Processing of DNA base damage by DNA polymerases. Dihydrothymine and beta-ureidoisobutyric acid as models for instructive and noninstructive lesions.
The processing of unrepaired DNA lesions is a key to understanding and predicting the biological end points of particular DNA damages. In this study, we prepared single-stranded f1 phage (f1-K12) DNA containing dihydrothymine or beta-ureidoisobutyric acid as models for instructive or noninstructive base lesions and assessed the potential biological consequences of these lesions in vitro and in vivo. To determine the effect of the two lesions on in vitro DNA synthesis, the extent of DNA synthesis was measured by 3H-labeled nucleotide incorporation, and the newly synthesized DNA was analyzed by DNA sequencing gels. The results showed that dihydrothymine in the template was at most a weak block to in vitro DNA synthesis catalyzed by Escherichia coli DNA polymerase I Klenow fragment (Pol I) and T4 DNA polymerase. In contrast, beta-ureidoisobutyric acid constituted a very strong (probably absolute) replicative block in vitro. With Pol I, termination bands were observed either opposite or one base prior to (3' to) the putative beta-ureidoisobutyric acid depending on its position in the template. However, when DNA synthesis was catalyzed by Pol I lacking a 3'----5' exonuclease activity, termination bands were only observed opposite beta-ureidoisobutyric acid, with purine nucleotides being incorporated preferentially opposite the lesion. With T4 DNA polymerase that contains a very active 3'----5' exonuclease activity, DNA synthesis was arrested almost exclusively one base prior to (3' to) the putative beta-ureidoisobutyric acid site in the template. We also measured survival of transfecting DNA containing dihydrothymine or beta-ureidoisobutyric acid in an attempt to correlate the in vitro data with in vivo processing. In keeping with the results obtained in vitro, dihydrothymine present in transfecting f1-K12 DNA did not constitute an inactivating lesion. On the other hand, it took 0.9 beta-ureidoisobutyric acid residues per molecule to inactivate transfecting f1-K12 DNA, indicating that the lesion was an absolute replicative block in vivo. When host cells were ultraviolet-irradiated to induce the SOS response, a slight increase (about 2-fold) in survival of transfecting f1-K12 DNA containing beta-ureidoisobutyric acid was observed. The potential effects of the structures of base lesions on lesion-polymerase interactions are discussed.


Jejunal and multiple mesenteric calcifying fibrous pseudotumor induced jejunojejunal intussusception.
We describe here a patient with an unusual presentation--mesenteric calcifying fibrous pseudotumor in association with jejunojejunal intussusception. This 25-year-old woman came to our emergency department with severe abdominal distension and intermittent epigastric cramping pain. She was found to have rebound tenderness and an ill-defined mass palpable in her lower abdomen. Abdominal computed tomography revealed an inhomogeneous soft tissue mass with target sign and intussusception of small intestine was suspected. Emergency laparotomy showed jejunojejunal intussusception involving ~30cm of jejunum with multiple tumors on the mesentery surface extending over the whole bowel mesenteric and peritoneal surfaces. One of the mesenteric tumors formed the leading point of the intussusception. Segmental resection of jejunum with primary anastomosis was done. Some larger tumors were resected but most of the other tumors were left in place because they were small and numerous and total resection was impossible. Pathology confirmed that the lesions were benign mesenteric calcifying fibrous pseudotumors. In such patients, surgery might be curative. If a large segment of the bowel is affected by calcifying fibrous pseudotumor, smaller pseudotumors might be left in place because these tend to be asymptomatic. But they might become the leading points of recurrent intussusception.


The value of real-time myocardial contrast echocardiography for detecting coronary microcirculation function in coronary artery disease patients.
The aim of this study was to evaluate the value of real-time myocardial contrast echocardiography (RT-MCE) for detecting coronary microcirculation (CM) function in coronary artery disease (CAD) patients. Sixty-five consecutive patients were divided into CAD (n=52) and no-CAD (n=13) groups using coronary angiography (CAG). All patients underwent RT-MCE at rest and CAG within 1 week after RT-MCE. The ventricular segments in CAD patients were divided semi-quantitatively into ischemic and non-ischemic myocardial groups based on RT-MCE images. Myocardial blood volume (A), myocardial blood flow velocity (ß), and mean myocardial blood flow (Axβ) were obtained. The Gensini scores were calculated for CAD patients. The receiver operating characteristic (ROC) curve areas of A, ß, and Axß were calculated to assess CM function in CAD patients. A total of 798 and 204 segments were investigated in the CAD and non-CAD groups, respectively. In CAD patients, 332 ischemic and 466 non-ischemic segments were identified. The values of A, ß, and Axß were significantly different among non-CAD, CAD, ischemic, and nonischemic groups. ROC curve areas of A, ß, and Axß were 0.85, 0.79, and 0.83, respectively, and significant differences were observed in these values among three Gensini score groups of the CAD patients. Varying degrees of CM function deterioration was observed in CAD patients both in ischemic and non-ischemic areas, with the deterioration being more sever in the former.


Determinants of plasma vitamin E in healthy males.
Vitamin E or tocopherol, a known antioxidant, may play a role in the etiology of chronic diseases such as cancer and heart disease. This study examined both "internal" (lipids, lipoproteins, and apoproteins) and "external" (dietary components, physical activity, and body mass index) factors which may influence plasma alpha-tocopherol and gamma-tocopherol levels. Analyses were done using dietary questionnaires and plasma obtained from 65 nonsmoking male volunteers aged 30-59 years. Forty-six men did not take any supplements while 19 took supplements containing vitamin E. A positive correlation (r = 0.32; P < 0.01) between vitamin E intake and alpha-tocopherol status [(ratio of plasma alpha- or gamma-tocopherol/(total triglycerides + total cholesterol)] and a negative correlation (r = -0.33; P < 0.007) between intake and gamma-tocopherol status were observed. The main internal factors, or determinants, for plasma alpha-tocopherol for nonsupplement users were plasma triglycerides and apoproteins, apoA1 and apoB, but neither lipids nor apoproteins appeared to affect tocopherol levels in supplement users. External determinants of alpha-tocopherol status in nonsupplement users were vitamin E intake, total fat intake, and body mass index, while in supplement users only vitamin E intake was important. Both vitamin E intake and alcohol intake appeared to affect plasma gamma-tocopherol status in a negative manner.


Control of the terminal step of intracellular membrane fusion by protein phosphatase 1.
Intracellular membrane fusion is crucial for the biogenesis and maintenance of cellular compartments, for vesicular traffic between them, and for exo- and endocytosis. Parts of the molecular machinery underlying this process have been identified, but most of these components operate in mutual recognition of the membranes. Here it is shown that protein phosphatase 1 (PP1) is essential for bilayer mixing, the last step of membrane fusion. PP1 was also identified in a complex that contained calmodulin, the second known factor implicated in the regulation of bilayer mixing. The PP1-calmodulin complex was required at multiple sites of intracellular trafficking; hence, PP1 may be a general factor controlling membrane bilayer mixing.


IGFBP2 Activates the NF-κB Pathway to Drive Epithelial-Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma.
The molecular basis underlying the particularly aggressive nature of pancreatic ductal adenocarcinoma (PDAC) still remains unclear. Here we report evidence that the insulin-like growth factor-binding protein IGFBP2 acts as a potent oncogene to drive its extremely malignant character. We found that elevated IGFBP2 expression in primary tumors was associated with lymph node metastasis and shorter survival in patients with PDAC. Enforced expression of IGFBP2 promoted invasion and metastasis of PDAC cells in vitro and in vivo by inducing NF-κB-dependent epithelial-mesenchymal transition (EMT). Mechanistic investigations revealed that IGFBP2 induced the nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKβ pathway. Conversely, enforced expression of PTEN blunted this signaling pathway and restored an epithelial phenotype to PDAC cells in the presence of overexpressed IGFBP2. Overall, our results identify IGFBP2 as a pivotal regulator of an EMT axis in PDAC, the activation of which is sufficient to confer the characteristically aggressive clinical features of this disease. Cancer Res; 76(22); 6543-54. ©2016 AACR.


