinatal outcomes. We aimed to establish whether untreated maternal HIV infection is associated with specific perinatal outcomes. We did a systematic review and meta-analysis of the scientific literature by searching PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) for studies published from Jan 1, 1980, to Dec 7, 2014. Two authors independently reviewed the studies retrieved by the scientific literature search, identified relevant studies, and extracted the data. We investigated the associations between maternal HIV infection in women naive to antiretroviral therapy and 11 perinatal outcomes: preterm birth, very preterm birth, low birthweight, very low birthweight, term low birthweight, preterm low birthweight, small for gestational age, very small for gestational age, miscarriage, stillbirth, and neonatal death. We included prospective and retrospective cohort studies and case-control studies reporting perinatal outcomes in HIV-positive women naive to antiretroviral therapy and HIV-negative controls. We used a random-effects model for the meta-analyses of specific perinatal outcomes. We did subgroup and sensitivity analyses and assessed the effect of adjustment for confounders. This systematic review and meta-analysis is registered with PROSPERO, number CRD42013005638. Of 60,750 studies identified, we obtained data from 35 studies (20 prospective cohort studies, 12 retrospective cohort studies, and three case-control studies) including 53 623 women. Our meta-analyses of prospective cohort studies show that maternal HIV infection is associated with an increased risk of preterm birth (relative risk 1·50, 95% CI 1·24-1·82), low birthweight (1·62, 1·41-1·86), small for gestational age (1·31, 1·14-1·51), and stillbirth (1·67, 1·05-2·66). Retrospective cohort studies also suggest an increased risk of term low birthweight (2·62, 1·15-5·93) and preterm low birthweight (3·25, 2·12-4·99). The strongest and most consistent evidence for these associations is identified in sub-Saharan Africa. No association was identified between maternal HIV infection and very preterm birth, very small for gestational age, very low birthweight, miscarriage, or neonatal death, although few data were available for these outcomes. Correction for confounders did not affect the significance of these findings. Maternal HIV infection in women who have not received antiretroviral therapy is associated with preterm birth, low birthweight, small for gestational age, and stillbirth, especially in sub-Saharan Africa. Research is needed to assess how antiretroviral therapy regimens affect these perinatal outcomes. None.


Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGF(c) chimeric protein targeting tissue factor.
We evaluated the expression of tissue factor (TF) in ovarian cancer (EOC) and the potential of hI-con1, an antibody-like molecule targeting TF, as a novel form of therapy against chemotherapy-resistant ovarian disease. We studied the expression of TF in 88 EOC by immunohistochemistry (IHC) and real-time-PCR (qRT-PCR) and the levels of membrane-bound-complement-regulatory-proteins CD46, CD55 and CD59 in primary EOC cell lines by flow-cytometry. Sensitivity to hI-con1-dependent-cell-mediated-cytotoxicity (IDCC), complement-dependent-cell-cytotoxicity and inhibition of IDCC by γ-immunoglobulin were evaluated in 5-h (51)chromium-release-assays. Cytoplasmic and/or membrane TF expression was observed in 24 out of 25 (96%) of the EOC samples tested by IHC, but not in normal ovarian-tissue. EOC with clear cell histology significantly overexpress TF when compared to serous, endometrioid, or undifferentiated tumors by qRT-PCR. With a single exception, all primary EOC that overexpressed TF demonstrated high levels of CD46, CD55 and CD59 and regardless of their histology or resistance to chemotherapy, were highly sensitive to IDCC. The effect of complement and physiologic doses of γ-immunoglobulin on IDCC in ovarian cancer cell lines overexpressing TF was tumor specific and related to the overexpression of CD59 on tumor cells. Small-interfering-RNA-mediated knockdown of CD59 expression in ovarian tumors significantly increased hI-con1-mediated cytotoxic activity in vitro. Finally, low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (P < 0.01). hI-con1 molecule induces strong cytotoxicity against primary chemotherapy-resistant ovarian cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of ovarian tumors refractory to standard treatment modalities.