Comparison of PM2.5 carbonaceous pollutants between an urban site in Shanghai and a background site in a coastal East China Sea island in summer: concentration, composition and sources.
Nine paired samples of atmospheric particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM2.5) were collected concurrently from an urban site in Shanghai, China and a background site in Huaniao Island (HNI) in the coastal East China Sea (ECS) between July 21 and 29, 2011. The samples were analyzed for 16 United States Environmental Protection Agency (USEPA) priority polycyclic aromatic hydrocarbons (PAHs), n-alkanes (20 species, C14-C33), hopanes (10 species, C29-C32), and steranes (12 species, C27-C29). These two sites, approximately 66 km apart, are both on the pathway of land-based pollutants as they are transported to the ECS by seasonal winds. As expected, concentrations in Shanghai were higher (average: 8.4 and 67.8 ng m-3 for the 16 PAHs and n-alkanes, respectively) than those in HNI (average: 1.8 and 8.5 ng m-3, respectively). The dominant contributor to the 16 PAHs in Shanghai was 5-6-ring PAHs (60.0%), whereas 2-3-ring PAHs contributed the most (72.5%) in HNI. Plant waxes contributed 45.7% and 25.9% of the n-alkanes in Shanghai and HNI, respectively, implying a relatively greater contribution from petroleum residues to the n-alkanes in HNI. Principal component analysis (PCA) and the compositions of hopanes and steranes highlighted a prominent contribution from traffic emissions to carbonaceous PM2.5 aerosols. This study provides comprehensive details about the sources, formation, and transport of pollutants from eastern China to the coastal ECS.


Effects of motivational interviewing to promote weight loss in obese children.
To assess the effects of motivational interviewing for obese children and telephone consultation for parents to promote weight loss in obese children. Childhood obesity is a worldwide health problem that leads to serious metabolic and physiological consequences. An effective intervention to manage obesity is essential. Motivational interviewing is designed to resolve ambivalence, enhance intrinsic motivation and promote confidence in a person's ability to make behaviour changes. It has shown promise in the adult obesity literature as effecting positive health behaviour changes. Motivational interviewing has also been proposed as an effective method for improving the weight loss of obese children. A pre-post quasi-experimental design with repeated measures was used. The study was conducted in four primary schools over an 11-month period in 2010-2011. Obese children (n = 185) were screened from 791 school children studying the equivalent to UK grades 5 and 6 and were divided into three groups: motivational interviewing, motivational interviewing+ and a control group. The motivational interviewing group (n = 70) children were provided with motivational interviewing counselling; the motivational interviewing+ group (n = 66) children were provided with motivational interviewing counselling while telephone consultation was provided for their parents; and the control group did not receive any intervention (n = 49). Children in both the motivational interviewing and motivational interviewing+ groups showed significant improvement in their weight-related behaviour and obesity-related anthropometric measures from the baseline to the end of the 14-week intervention, while the control group had significant deterioration in their anthropometric measures. Motivational interviewing appears to be a promising intervention for promoting weight loss in obese children. Motivational interviewing counselling may be extended to obese children of different age groups. This study indicates that motivational interviewing is a useful method for improving behaviour changes in eating, physical activity and weight loss for obese children, suggesting the benefits of such intervention.


Genome-wide pharmacogenetics of antidepressant response in the GENDEP project.
The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association analysis of improvement of depression severity with two antidepressant drugs. High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial. Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11. While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.


Detecting wrong notes in advance: neuronal correlates of error monitoring in pianists.
Music performance is an extremely rapid process with low incidence of errors even at the fast rates of production required. This is possible only due to the fast functioning of the self-monitoring system. Surprisingly, no specific data about error monitoring have been published in the music domain. Consequently, the present study investigated the electrophysiological correlates of executive control mechanisms, in particular error detection, during piano performance. Our target was to extend the previous research efforts on understanding of the human action-monitoring system by selecting a highly skilled multimodal task. Pianists had to retrieve memorized music pieces at a fast tempo in the presence or absence of auditory feedback. Our main interest was to study the interplay between auditory and sensorimotor information in the processes triggered by an erroneous action, considering only wrong pitches as errors. We found that around 70 ms prior to errors a negative component is elicited in the event-related potentials and is generated by the anterior cingulate cortex. Interestingly, this component was independent of the auditory feedback. However, the auditory information did modulate the processing of the errors after their execution, as reflected in a larger error positivity (Pe). Our data are interpreted within the context of feedforward models and the auditory-motor coupling.


Association between dietary behavior and mortality among American adults with mobility limitations.
Limited research has evaluated the relationship between dietary behavior and mortality among those with mobility limitations. To examine the association between dietary behavior and mortality in a national sample of American adults with mobility limitations. Data from the 2003-2006 National Health and Nutrition Examination Survey were utilized. Participants were followed through 2011. Based on self-report, analyzed participants included those with mobility limitations (N = 1369). Dietary behavior was assessed from the alternate healthy eating index (AHEI). For the sample, 108,010 person-months occurred with an all-cause mortality rate of 2.07 per 1000 person-months. Dietary behavior was associated with reduced all-cause mortality risk when expressed both as a continuous variable and binary variable (i.e., meeting dietary guidelines). With regard to the latter, and after adjustments, those meeting dietary guidelines (vs. not) had a 40% reduced hazard of all-cause death (HR = 0.60; 95% CI: 0.38-0.97; P = 0.03). Among adults with mobility limitations, and thus, who unable to engage in sufficient physical activity, dietary behavior may have survival benefits.


Bioluminescence tomography with Gaussian prior.
Parameterizing the bioluminescent source globally in Gaussians provides several advantages over voxel representation in bioluminescence tomography. It is mathematically unique to recover Gaussians [Med. Phys. 31(8), 2289 (2004)] and practically sufficient to approximate various shapes by Gaussians in diffusive medium. The computational burden is significantly reduced since much fewer unknowns are required. Besides, there are physiological evidences that the source can be modeled by Gaussians. The simulations show that the proposed model and algorithm significantly improves accuracy and stability in the presence of Gaussian or non- Gaussian sources, noisy data or the optical background mismatch. It is also validated through in vivo experimental data.


Sub-wavelength grating components for integrated optics applications on SOI chips.
In this paper we demonstrate silicon on insulator (SOI) sub-wavelength grating (SWG) optical components for integrated optics and sensing. Light propagation in SWG devices is studied and realized with no cladding on top of the waveguide. In particular, we focused on SWG bends, tapers and directional couplers, all realized with compatible geometries in order to be used as building blocks for more complex integrated optics devices (interferometers, switches, resonators, etc.). Fabricated SWG tapers for TE and TM polarizations are described; they allow for connecting SWG devices to regular strip waveguides with loss lower than 1 dB per taper. Our SWG directional coupler presents a very compact design and a negligible wavelength dependence of its crossover length (and as a consequence of its coupling coefficient, κ), over a 40 nm bandwidth. This wavelength flatten response represents a bandwidth enhancement with respect to standard directional couplers (made using strip or rib waveguides), in particular for the TE mode. SWG bends are demonstrated, their loss dependence on radius is analyzed, and fabricated bends have a loss in the range 0.8-1.6 dB per 90 degrees bend. Simulated and measured results show promise for large-scale fabrication of complex optical devices and high sensitivity sensors based on SWG waveguides with engineered optical properties, tailored to specific applications.


Allodynography: Reliability of a New Procedure for Objective Clinical Examination of Static Mechanical Allodynia.
There is a need for reliable and valid clinical assessment tools for quantifying allodynia in neuropathic pain. Allodynography has been proposed as a useful standardized procedure for clinical assessment of mechanical allodynia. This study (www.clinicaltrials.gov NCT02070367) undertook preliminary investigation of the measurement properties of allodynography, a new standardized clinical examination procedure for mapping the area of cutaneous allodynia. Persons with pain in one upper extremity after complex regional pain syndrome, a peripheral nerve injury, or who had recently experienced a hand fracture were recruited for assessment of static mechanical allodynia (based on perception of a 15g force stimulus delivered by Semmes-Weinstein monofilament #5.18 as painful) by two raters at baseline; the assessment was repeated one week later. Single-measures estimates suggested inter-rater reliability for allodynography was excellent at an intraclass correlation coefficient (ICC) of 0.97 (N = 12); test-retest reliability was also excellent at ICC = 0.89 (N = 10) for allodynography (P < 0.001 for both). Confidence intervals' lower bounds confirm inter-rater reliability as excellent (0.90) but were less definitive for test-retest (0.59). This preliminary study supports the inter-rater and test-retest reliability of allodynography. Studies on larger samples in multiple contexts and reporting other measurement properties are warranted.


In vivo axonal transport deficits in a mouse model of fronto-temporal dementia.
Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4-5 months of age. rTg4510 transgenic mice were used in these studies. Mice were given 2 μL of MnCl2 in each nostril 1 h prior to Magnetic Resonance Imaging (MRI). Following MnCl2 nasal lavage, mice were imaged using Manganese enhanced Magnetic Resonance Imaging (MEMRI) Protocol with TE = 8.5 ms, TR = 504 ms, FOV = 3.0 cm, matrix size = 128 × 128 × 128, number of cycles = 15 with each cycle taking approximately 2 min, 9 s, and 24 ms using Paravision software (BrukerBioSpin, Billerica, MA). During imaging, body temperature was maintained at 37.0 °C using an animal heating system (SA Instruments, Stony Brook, NY). Resulting images were analyzed using Paravision software. Regions of interest (ROI) within the olfactory neuronal layer (ONL) and the water phantom consisting of one pixel (ONL) and 9 pixels (water) were selected and copied across each of the 15 cycles. Signal intensities (SI) of ONL and water phantom ROIs were measured. SI values obtained for ONL were then normalized the water phantom SI values. The correlation between normalized signal intensity in the ONL and time were assessed using Prism (GraphPad Software, San Diego, CA). Using the MEMRI technique on 1.5, 3, 5, and 10-month old rTg4510 mice and littermate controls, we found significant axonal transport deficits present in the rTg4510 mice beginning at 3 months of age in an age-dependent manner. Using linear regression analysis, we measured rates of axonal transport at 1.5, 3, 5, and 10 months of age in rTg4510 and WT mice. Axonal transport rates were observed in rTg4510 mice at 48% of WT levels at 3 months, 40% of WT levels at 5 months, and 30% of WT levels at 10 months of age. In order to determine the point at which tau appears in the cortex, we probed for phosphorylated tau levels, and found that pSer262 is present at 3 months of age, not earlier at 1.5 months of age, but observed no pathological tau species until 6 months of age, months after the onset of the transport deficits. In addition, we saw localization of tau in the ONL at 6 months of age. In our study, we identified the presence of age-dependent axonal transport deficits beginning at 3 months of age in rTg4510 mice. We correlated these deficits at 3 months to the presence of hyperphosphorylated tau in the brain and the presence within the olfactory epithelium. We observed tau pathology not only in the soma of these neurons but also within the axons and processes of these neurons. Our characterization of axonal transport in this tauopathy model provides a functional time point that can be used for future therapeutic interventions.


Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.
We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment.


Intra-operative cell salvage in South Africa: feasible, beneficial and economical.
Healthcare services in KwaZulu-Natal (KZN) frequently experience shortages of blood products. Alternatives to traditional blood sources are needed. One possibility is cell salvage and autologous blood transfusion. Few data exist relating to their use in the South African context. To ascertain whether cell salvage (CS) is beneficial, feasible and economical in our setting, with the anticipation that results would excite further studies and potentially change current practice and improve existing protocols. Methods. This study reviewed current intraoperative Cell Saver use at Grey's and Edendale hospitals in Pietermaritzburg, KZN. Current practices were observed and compared with the costs of the equivalent amount of red cell concentrate (RCC) purchased from the South African National Blood Service (SANBS). All cases of Cell Saver usage over a 1-year period from July 2012 to June 2013 were analysed. The total volume of blood transfused from CS was 55 735 ml, approximately equivalent to 186 RCC units. The comparative cost of equivalent units of RCC from SANBS was R258 445. The total cost of Cell Saver disposables during the study period was R206 047, or R263 478 when Cell Saver machine depreciation costs were included. More than one CS blood unit was available for transfusion in 66% of cases. No additional staff were required to operate the Cell Saver, which was successfully used by medical officers. This study showed that intraoperative CS use is feasible, has potential patient benefit by reducing blood bank blood transfusion, and is financially comparable to purchasing the equivalent number of SANBS RCC.


Electrophysiological correlates of visual consciousness and selective attention.
It is not clear whether attention is necessary or not for consciousness. We studied the relationship between attention and consciousness by tracking their electrophysiological correlates. The participants attended to visual targets, ignored nontargets in the prespecified visual field and ignored all stimuli in the opposite field. Visual consciousness was varied by masking. Our results showed that the earliest electrophysiological correlate of consciousness emerged independent of the manipulations of spatial and nonspatial attention. Conversely, the electrophysiological correlate of attention, selection negativity, was elicited regardless of the presence or absence of consciousness. Only the correlates of later, higher-level conscious processes strongly depended on attention. Thus, the electrophysiological brain responses reflecting visual consciousness and attention are initially independent of each other.


Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum.
The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.


Socioeconomic restraints and brain tumor surgery in low-income countries.
Healthcare spending has become a grave concern to national budgets worldwide, and to a greater extent in low-income countries. Brain tumors are a serious disease that affects a significant percentage of the population, and thus proper allocation of healthcare provisions for these patients to achieve acceptable outcomes is a must. The authors reviewed patients undergoing craniotomy for tumor resection at their institution for the preceding 3 months. All the methods used for preoperative planning, intraoperative management, and postoperative care of these patients were documented. Compromises to limit spending were made at each stage to limit expenditure, including low-resolution MRI, sparse use of intraoperative monitoring and image guidance, and lack of dedicated postoperative neurocritical ICU. This study included a cohort of 193 patients. The average cost from diagnosis to discharge was $1795 per patient (costs are expressed in USD). On average, there was a mortality rate of 10.5% and a neurological morbidity rate of 14%, of whom only 82.2% improved on discharge or at follow-up. The average length of stay at the hospital for these patients was 9.09 days, with a surgical site infection rate of only 3.5%. The authors believe that despite the great number of financial limitations facing neurosurgical practice in low-income countries, surgery can still be performed with reasonable outcomes.


Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?
Artemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the 'premier' combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.


Development of models to predict anabolic response to testosterone administration in healthy young men.
Considerable heterogeneity exists in the anabolic response to androgen administration; however, the factors that contribute to variation in an individual's anabolic response to androgens remain unknown. We investigated whether testosterone dose and/or any combination of baseline variables, including concentrations of hormones, age, body composition, muscle function, and morphometry or polymorphisms in androgen receptor could explain the variability in anabolic response to testosterone. Fifty-four young men were treated with a long-acting gonadotropin-releasing hormone (GnRH) agonist and one of five doses (25, 50, 125, 300, or 600 mg/wk) of testosterone enanthate (TE) for 20 wk. Anabolic response was defined as a change in whole body fat-free mass (FFM) by dual-energy X-ray absorptiometry (DEXA), appendicular FFM (by DEXA), and thigh muscle volume (by magnetic resonance imaging) during TE treatment. We used univariate and multivariate analysis to identify the subset of baseline measures that best explained the variability in anabolic response to testosterone supplementation. The three-variable model of TE dose, age, and baseline prostate-specific antigen (PSA) level explained 67% of the variance in change in whole body FFM. Change in appendicular FFM was best explained (64% of the variance) by the linear combination of TE dose, baseline PSA, and leg press strength, whereas TE dose, log of the ratio of luteinizing hormone to testosterone concentration, and age explained 66% of the variation in change in thigh muscle volume. The models were further validated by using Ridge analysis and cross-validation in data subsets. Only the model using testosterone dose, age, and PSA was a consistent predictor of change in FFM in subset analyses. The length of CAG tract was only a weak predictor of change in thigh muscle volume and lean body mass. Hence, the anabolic response of healthy, young men to exogenous testosterone administration can largely be predicted by the testosterone dose.