Effects of interval between diagnosis and time of survey upon preferred information format for prostate cancer patients.
Previous data indicate that receiving adequate information about their cancer can assist patients to cope with treatment and comply with treatment regimes. The aim of the present study was to determine whether time since diagnosis affected patients' evaluations of the information they had received at the time of their diagnosis. Two hundred and thirty-seven patients who had received a diagnosis and treatment for prostate cancer 4 months earlier completed a questionnaire about their ratings of, and preferences for, various types of information, their anxiety and depression levels and some background data. The most common and preferred form of information that the patients in the current study received was verbal information during an interview with their oncologist. Demographic factors and levels of anxiety and depression did not influence patient information preferences. Time since diagnosis was associated with elevated anxiety and depression, and consequent lower recall of having received information, but also with positive inflation of the value of the material that they did recall having received. Patients may not recall information given to them early after diagnosis and may make unreliable evaluations of its value to them due to psychological state.


Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress.
We have studied the potential effect against human malignant mesotheliomas (MM) of alpha-tocopheryl succinate (alpha-TOS), a redox-silent vitamin E analog with strong pro-apoptotic and anti-cancer activity. alpha-TOS at sub-apoptotic levels inhibited proliferation of MM cell lines, while being nontoxic to nonmalignant mesothelial cells. Because MM cells are typified by a highly metastatic phenotype, we investigated the effect of alpha-TOS on genes playing a major role in MM progression. Of these, alpha-TOS down regulated fibroblast growth factor (FGF)-1 and, in particular, FGF-2 on the transcriptional level in MM cells, and this was not observed in their nonmalignant counterparts. FGF-2 short interfering RNA suppressed proliferation of MM cells. Down-regulation of FGF-2 was likely because of inhibition of the egr-1 transcription activity that was decreased in MM cells via oxidative stress induced by alpha-TOS, as evidenced by EPR spectroscopy, whereas nonmalignant cells did not show this response. Treatment of MM cells with egr-1 short interfering RNA suppressed proliferation, which was overridden by exogenously added recombinant FGF-1 and, in particular, FGF-2. An analog of coenzyme Q targeted to mitochondria and superoxide dismutase overrode inhibition of MM cell proliferation by alpha-TOS as well as alpha-TOS-induced inhibition of egr-1-dependent transactivation. Finally, alpha-TOS significantly suppressed experimental MM in immunocompromised mice. Our data suggest that alpha-TOS suppresses MM cell proliferation by disrupting the FGF-FGF receptor autocrine signaling loop by generating oxidative stress and point to the agent as a selective drug against thus far fatal mesotheliomas.


Spatial aspects of reproduced sound in small rooms.
This paper reports on the influence of individual reflections on the auditory spatial aspects of reproduced sound. The sound field produced by a single loudspeaker positioned in a normal listening room has been simulated using an electroacoustical synthesis of the direct sound, 17 individual reflections and the reverberant field. The threshold of detection was measured using the method of adjustment for five reflections using three subjects for noise and speech. The thresholds have been measured for two simulated situations (1) a loudspeaker with a frequency independent directivity characteristics and frequency independent absorption coefficients of the room surfaces and (2) a loudspeaker with directivity similar to a standard two-way system and absorption coefficients according to measurements of real materials. The results have shown that subjects can reliably distinguish between timbre and spatial aspect of the sound field, that the spectral energy above 2 kHz of the individual reflection determines the importance of the reflection for the spatial aspects, and that only the first order floor reflection will contribute to the spatial aspects.


Oregon 'Pinot noir' grape anthocyanin enhancement by early leaf removal.
Complete cluster zone leaf removal of 'Pinot noir' was initiated at three separate pre-véraison growth stages (bloom, grain-pea size, and bunch closure) and maintained leaf free until harvest, for four growing seasons (2008-2011). Fruit anthocyanin composition was examined at harvest for the last two vintages (2010 and 2011) and compared to a control-no cluster zone leaf removal. Experiments were conducted at two commercially operating Oregon vineyards (site A=420 rootstock/'Pinot noir' 115 scion and site B=3309C rootstock/'Pinot noir' 777 scion). All clusters contained the five anthocyanins typically found in 'Pinot noir'. Leaf removal at bloom and maintained until harvest produced maximum anthocyanin accumulation in 'Pinot noir' grapes (site A=85.24 mg/100 g and site B=125.06 mg/100 g), compared to no leaf removal (control; site A=57.91 mg/100 g and site B=97.56 mg/100 g). Even leaf removal at bunch closure (last leaf removal initiation period) increased grape anthocyanin (site A=73.22 mg/100 g and site B=118.93 mg/100 g) compared to control, but total anthocyanins were lower than grapes from bloom leaf removal (first time period). Results differed slightly by vineyard site and rootstock/scion combination.