Supplementation-induced change in muscle carnosine is paralleled by changes in muscle metabolism, protein glycation and reactive carbonyl species sequestering.
Carnosine is a performance-enhancing food supplement with a potential to modulate muscle energy metabolism and toxic metabolites disposal. In this study we explored interrelations between carnosine supplementation (2 g/day, 12 weeks) induced effects on carnosine muscle loading and parallel changes in (i) muscle energy metabolism, (ii) serum albumin glycation and (iii) reactive carbonyl species sequestering in twelve (M/F=10/2) sedentary, overweight-to-obese (BMI: 30.0+/-2.7 kg/m2) adults (40.1+/-6.2 years). Muscle carnosine concentration (Proton Magnetic Resonance Spectroscopy; 1H-MRS), dynamics of muscle energy metabolism (Phosphorus Magnetic Resonance Spectroscopy; 31P-MRS), body composition (Magnetic Resonance Imaging; MRI), resting energy expenditure (indirect calorimetry), glucose tolerance (oGTT), habitual physical activity (accelerometers), serum carnosine and carnosinase-1 content/activity (ELISA), albumin glycation, urinary carnosine and carnosine-propanal concentration (mass spectrometry) were measured. Supplementation-induced increase in muscle carnosine was paralleled by improved dynamics of muscle post-exercise phosphocreatine recovery, decreased serum albumin glycation and enhanced urinary carnosine-propanal excretion (all p<0.05). Magnitude of supplementation-induced muscle carnosine accumulation was higher in individuals with lower baseline muscle carnosine, who had lower BMI, higher physical activity level, lower resting intramuscular pH, but similar muscle mass and dietary protein preference. Level of supplementation-induced increase in muscle carnosine correlated with reduction of protein glycation, increase in reactive carbonyl species sequestering, and acceleration of muscle post-exercise phosphocreatine recovery.


Communication with older, seriously ill patients.
This article describes effective communication strategies in caring for older, seriously ill patients and their surrogates/caregivers. Specific skills in three core functions are highlighted: (i) empathic communication (ii) information provision and (iii) enabling decision making. Empathy skills include using 'NURSE' statements and assuring a continuous relationship. Tailored information and empathic communication can be used to facilitate information processing and overcome age-related communication barriers. Eliciting patients' goals of care is critical in decision making. Surrogates need assistance when making decisions for patients and often themselves have support and information needs. Suggestions are made to ensure patients' and caregivers' needs are met.


Recent developments in myelodysplastic syndromes.
Once thought to be rare disorders, the myelodysplastic syndromes (MDS) are now recognized as among the most common hematological neoplasms, probably affecting >30 000 patients per year in the United States. US regulatory approval of azacitidine, decitabine, and lenalidomide between 2004 and 2006 seemed to herald a new era in the development of disease-modifying therapies for MDS, but there have been no further drug approvals for MDS indications in the United States in the last 8 years. The available drugs are not curative, and few of the compounds that are currently in development are likely to be approved in the near future. As a result, MDS diagnoses continue to place a heavy burden on both patients and health care systems. Incomplete understanding of disease pathology, the inherent biological complexity of MDS, and the presence of comorbid conditions and poor performance status in the typical older patient with MDS have been major impediments to development of effective novel therapies. Here we discuss new insights from genomic discoveries that are illuminating MDS pathogenesis, increasing diagnostic accuracy, and refining prognostic assessment, and which will one day contribute to more effective treatments and improved patient outcomes.


Intensity invariant nonlinear correlation filtering in spatially disjoint noise.
We analyze the performance of a nonlinear correlation called the Locally Adaptive Contrast Invariant Filter in the presence of spatially disjoint noise under the peak-to-sidelobe ratio (PSR) metric. We show that the PSR using the nonlinear correlation improves as the disjoint noise intensity increases, whereas, for common linear filtering, it goes to zero. Experimental results as well as comparisons with a classical matched filter are given.


Recreational drug use, polydrug use, and sexual behaviour in HIV-diagnosed men who have sex with men in the UK: results from the cross-sectional ASTRA study.
Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK. We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours. Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4-methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n = 68). Drug use was independently associated with younger age (p < 0·0001), not being religious (p = 0·001), having an HIV-positive stable partner (p = 0·0008), HIV-serostatus disclosure (p = 0·009), smoking (p < 0·0001), evidence of harmful alcohol drinking (p = 0·0001), and ART non-adherence (p < 0·0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p ≤ 0·005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs. Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections. National Institute for Health Research.


Presurgical localization of the artery of Adamkiewicz with time-resolved 3.0-T MR angiography.
To evaluate the use of time-resolved magnetic resonance (MR) angiography in the presurgical localization of the artery of Adamkiewicz prior to reimplantation of the feeding intercostal artery, lumbar artery, or both during aortic aneurysm repair. This institutional review board-approved retrospective study included 68 patients (36 men, 32 women) who underwent time-resolved spinal MR angiography (0.2 mmol per kilogram of body weight gadobenate dimeglumine administered at a rate of 2.0 mL per second) performed with a 3.0-T imager with a dedicated eight-element spine coil. Images were reviewed at a three-dimensional workstation by two experienced radiologists in consensus. The artery of Adamkiewicz was identified, and the location of the feeding intercostal and/or lumbar artery was ascertained by using a five-point confidence index (scores ranged from 1 to 5). The phases in which the artery of Adamkiewicz, aorta, and great anterior radiculomedullary vein (GARV) demonstrated peak enhancement were also recorded. The artery of Adamkiewicz and the location of the feeding intercostal and/or lumbar artery were identified with high confidence in 60 (88%) of the 68 patients. Origins of the artery of Adamkiewicz were on the left side of the body in 65% of patients and on the right side in 35%. The level of origin ranged from the T6 neuroforamina to the L1 neuroforamina. The arrival of contrast material was highly variable in this patient population, which had substantial aortic disease. The highest signal intensity in the aorta, artery of Adamkiewicz, and GARV occurred a mean of 55 seconds (range, 27-99 seconds; 95% confidence interval [CI] 51, 58), 72 seconds (range, 38-110 seconds; 95% CI: 68, 76), and 95 seconds (range, 46-156 seconds; 95% CI: 89, 101) after contrast material administration, respectively. The artery of Adamkiewicz and the anterior spinal artery can be identified and differentiated from the GARV even in patients with substantially altered hemodynamics by using time-resolved 3.0-T MR angiography.


Frequency of Direct Oral Anticoagulants Usage in Acute Pulmonary Thromboembolism Treatment in Turkey (TUPEDO).
Direct oral anticoagulants (DOACs) have been used in acute pulmonary thromboembolism as an alternative to warfarin due to drug interactions, narrow therapeutic range, and necessary close International Normalized Ratio (INR) monitoring. Phase 3 study results have reported that these drugs are at least as effective as warfarin and beneficial in terms of bleeding; however, studies that present up-to-date life data are necessary. To evaluate the frequency of using DOACs, which are prescribed with a limited number of indications in our country, and real-life data results. Cross-sectional study. This cross-sectional survey collected the clinical data (history, current treatment, treatment duration, etc.) of patients with pulmonary thromboembolism and who applied to the physician for follow-up between October 15, 2019, and March 15, 2020. The researchers kept the patient records sequentially. Data from 836 patients with acute pulmonary thromboembolism from 25 centers were collected, and DOAC was used in 320 (38.5%) of them. The most preferred DOAC was rivaroxaban (n = 294, 91.9%). DOAC was mostly preferred because it could not provide an effective INR level with warfarin (n=133, 41.6%). Bleeding was observed in 13 (4%) patients. The use of direct oral anticoagulants is becoming almost as widespread as conventional therapy. Real-life data results are important for their contribution to clinical practice.


Reference values for cardiopulmonary exercise testing in healthy subjects - an updated systematic review.
Introduction: Reference values for cardiopulmonary exercise testing (CPET) parameters provide the comparative basis for answering important questions concerning the normalcy of exercise responses in patients, and significantly impacts the clinical decision-making process. Areas covered: The aim of this study was to provide an updated systematic review of the literature on reference values for CPET parameters in healthy subjects across the life span. A systematic search in MEDLINE, Embase, and PEDro databases were performed for articles describing reference values for CPET published between March 2014 and February 2019. Expert opinion: Compared to the review published in 2014, more data have been published in the last five years compared to the 35 years before. However, there is still a lot of progress to be made. Quality can be further improved by performing a power analysis, a good quality assurance of equipment and methodologies, and by validating the developed reference equation in an independent (sub)sample. Methodological quality of future studies can be further improved by measuring and reporting the level of physical activity, by reporting values for different racial groups within a cohort as well as by the exclusion of smokers in the sample studied. Normal reference ranges should be well defined in consensus statements.


First experiences in treatment of low-grade glioma grade I and II with proton therapy.
To retrospectively assess feasibility and toxicity of proton therapy in patients with low-grade glioma (WHO °I/II). Proton beam therapy only administered in 19 patients (median age 29 years; 9 female, 10 male) for low-grade glioma between 2010 and 2011 was reviewed. In 6 cases proton therapy was performed due to tumor progression after biopsy, in 8 cases each due to tumor progression after (partial-) resection, and in 5 cases due to tumor progression after chemotherapy. Median total dose applied was 54 GyE (range, 48,6-54 GyE) in single fractions of median 1.8 GyE. Median clinical target volume was 99 cc (range, 6-463 cc) and treated using median 2 beams (range, 1-2). Proton therapy was finished as planned in all cases. At end of proton therapy, 13 patients showed focal alopecia, 6 patients reported mild fatigue, one patient with temporal tumor localization concentration deficits and speech errors and one more patient deficits in short-term memory. Four patients did not report any side effects. During follow-up, one patient presented with pseudo-progression showing worsening of general condition and brain edema 1-2 months after last irradiation and restitution after 6 months. In the present MR imaging (median follow-up 5 months; range 0-22 months) 12 patients had stable disease, 2 (1) patients partial (complete) remission, one more patient pseudo-progression (differential diagnosis: tumor progression) 4 weeks after irradiation without having had further follow-up imaging so far, and one patient tumor progression approximately 9 months after irradiation. Regarding early side effects, mild alopecia was the predominant finding. The rate of alopecia seems to be due to large treatment volumes as well as the anatomical locations of the target volumes and might be avoided by using multiple beams and the gantry in the future. Further evaluations including neuropsychological testing are in preparation.


The traditional chinese medicine prescription pattern of endometriosis patients in taiwan: a population-based study.
Background. Traditional Chinese medicine (TCM), when given for symptom relief, has gained widespread popularity among women with endometriosis. The aim of this study was to analyze the utilization of TCM among women with endometriosis in Taiwan. Methods. The usage, frequency of service, and the Chinese herbal products prescribed for endometriosis, among endometriosis patients, were evaluated using a randomly sampled cohort of 1,000,000 beneficiaries recruited from the National Health Insurance Research Database. Results. Overall, 90.8% (N = 12, 788) of reproductive age women with endometriosis utilized TCM and 25.2% of them sought TCM with the intention of treating their endometriosis-related symptoms. Apart from the usage of either analgesics or more than one type of medical treatment, the odds of using TCM and Western medicine were similar in all types of conventional endometriosis treatment. However, endometriosis patients suffering from symptoms associated with endometriosis were more likely to seek TCM treatment than those with no symptoms. There were 21,056 TCM visits due to endometriosis and its related symptoms, of which more than 98% were treated with Chinese herbal products (CHPs). Conclusion. Gui-Zhi-Fu-Ling-Wan (Cinnamon Twig and Poria Pill) containing sedative and anti-inflammatory agents is the most commonly prescribed Chinese herbal formula mainly for the treatment of endometriosis-related symptomatic discomfort and the effects of these TCMs should be taken into account by healthcare providers.


Dermal uptake and percutaneous penetration of organophosphate esters in a human skin ex vivo model.
Organophosphate esters (OPEs) are used as flame retardants, plasticizers, and as hydraulic fluids. They are present in indoor environments in high concentrations compared with other flame retardants, and human exposure is ubiquitous. In this study we provide data for estimating dermal uptake for eight OPEs and ranking in OPEs risk assessment. Dermal uptake and percutaneous penetration of the OPEs were studied in a Franz diffusion cell system using human skin dosed with a mixture of OPEs in an ethanol:toluene (4:1) solution. Large variation in penetration profiles was observed between the OPEs. The chlorinated OPEs tris(2-chloroisopropyl) phosphate (TCIPP), and in particular tris(2-chloroethyl) phosphate (TCEP), penetrated the skin quite rapidly while tris(1,3-dichlor-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) tended to build up in the skin tissue and only smaller amounts permeated through the skin. For tris(isobutyl) phosphate (TIBP), tris(n-butyl) phosphate (TNBP), and tris(methylphenyl) phosphate (TMPP) the mass balance was not stable over time indicating possible degradation during the experimental period of 72 h. The rates at which OPEs permeated through the skin decreased in the order TCEP > TCIPP ≥ TBOEP > TIBP ≥ TNBP > TDCIPP > TPHP > TMPP. Generally, the permeation coefficient, kp, decreased with increasing log Kow, whereas lag time and skin deposition increased with log Kow. The present data indicate that dermal uptake is a non-negligible human exposure pathway for the majority of the studied OPEs.


Inheritance and flexibility of cell polarity: a clue for understanding human brain development and evolution.
Cell polarity is fundamentally important for understanding brain development. Here, we hypothesize that the inheritance and flexibility of cell polarity during neocortex development could be implicated in neocortical evolutionary expansion. Molecular and morphological features of cell polarity may be inherited from one type of progenitor cell to the other and finally transmitted to neurons. Furthermore, key cell types, such as basal progenitors and neurons, exhibit a highly flexible polarity. We suggest that both inheritance and flexibility of cell polarity are implicated in the amplification of basal progenitors and tangential dispersion of neurons, which are key features of the evolutionary expansion of the neocortex.


Effects of anhedonia on days to relapse among smokers with a history of depression: a brief report.
Despite the strong co-occurrence between lifetime prevalence of depression and smoking, a history of major depressive disorder (MDD history) does not reliably predict smoking cessation outcomes. However, depression is a heterogeneous syndrome comprising several dimensions (e.g., anhedonia, vegetative symptoms, negative affect), and each symptom expression may differentially influence cessation failure. Measuring proximal depressive dimensions may provide a more reliable way of identifying MDD history smokers most at risk for smoking relapse. Anhedonia, in particular, is a core feature of depression that may increase risk for smoking relapse among MDD history smokers. The primary goal of the present study was to investigate the relation between anhedonia and relapse latency among MDD history smokers following a brief smoking cessation workshop. Participants (N = 45, 48.9% female), who were euthymic regular smokers with a history of MDD, were randomized to 1 of 3 treatment groups that all involved participation in a daylong group workshop. Workshops were followed by 48 hr of bioverified abstinence and weekly follow-up visits for 1 month. Cox proportional hazard modeling was used to evaluate the effect of anhedonia on relapse latency 30 days following quitting smoking. Results showed that higher levels of anhedonia predicted reduced relapse latencies, both with and without prequit depressive symptom severity included in the model. Results suggest that anhedonia may constitute a proximal risk factor identifying depressive history smokers more likely to relapse to smoking.