Electrophysiological evidence for the involvement of the approximate number system in preschoolers' processing of spoken number words.
Little is known about the neural underpinnings of number word comprehension in young children. Here we investigated the neural processing of these words during the crucial developmental window in which children learn their meanings and asked whether such processing relies on the Approximate Number System. ERPs were recorded as 3- to 5-year-old children heard the words one, two, three, or six while looking at pictures of 1, 2, 3, or 6 objects. The auditory number word was incongruent with the number of visual objects on half the trials and congruent on the other half. Children's number word comprehension predicted their ERP incongruency effects. Specifically, children with the least number word knowledge did not show any ERP incongruency effects, whereas those with intermediate and high number word knowledge showed an enhanced, negative polarity incongruency response (N(inc)) over centroparietal sites from 200 to 500 msec after the number word onset. This negativity was followed by an enhanced, positive polarity incongruency effect (P(inc)) that emerged bilaterally over parietal sites at about 700 msec. Moreover, children with the most number word knowledge showed ratio dependence in the P(inc) (larger for greater compared with smaller numerical mismatches), a hallmark of the Approximate Number System. Importantly, a similar modulation of the P(inc) from 700 to 800 msec was found in children with intermediate number word knowledge. These results provide the first neural correlates of spoken number word comprehension in preschoolers and are consistent with the view that children map number words onto approximate number representations before they fully master the verbal count list.


Combination therapy with an anti-IL-1β antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.
Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic β-cells. As a proinflammatory cytokine produced by β-cells or macrophages, interleukin-1β (IL-1β) represents a potential therapeutic target in diabetes. We reasoned IL-1β blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3. Thus, we investigated whether anti-IL-1β antibody alone or combined with GAD65 vaccine could reverse diabetes development in a virus-induced mouse model. Given alone, anti-IL-1β had no effect on diabetes, while GAD65 plasmid resulted in 33% disease reversal after a 5-week observation. However, CTs cured 53% of animals and prevented worsening of glycemic control in nonprotected individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased forkhead box p3(+) regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b(+/high) cells was less frequent upon CT, and its extent correlated with treatment success or failure. Altogether, our CTs provided prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1β monotherapy, these data hold promise for treatment of type 1 diabetic patients with IL-1β blockade combined with antigen-specific vaccines.


Concordance of human leukocyte antigen haplotype-sharing, CD4 decline and AIDS in hemophilic siblings. Multicenter Hemophilia Cohort and Hemophilia Growth and Development Studies.
To assess the association between human leukocyte antigen (HLA) haplotypes and the incidence rates of CD4 decline to < 20% and to AIDS. Retrospective cohort study of 95 HIV-1-infected hemophilic sibling pairs. HLA haplotype-sharing between siblings was assigned on the basis of serologic typing of HLA class I alleles and molecular typing of HLA class II alleles. Concordance of time to CD4 decline to < 20% and to AIDS within and between sibling pairs was assessed by analysis of variance models and calculations of intraclass correlation coefficients. The age-adjusted relative risks of these two endpoints for unique class II haplotypes were determined from proportional hazards models. Sibling pairs sharing one or two haplotypes were significantly concordant in CD4 decline and AIDS status within 5 years of seroconversion. No concordance was found in pairs sharing zero haplotypes. At 6-10 years after seroconversion, significant concordance of these two endpoints was also observed in the pairs sharing one haplotype. The concordant results were not explained by the use of zidovudine within the pairs. Among the individuals in this cohort, the relative hazards for CD4 decline to < 20% and for AIDS were significantly elevated for one class II haplotype (DQB1*0501, DQA1*0101, DRB1*0101). In addition, the risk for AIDS was significantly increased for two other class II haplotypes (DQB1*0603, DQA1*0103, DRB1*1300, DRB3*0202 and DQB1*0301, DQA1*0501, DRB1*1400, DRB3*0202) and significantly decreased for one haplotype (DQB1*0302, DQA1*0301, DRB1*0401, DRB4*0101). These data demonstrate that HIV-1 disease progression is associated with the genes in the major histocompatibility complex that regulate the host's immune response.


Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury.
Early diagnosis of acute kidney injury (AKI) and accurate prognostic stratification is a prerequisite for optimal medical management. To identify novel prognostic markers of AKI, urine was collected on the first day of AKI in critically ill patients. Twelve patients with early recovery and 12 matching patients with late/non-recovery were selected and their proteome analyzed by gel electrophoresis and mass spectrometry. We identified eight prognostic candidates including α-1 microglobulin, α-1 antitrypsin, apolipoprotein D, calreticulin, cathepsin D, CD59, insulin-like growth factor-binding protein 7 (IGFBP-7), and neutrophil gelatinase-associated lipocalin (NGAL). Subsequent quantification by ELISA showed that IGFBP-7 was the most potent predictor of renal recovery. IGFBP-7 and NGAL were then chosen for further analyses in an independent verification group of 28 patients with and 12 control patients without AKI. IGFBP-7 and NGAL discriminated between early and late/non-recovery patients and patients with and without AKI. Significant upregulation of the urinary markers predicted mortality (IGFBP-7: AUC 0.68; NGAL: AUC 0.81), recovery (IGFBP-7: AUC 0.74; NGAL: AUC 0.70), and severity of AKI (IGFBP-7: AUC 0.77; NGAL: AUC 0.69), and were associated with the duration of AKI. IGFBP-7 was a more accurate predictor of renal outcome than NGAL. Thus, IGFBP-7 is a novel prognostic urinary marker that warrants further investigation.


Changing drinking pattern does not influence health perception: a longitudinal study of the atherosclerosis risk in communities study.
To investigate if dynamic changes in the pattern of alcoholic beverages consumption are associated with modifications in health perception. This study investigated 12 332 middle aged men and women from the atherosclerosis risk in communities study who reported drinking status and perceived health triennially from 1987 to 1995. Crude and adjusted risks for change in health perception between visits two and three by change in drinking status between visits one and two were computed. In the multivariate analysis the sample was restricted to participants with stable drinking status between visit two and three and stable health perception between visits one and two, to assure that exposure and outcome were not temporary. Covariates included age, sex, race, income, smoking status, educational level, and obesity. Health for persons who stopped or started drinking, or continued to abstain was more likely to decline than was health for persons who continued to drink even after adjustment and restrictions (drinking cessation: OR = 1.6, 95% CI = 1.1, 2.3; started drinking; OR = 1.4, 95% CI = 0.9, 2.2; continued abstaining from alcohol: OR = 1.5, 95% CI = 1.3, 1.9). Among participants with poor perceived health, starting, stopping, or continuing to abstain from alcohol did not improve health in relation to participants that continued to drink. Increasing and decreasing drinking patterns and continuous abstinence were associated with declining health perception in comparison with continuous drinking, while starting or stopping drinking did not improve health perception of persons with poor perceived health. These findings suggest that change in health perception was not biologically related to alcohol consumption.


Building phylogenetic trees from molecular data with MEGA.
Phylogenetic analysis is sometimes regarded as being an intimidating, complex process that requires expertise and years of experience. In fact, it is a fairly straightforward process that can be learned quickly and applied effectively. This Protocol describes the several steps required to produce a phylogenetic tree from molecular data for novices. In the example illustrated here, the program MEGA is used to implement all those steps, thereby eliminating the need to learn several programs, and to deal with multiple file formats from one step to another (Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S. 2011. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 28:2731-2739). The first step, identification of a set of homologous sequences and downloading those sequences, is implemented by MEGA's own browser built on top of the Google Chrome toolkit. For the second step, alignment of those sequences, MEGA offers two different algorithms: ClustalW and MUSCLE. For the third step, construction of a phylogenetic tree from the aligned sequences, MEGA offers many different methods. Here we illustrate the maximum likelihood method, beginning with MEGA's Models feature, which permits selecting the most suitable substitution model. Finally, MEGA provides a powerful and flexible interface for the final step, actually drawing the tree for publication. Here a step-by-step protocol is presented in sufficient detail to allow a novice to start with a sequence of interest and to build a publication-quality tree illustrating the evolution of an appropriate set of homologs of that sequence. MEGA is available for use on PCs and Macs from www.megasoftware.net.