Solid acid-catalyzed cellulose hydrolysis monitored by in situ ATR-IR spectroscopy.
The solid acid-catalyzed hydrolysis of cellulose was studied under elevated temperatures and autogenous pressures using in situ ATR-IR spectroscopy. Standards of cellulose and pure reaction products, which include glucose, fructose, hydroxymethylfurfural (HMF), levulinic acid (LA), formic acid, and other compounds, were measured in water under ambient and elevated temperatures. A combination of spectroscopic and HPLC analysis revealed that the cellulose hydrolysis proceeds first through the disruption of the glycosidic linkages of cellulose to form smaller cellulose molecules, which are readily observed by their distinctive C-O vibrational stretches. The continued disruption of the linkages in these oligomers eventually results in the formation and accumulation of monomeric glucose. The solid-acid catalyst accelerated the isomerization of glucose to fructose, which then rapidly reacted under hydrothermal conditions to form degradation products, which included HMF, LA, formic acid, and acetic acid. The formation of these species could be suppressed by decreasing the residence time of glucose in the reactor, reaction temperature, and contact with the metal reactor. The hydrolysis of regenerated cellulose proceeded faster and under milder conditions than microcrystalline cellulose, which resulted in increased glucose yield and selectivity.


Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase.
Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (ELANE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells in vitro IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33+ MDSCs.Implications: This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138-52. ©2017 AACR.


Phenotype changes in tumor vessels associated with the progression of hepatocellular carcinoma.
Human hepatocellular carcinoma (HCC) is characterized by hypervascularity and tumor staining in angiograms, and tumor angiogenesis is considered indispensable for tumor growth. HCC is also characterized by an obvious multistage process of tumor progression. To find out in which stage of human hepatocarcinogenesis angiogenesis occurs, we have carried out a pathological study, of the phenotypic changes in tumor vessels taken from surgically resected liver tumors showing each step of the progression. Eleven early advanced HCCs (advanced HCC component in early HCC nodule, eAd HCC), seven early HCCs (eHCC) and six adenomatous hyperplasias (AH), the non-tumorous liver surrounding each and five normal livers were studied by lectin histochemistry and immunohistochemistry. The sinusoidal endothelial cells from the non-tumorous liver were shown to be negative for UEA-I (Ulex europaeus I), but the endothelial cells from the sinusoidal tumor vessels in advanced HCC components were strongly positive. In AH and eHCC, half the tumors were negative and the other half focally positive. In the early HCC lesion of eAdHCC, the rate of positivity for UEA-I was a little higher than in AH and eHCC but lower than in advanced HCC lesions in eAdHCC. Immunohistochemically, laminin was not detected in the sinusoids in the non-tumorous liver or in the sinusoidal tumor vessels in AH and eHCC. In eAdHCC, however, two early HCC lesions and four advanced HCC lesions were positive. An immunohistochemical examination for muscle actin revealed an increase in arterial tumor vessels in six advanced HCC lesions and one early HCC lesion of eAdHCC. The results indicate the emergence of UEA-I-positive sinusoidal tumor vessels to be most pronounced during the progression from eHCC to advanced HCC, and laminin-positive sinusoidal tumor vessels or actin-positive arterial tumor vessels to emerge mainly in advanced HCC.


Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.
The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.


Plasma adiponectin concentration is associated with the average accelerometer daily steps counts in healthy elderly females.
This study is aimed to evaluate whether circulating adiponectin concentration is associated with physical activity (PA) level in healthy older females. To date, daily PA in older adults (> or = 65 years) has primarily relied on self-report. This study used accelerometry, which objectively measured minute-by-minute movement to assess PA volume and intensity performed by elderly females. In addition, body composition, leptin and insulin resistance values were measured to assess the influence of these parameters on the possible relationship between adiponectin and PA levels in this specific age group of older women. On 49 women (mean age: 73.6 +/- 4.2 years), adiponectin, leptin, insulin resistance, body composition and 7-day PA parameters were measured. Average daily accelerometer step counts and time spent in different PA levels were obtained from 7-day PA measurement. Average daily accelerometer step-count was 7,722 +/- 3,069 steps day(-1) and the recommended 150 min weekly of at least moderate/vigorous PA in bouts of at least 10 min was achieved by 71.4% (35/49) of the participants. Correlation analysis showed that plasma adiponectin concentration (16.0 +/- 6.1 microg ml(-1) ) was related (P < 0.001) to steps per day (r = 0.438) and leptin (r = -0.443) values. Multivariate regression analysis further revealed that only steps per day and leptin were independent predictors of circulating adiponectin concentration in healthy elderly females. In conclusion, these data support the hypothesis that being physically active is associated with better adiponectin concentration and a reduced risk of having metabolic disease risk in the specific group of healthy elderly females.


First Report of Monosporascus cannonballus on Watermelon in Northern Mexico.
In 2010 and 2011, diseased watermelon plants (Citrillus lanatus [Thunb.] Matsun and Nakai) had chlorotic and wilted leaves and vines prior to harvest in three out of four sampled commercial fields in the Municipality of Matamoros, State of Coahuila, in the north-central region of Mexico known as La Comarca Lagunera. Disease incidence across the fields was 30%. Diseased plants also showed necrotic lesions and loss of secondary and tertiary roots, which can render roots unable to obtain an adequate supply of water and nutrients supporting the aboveground part of the plant before fruit maturity. Roots of affected plants contained perithecia with asci and ascospores typical of Monosporascus cannonballus Pollack & Uecker (4). This fungus has been found in hot semi-arid climates with saline and alkaline soils. Daytime temperatures above 40°C are frequent in north-central Mexico during the watermelon growing season. Small root pieces from 30 plants with disease symptoms (10 plants per field) were taken and surface-sterilized with 1.5% sodium hypochlorite, placed on potato dextrose agar (PDA) medium with 0.5 g/L of streptomycin sulfate at two petri dishes per plant and five root pieces per petri dish, and incubated for 7 days at 25°C in the dark. The fungus was isolated with a frequency of 60%. Mycelia were identified from root tissue based on morphological characteristics. DNA was also extracted in CTAB buffer followed by a phenol/chloroform purification and precipitation in isopropanol and ethanol (2). The internal transcribed spacer region was then amplified from isolate 1 using PCR, sequenced, and submitted to GenBank (Accession Number JQ599552). Pathogenicity of isolates was confirmed on watermelon plants (cv. Sweet summer 800) under greenhouse conditions at 25 to 32°C. Inoculum was produced in a sand-oat hull (Avena sativa) medium (0.5 l of sand, 45 g of oat hulls, and 100 ml of distilled water) and incubated for 50 days (1). Watermelon seeds were sown in sterile sand in 20-cm diameter and 12-cm deep polyurethane containers, where inoculum was added to reach a soil concentration of 20 CFU/g. Four seeds were sown in each of five inoculated containers; plants were thinned to two per container after emergence (each container representing a replication). Similarly, plants were also grown in four noninoculated containers and used as controls. After 50 days, all watermelon plants inoculated with M. cannonballus showed root necrosis in contrast with roots from noninoculated plants. M. cannonballus was reisolated from 80% of inoculated plants, confirming Koch's postulates. M. cannonballus causes severe damage on watermelon and other cucurbits such as cantaloupe (Cucumis melo). This fungus has been reported in the United States, Spain, Tunisia, Libya, Israel, Italy, the Netherlands (plants from Russia), Saudi Arabia, India, Japan, Taiwan, Brazil, Guatemala, and Honduras. To date, M. cannonballus has been reported on watermelon in 1996 in the State of Colima in southeastern Mexico (3). However, to the best of our knowledge, this is the first report of M. cannonballus on watermelon in northern Mexico. References: (1) B. D. Bruton et al. Plant Dis. 84:907, 2000. (2) B. R. Lovic et al. Phytopathology 85:655, 1995. (3) R. D. Martyn et al. Plant Dis. 80:1430, 1996. (4) F. G. Pollack and F. A. Uecker. Mycol. 66:346, 1974.


In vitro production of cattle-water buffalo (Bos taurus--Bubalus bubalis) hybrid embryos.
Interspecific hybrid embryos are useful models for the study of maternal-fetal interactions, transmission pattern of species-specific markers and parental contributions to growth and developmental potential of pre-attachment embryos. In an attempt to investigate the possibility of producing hybrid embryos of domestic cattle (Bos taurus) and water buffalo (Bubalus bubalis), cattle oocytes were exposed to buffalo sperm and buffalo oocytes were exposed to cattle sperm and the cleavage rate and the post-fertilisation features of hybrid embryos up to the blastocyst stage were compared with those of buffalo and cattle embryos. The cleavage rate in buffalo oocytes exposed to cattle sperm was low (40.8%), with only 8.8% of these hybrid embryos reaching the blastocyst stage. Cattle oocytes exposed to buffalo sperm showed 86.3% cleavage, while 25.9% of these attained the blastocyst stage. The speed of development of both types of hybrids was intermediate between that of cattle and buffalo embryos, with hatching occurring on day 7.5 in hybrid embryos, day 8-9 in cattle and day 7 in buffalo. The proportions of cells contributing to the trophectoderm and the inner cell mass were closer to those of the maternal species in both types of hybrid embryos. Our results indicate that cattle-water buffalo hybrid embryos produced using inter species gametes are capable of developing to advanced blastocyst stages and that their in vitro fate, and developmental potential, are influenced by the origin of the oocyte.


Personality traits modulate emotional and physiological responses to stress.
An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined the relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardized laboratory psychosocial stress task, the Trier Social Stress Test. Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the Trier Social Stress Test. Individuals with high agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease.


Topological two-dimensional polymers.
There are more than 200 two-dimensional (2D) networks with different topologies. The structural topology of a 2D network defines its electronic structure. Including the electronic topological properties, it gives rise to Dirac cones, topological flat bands and topological insulators. In this Tutorial Review, we show how electronic properties of 2D networks can be calculated by means of a tight-binding approach, and how these properties change when 2nd-neighbour interactions and spin-orbit coupling are included. We explain how to determine whether or not the resulting electronic features have topological signatures by calculation of Chern numbers, Z2 invariants, and by the nanoribbon approach. This tutorial gives suggestions how such topological properties could be realized in explicit atomistic chemical 2D systems made of molecular frameworks, in particular in 2D polymers, where the edges and vertices of a given 2D net are substituted by properly selected molecular building blocks and stitched together in such a way that long-range π-conjugation is retained.


Molecular Triage of Premalignant Lesions in Liquid-Based Cervical Cytology and Circulating Cell-Free DNA from Urine, Using a Panel of Methylated Human Papilloma Virus and Host Genes.
Clinically useful molecular tools to triage women for a biopsy upon referral to colposcopy are not available. We aimed to develop a molecular panel to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher lesions (CIN2+) in women with abnormal cervical cytology and high-risk HPV (HPV+). We tested a biomarker panel in cervical epithelium DNA obtained from 211 women evaluated in a cervical cancer clinic in Chile from 2006 to 2008. Results were verified in a prospective cohort of 107 women evaluated in a high-risk clinic in Puerto Rico from 2013 to 2015. Promoter methylation of ZNF516, FKBP6, and INTS1 discriminated cervical brush samples with CIN2+ lesions from samples with no intraepithelial lesions or malignancy (NILM) with 90% sensitivity, 88.9% specificity, 0.94 area under the curve (AUC), 93.1% positive predictive value (PPV), and 84.2% negative predictive value (NPV). The panel results were verified in liquid-based cervical cytology samples from an independent cohort with 90.9% sensitivity, 60.9% specificity, 0.90 AUC, 52.6% PPV, and 93.3% NPV, after adding HPV16-L1 methylation to the panel. Next-generation sequencing results in HPV+ cultured cells, and urine circulating cell-free DNA (ccfDNA) were used to design assays that show clinical feasibility in a subset (n = 40) of paired plasma (AUC = 0.81) and urine (AUC = 0.86) ccfDNA samples obtained from the prospective cohort. Viral and host DNA methylation panels can be tested in liquid cytology and urine ccfDNA from women referred to colposcopy, to triage CIN2+ lesions for biopsy and inform personalized screening algorithms. Cancer Prev Res; 9(12); 915-24. ©2016 AACR.


Pathogenomics: an updated European Research Agenda.
The emerging genomic technologies and bioinformatics provide novel opportunities for studying life-threatening human pathogens and to develop new applications for the improvement of human and animal health and the prevention, treatment, and diagnosis of infections. Based on the ecology and population biology of pathogens and related organisms and their connection to epidemiology, more accurate typing technologies and approaches will lead to better means of disease control. The analysis of the genome plasticity and gene pools of pathogenic bacteria including antigenic diversity and antigenic variation results in more effective vaccines and vaccine implementation programs. The study of newly identified and uncultivated microorganisms enables the identification of new threats. The scrutiny of the metabolism of the pathogen in the host allows the identification of new targets for anti-infectives and therapeutic approaches. The development of modulators of host responses and mediators of host damage will be facilitated by the research on interactions of microbes and hosts, including mechanisms of host damage, acute and chronic relationships as well as commensalisms. The study of multiple pathogenic and non-pathogenic microbes interacting in the host will improve the management of multiple infections and will allow probiotic and prebiotic interventions. Needless to iterate, the application of the results of improved prevention and treatment of infections into clinical tests will have a positive impact on the management of human and animal disease. The Pathogenomics Research Agenda draws on discussions with experts of the Network of Excellence "EuroPathoGenomics" at the management board meeting of the project held during 18-21 April 2007, in the Villa Vigoni, Menaggio, Italy. Based on a proposed European Research Agenda in the field of pathogenomics by the ERA-NET PathoGenoMics the meeting's participants updated the established list of topics as the research agenda for the future.


Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.
The intensive use of pesticides has led to their increasing presence in water, soil, and agricultural products. Mounting evidence indicates that some pesticides may be endocrine disrupting chemicals (EDCs), being therefore harmful for the human health and the environment. In this study, three pesticides, glyphosate, thiacloprid, and imidacloprid, were tested for their ability to interfere with estrogen biosynthesis and/or signaling, to evaluate their potential action as EDCs. Among the tested compounds, only glyphosate inhibited aromatase activity (up to 30%) via a non-competitive inhibition or a mixed inhibition mechanism depending on the concentration applied. Then, the ability of the three pesticides to induce an estrogenic activity was tested in MELN cells. When compared to 17β-estradiol, thiacloprid and imidacloprid induced an estrogenic activity at the highest concentrations tested with a relative potency of 5.4 × 10-10 and 3.7 × 10-9, respectively. Molecular dynamics and docking simulations predicted the potential binding sites and the binding mode of the three pesticides on the structure of the two key targets, providing a rational for their mechanism as EDCs. The results demonstrate that the three pesticides are potential EDCs as glyphosate acts as an aromatase inhibitor, whereas imidacloprid and thiacloprid can interfere with estrogen induced signaling.


Integrated selective enrichment target--a microtechnology platform for matrix-assisted laser desorption/ionization-mass spectrometry applied on protein biomarkers in prostate diseases.
The performance of a miniaturized sample processing platform for matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), manufactured by silicon microfabrication, called integrated selective enrichment target (ISET) technology was evaluated in a biological context. The ISET serves as both sample treatment device and MALDI-MS target, and contains an array of 96 perforated nanovials, which each can be filled with 40 nL of reversed-phase beads. This methodology minimizes the number of sample transfers and the total surface area available for undesired adsorption of the analytes in order to provide high-sensitivity analysis. ISET technology was successfully applied for characterization of proteins coisolated by affinity chromatography of prostate-specific antigen (PSA) from human seminal fluid. The application of ISET sample preparation enabled multiple analyses to be performed on a limited sample volume, which resulted in the discovery that prolactin inducible protein (PIP) was coisolated from the samples.


Prevention of allogeneic cardiac graft rejection by transfer of ex vivo expanded antigen-specific regulatory T-cells.
The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants.


A whole genome association study of mother-to-child transmission of HIV in Malawi.
More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value < 5 × 10(-5) associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings.