Association of Race/Ethnicity With Hospital Discharge Disposition After Elective Total Knee Arthroplasty.
Total knee arthroplasty (TKA) is one of the most common elective procedures performed in adults with end-stage arthritis. Racial disparities in TKA outcomes have been described in the literature. To assess the association of race/ethnicity with discharge disposition and hospital readmission after elective primary TKA and to assess the association of nonhome discharge disposition with hospital readmission risk. This retrospective cohort study used data from the Pennsylvania Health Care Cost Containment Council Database, a large regional database that included demographic data from all discharges of patients who underwent elective primary TKA in 170 nongovernmental acute care hospitals in Pennsylvania from April 1, 2012, to September 30, 2015. Data analyses were conducted from September 29, 2017, to November 29, 2017. Patient race/ethnicity and discharge disposition. Discharge disposition and 90-day hospital readmission. Among 107 768 patients, 7287 (6.8%) were African American, 68 372 (63.4%) were women, 46 420 (43.1%) were younger than 65 years, and 60 636 (56.3%) were insured by Medicare. In multivariable logistic regression, among patients younger than 65 years, African American patients were more likely than white patients to be discharged to inpatient rehabilitation facility (IRF) (adjusted relative risk ratio [aRRR], 2.49 [95% CI, 1.42-4.36]; P = .001) or a skilled nursing facility (SNF) (aRRR, 3.91 [95% CI, 2.17-7.06]; P < .001) and had higher odds of 90-day hospital readmission (adjusted odds ratio [aOR], 1.30 [95% CI, 1.02-1.67]; P = .04). Compared with white patients 65 years or older, African American patients 65 years or older were more likely to be discharged to SNF (aRRR, 3.30 [95% CI, 1.81-6.02]; P < .001). In both age groups, discharge to an IRF (age <65 years: aOR, 3.62 [95% CI, 2.33-5.64]; P < .001; age ≥65 years: aOR, 2.85 [95% CI, 2.25-3.61]; P < .001) or SNF (age <65 years: aOR, 1.91 [95% CI, 1.37-2.65]; P < .001; age ≥65 years: aOR, 1.55 [95% CI, 1.27-1.89]; P < .001) was associated with higher odds of 90-day readmission. This cohort study found that race/ethnicity was associated with higher odds of discharge to an IRF or SNF for postoperative care after primary TKA. Among patients younger than 65 years, African American patients were more likely than white patients to be readmitted to the hospital within 90 days. Discharge to an IRF or SNF for postoperative care and rehabilitation was also associated with a higher risk of readmission to an acute care hospital.


A decision support system for the prediction of mortality in patients with acute kidney injury admitted in intensive care unit.
Intensive care unit (ICU) is a very special unit of a hospital, where healthcare professionals provide treatment and, later, close follow-up to the patients. It is crucial to estimate mortality in ICU patients from many viewpoints. The purpose of this study is to classify the status of patients with acute kidney injury (AKI) in ICU as early mortality, late mortality, and survival by the application of Classification and Regression Trees (CART) algorithm to the patients' attributes such as blood urea nitrogen, creatinine, serum and urine neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase, lactate dehydrogenase (LDH), gamma-glutamyl transferase, laboratory electrolytes, blood gas, mean arterial pressure, central venous pressure and demographic details of patients. This study was conducted 50 patients with AKI who were followed up in the ICU. The study also aims to determine the significance of relationship between the attributes used in the prediction of mortality in CART and patients' status by employing the Kruskal-Wallis H test. The classification accuracy, sensitivity, and specificity of CART for the tested attributes for the prediction of early mortality, late mortality, and survival of patients were 90.00%, 83.33%, and 91.67%, respectively. The values of both urine NGAL and LDH on day 7 showed a considerable difference according to the patients' status after being examined by the Kruskal-Wallis H test.


Deterministic convergence in iterative phase shifting.
Previous implementations of the iterative phase shifting method, in which the phase of a test object is computed from measurements using a phase shifting interferometer with unknown positions of the reference, do not provide an accurate way of knowing when convergence has been attained. We present a new approach to this method that allows us to deterministically identify convergence. The method is tested with a home-built Fizeau interferometer that measures optical surfaces polished to lambda/100 using the Hydra tool. The intrinsic quality of the measurements is better than 0.5 nm. Other possible applications for this technique include fringe projection or any problem where phase shifting is involved.


Endotoxin conditioning induces VCP/p97-mediated and inducible nitric-oxide synthase-dependent Tyr284 nitration in protein phosphatase 2A.
Endotoxins activate Toll-like receptors and reprogram cells to be refractory to secondary exposure. Here we found that activation of different Toll-like receptors elicited a time- and dose-dependent increase in the levels of the protein phosphatase 2A catalytic subunit (PP2Ac) but not its partner A subunit. We purified the lipopolysaccharide-induced form of PP2A by chromatography plus immunoprecipitation and used mass spectrometry to identify VCP/p97 as a novel partner for PP2Ac. Endogenous VCP/p97 and PP2Ac were co-immunoprecipitated from primary murine macrophages and human lymphocytes. GST-VCP/p97 bound purified PP2A in pulldown assays, showing direct protein-protein interaction. Endotoxin conditioning of macrophages induced formation of 3-nitrotyrosine in the PP2Ac associated with VCP/p97, a response severely reduced in macrophages from iNOS knock-out mice. The reaction of purified PP2A with peroxynitrite dissociated the A subunit, and 3-nitro-Tyr(284) was identified in PP2Ac by mass spectrometry. Myc-PP2Ac (Y284F) expressed in cells was resistant to peroxynitrite-induced nitration and reduction of A subunit binding. Transient expression of either VCP/p97 or PP2Ac was sufficient to elevate levels of the dual specificity phosphatase DUSP1, reduce p38 MAPK activation, and suppress tumor necrosis factor-alpha release. We propose that VCP/p97-mediated Tyr nitration of PP2A increases the levels of phosphatases PP2A and DUSP1 to contribute to the refractory response of conditioned cells.


c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson's disease.
Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and α-synuclein (α-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates α-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established that α-syn is a bona fide substrate for c-Abl. In vitro studies demonstrate that c-Abl directly interacts with α-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39 α-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of α-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating α-syn clearance and contribute to the pathogenesis of PD.


Hemodynamic transition driven by stent porosity in sidewall aneurysms.
The healing process of intracranial aneurysms (IAs) treated with flow diverter stents (FDSs) depends on the IA flow modifications and on the epithelization process over the neck. In sidewall IA models with straight parent artery, two main hemodynamic regimes with different flow patterns and IA flow magnitude were broadly observed for unstented and high porosity stented IA on one side, and low porosity stented IA on the other side. The hemodynamic transition between these two regimes is potentially involved in thrombosis formation. In the present study, CFD simulations and multi-time lag (MTL) particle imaging velocimetry (PIV) measurements were combined to investigate the physical nature of this transition. Measurable velocity fields and non-measurable shear stress and pressure fields were assessed experimentally and numerically in the aneurysm volume in the presence of stents with various porosities. The two main regimes observed in both PIV and CFD showed typical flow features of shear and pressure driven regimes. In particular, the waveform of the averaged IA velocities was matching both the shear stress waveform at IA neck or the pressure gradient waveform in parent artery. Moreover, the transition between the two regimes was controlled by stent porosity: a decrease of stent porosity leads to an increase (decrease) of pressure differential (shear stress) through IA neck. Finally, a good PIV-CFD agreement was found except in transitional regimes and low motion eddies due to small mismatch of PIV-CFD running conditions.


All-fiber quasi-distributed polarimetric temperature sensor.
This paper presents an all-fiber design of a quasi-distributed polarimetric temperature sensor array that utilizes commercially available single polarization and high birefringence fibers. The modulation depth of temperature induced loss and the operational temperature range of individual sensors in the network are set by the rotational alignment of fibers before fusion splicing and through fine adjustment of the sensing fiber lengths. A practical sensor network was built with sensors that operated in the temperature range from 0 to 100 C. Individual sensors in the network generated temperature dependent loss that changed proportionally from 0.9 to 1.8 dB. With current standard telecommunication OTDRs, more than 20 prototype sensors could be interrogated.


Joint solution for PET image segmentation, denoising, and partial volume correction.
Segmentation, denoising, and partial volume correction (PVC) are three major processes in the quantification of uptake regions in post-reconstruction PET images. These problems are conventionally addressed by independent steps. In this study, we hypothesize that these three processes are dependent; therefore, jointly solving them can provide optimal support for quantification of the PET images. To achieve this, we utilize interactions among these processes when designing solutions for each challenge. We also demonstrate that segmentation can help in denoising and PVC by locally constraining the smoothness and correction criteria. For denoising, we adapt generalized Anscombe transformation to Gaussianize the multiplicative noise followed by a new adaptive smoothing algorithm called regional mean denoising. For PVC, we propose a volume consistency-based iterative voxel-based correction algorithm in which denoised and delineated PET images guide the correction process during each iteration precisely. For PET image segmentation, we use affinity propagation (AP)-based iterative clustering method that helps the integration of PVC and denoising algorithms into the delineation process. Qualitative and quantitative results, obtained from phantoms, clinical, and pre-clinical data, show that the proposed framework provides an improved and joint solution for segmentation, denoising, and partial volume correction.


Pazopanib-Induced Hepatotoxicity in an Experimental Rat Model.
Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity.


Affinity maturation of a Taq DNA polymerase specific affibody by helix shuffling.
The possibility of increasing the affinity of a Taq DNA polymerase specific binding protein (affibody) was investigated by an alpha-helix shuffling strategy. The primary affibody was from a naive combinatorial library of the three-helix bundle Z domain derived from staphylococcal protein A. A hierarchical library was constructed through selective re-randomization of six amino acid positions in one of the two alpha-helices of the domain, making up the Taq DNA polymerase binding surface. After selections using monovalent phage display technology, second generation variants were identified having affinities (K(D)) for Taq DNA polymerase in the range of 30-50 nM as determined by biosensor technology. Analysis of binding data indicated that the increases in affinity were predominantly due to decreased dissociation rate kinetics. Interestingly, the affinities observed for the second generation Taq DNA polymerase specific affibodies are of similar strength as the affinity between the original protein A domain and the Fc domain of human immunoglobulin G. Further, the possibilities of increasing the apparent affinity through multimerization of affibodies was demonstrated for a dimeric version of one of the second generation affibodies, constructed by head-to-tail gene fusion. As compared with its monomeric counterpart, the binding to sensor chip immobilized Taq DNA polymerase was characterized by a threefold higher apparent affinity, due to slower off-rate kinetics. The results show that the binding specificity of the protein A domain can be re-directed to an entirely different target, without loss of binding strength.


The human circadian clock's seasonal adjustment is disrupted by daylight saving time.
A quarter of the world's population is subjected to a 1 hr time change twice a year (daylight saving time, DST). This reflects a change in social clocks, not environmental ones (e.g., dawn). The impact of DST is poorly understood. Circadian clocks use daylight to synchronize (entrain) to the organism's environment. Entrainment is so exact that humans adjust to the east-west progression of dawn within a given time zone. In a large survey (n = 55,000), we show that the timing of sleep on free days follows the seasonal progression of dawn under standard time, but not under DST. In a second study, we analyzed the timing of sleep and activity for 8 weeks around each DST transition in 50 subjects who were chronotyped (analyzed for their individual phase of entrainment). Both parameters readily adjust to the release from DST in autumn but the timing of activity does not adjust to the DST imposition in spring, especially in late chronotypes. Our data indicate that the human circadian system does not adjust to DST and that its seasonal adaptation to the changing photoperiods is disrupted by the introduction of summer time. This disruption may extend to other aspects of seasonal biology in humans.