Feasibility and acceptability of the multi-component P3-MumBubVax antenatal intervention to promote maternal and childhood vaccination: A pilot study.
Pregnancy is a critical time for vaccine decision-making, but coverage remains suboptimal for maternal influenza (45-60%) and pertussis vaccination (65-80%) in Australia. The multi-component P3-MumBubVax intervention has been designed for Australian midwives to optimise antenatal vaccine discussions and improve maternal and childhood vaccine uptake. A pilot study was conducted to assess intervention feasibility and acceptability. P3-MumBubVax includes components at three levels: 1. Practice ('vaccine champions'; stickers to prompt and record vaccine discussions/delivery); 2. Provider (website with vaccine communication training; learning exercise; fact sheets; links to child vaccination resources); 3. Parent (SMS reminders; website; fact sheets). Midwives and pregnant women 18-22 weeks gestation were recruited at the Royal Women's Hospital, Melbourne. Post-intervention online surveys assessed intervention feasibility, implementation, acceptability and impact on vaccine uptake. Twenty-five midwives and 62 pregnant women were recruited and 19/25 midwives completed training. Surveys were returned by 18/25 midwives and 56/62 women. 14/18 midwives reported using the sticker prompts, 10/18 reported using or referring to the website, and 11/18 reported using the fact sheets. 48/56 pregnant women (86%) reported discussing influenza and 46/56 (82%) discussed pertussis vaccines with their midwives. These conversations were reported to be short (1-3 min) for 48/56 women (87%). All midwives were satisfied with the intervention and 17/18 reported feeling more confident discussing vaccines following the intervention. Women were very satisfied with SMS content (50/56; 94%) and timing (49/55; 89%), and with their vaccine discussions in general (34/56; 63%). However, 16/54 (30%) wanted more discussion about childhood vaccines. Self-reported maternal vaccine uptake was 82% (45/55) and 93% (51/55) for influenza and pertussis (baseline 2017-2018: 43% influenza, 60% pertussis) and 96% (50/52) of infants were fully vaccinated at 12 weeks. The P3-MumBubVax intervention is feasible and acceptable in the Australian public antenatal setting. Further evaluation is required to determine effectiveness.


Adoption of information technology by resident physicians.
The Internet represents a technological revolution that is transforming our society. In the healthcare industry, physicians have been typified as slow adopters of information technology. However, young physicians, having been raised in a computer-prevalent society, may be more likely to embrace technology. We attempt to characterize the use and acceptance of the Internet and information technology among resident physicians in a large academic medical center and to assess concerns regarding privacy, security, and credibility of information on the Internet. A 41-question survey was distributed to 150 pediatric, medical, and surgical residents at an urban, academic medical center. One hundred thirty-five residents completed the survey (response rate of 90%). Responses were evaluated and statistical analysis was done. The majority of resident physicians in our survey have adopted the tools of information technology. Ninety-eight percent used the Internet and 96% use e-mail. Two-thirds of the respondents used the Internet for healthcare-related purposes and a similar percentage thought that the Internet has affected their practice of medicine positively. The majority of residents thought that Internet healthcare services such as electronic medical records, peer-support websites, and remote patient monitoring would be beneficial for the healthcare industry. However, they are concerned about the credibility, privacy, and security of health and medical information online. The majority of resident physicians in our institution use Internet and information technology in their practice of medicine. Most think that the Internet will continue to have a beneficial role in the healthcare industry.


Search for gross illumination discrepancies in images of natural objects.
Shadows may be "discounted" in human visual perception because they do not provide stable, lighting-invariant, information about the properties of objects in the environment. Using visual search, R. A. Rensink and P. Cavanagh (2004) found that search for an upright discrepant shadow was less efficient than for an inverted one. Here we replicate and extend this work using photographs of real objects (pebbles) and their shadows. The orientation of the target shadows was varied between 30 and 180 degrees. Stimuli were presented upright (light from above, the usual situation in the world) or inverted (light from below, unnatural lighting). RTs for upright images were slower for shadows angled at 30 degrees, exactly as found by Rensink and Cavanagh. However, for all other shadow angles tested, the RTs were faster for upright images. This suggests, for small discrepancies in shadow orientation, a switch of processing from a relatively coarse-scaled shadow system to other general-purpose visual routines. Manipulations of the visual heterogeneity of the pebbles that cast the shadows differentially influenced performance. For inverted images, heterogeneity had the expected influence: reducing search efficiency and increasing overall search time. This effect was greatly reduced when images were presented upright, presumably when the distractors were processed as shadows. We suggest that shadows may be processed in a functionally separate, spatially coarse, mechanism. The pattern of results suggests that human vision does not use a shadow-suppressing system in search tasks.


Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.
Lipoxins are bioactive eicosanoids that are generated within the vascular lumen by leukocytes and transcellular biosynthetic routes during multicellular responses. Polymorphomuclear neutrophils (PMN) and endothelial cells express high affinity receptors for lipoxins, engagement of which invokes profiles of signaling events that differ from other lipid mediators. In this work, we report that lipoxins are potent inhibitors of PMN-endothelial cell interactions triggered by leukotrienes via dual-pronged actions with PMN and endothelial cells. Both lipoxin A4(LXA4) and B4(LXB4) blocked PMN migration stimulated by leukotriene B4 (LTB4), a well established agonist for PMN recruitment, a transmigration assay in vitro. Lipoxins were almost as effective in this regard as the pharmacologic LTB4 receptor antagonist, ONO 4057, and the blocking anti-CD18 mAb, R15.7. LXA4 and LXB4 blunted PMN transmigration, in part by inhibiting beta 2 integrin-dependent PMN adhesion. These modulatory actions of lipoxins were evident at subnanomolar concentrations, rapid in onset, and attenuated by prior exposure of PMN to a tyrosine kinase inhibitor, genistein. The peptidoleukotrienes, leukotriene C4 (LTC4) and leukotriene D4 (LTD4) also provoked PMN-endothelial cell adhesion, but via a different mechanism than LTB4. Both LTC4 and LTD4 enhanced endothelial adhesiveness for PMN, in part, by stimulating mobilization of P-selectin from intracellular Weibel-Palade bodies. LXA4 and LXB4, but not other lipoxygenase products, blocked P-selectin mobilization induced by peptidoleukotrienes and attenuated P-selectin-mediated PMN-endothelial cell adhesion. These results indicate that lipoxins attenuate PMN-endothelial cell interactions supported by selectins and beta 2 integrins in vitro, and are potential endogenous lipid-derived modulators of PMN trafficking in host defense, inflammation, and other vascular events.


Antimicrobial activity of essential oils and other plant extracts.
The antimicrobial activity of plant oils and extracts has been recognized for many years. However, few investigations have compared large numbers of oils and extracts using methods that are directly comparable. In the present study, 52 plant oils and extracts were investigated for activity against Acinetobacter baumanii, Aeromonas veronii biogroup sobria, Candida albicans, Enterococcus faecalis, Escherichia col, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica subsp. enterica serotype typhimurium, Serratia marcescens and Staphylococcus aureus, using an agar dilution method. Lemongrass, oregano and bay inhibited all organisms at concentrations of < or = 2.0% (v/v). Six oils did not inhibit any organisms at the highest concentration, which was 2.0% (v/v) oil for apricot kernel, evening primrose, macadamia, pumpkin, sage and sweet almond. Variable activity was recorded for the remaining oils. Twenty of the plant oils and extracts were investigated, using a broth microdilution method, for activity against C. albicans, Staph. aureus and E. coli. The lowest minimum inhibitory concentrations were 0.03% (v/v) thyme oil against C. albicans and E. coli and 0.008% (v/v) vetiver oil against Staph. aureus. These results support the notion that plant essential oils and extracts may have a role as pharmaceuticals and preservatives.


Model discrimination in dynamic molecular systems: application to parotid de-differentiation network.
In modern systems biology the modeling of longitudinal data, such as changes in mRNA concentrations, is often of interest. Fully parametric, ordinary differential equations (ODE)-based models are typically developed for the purpose, but their lack of fit in some examples indicates that more flexible Bayesian models may be beneficial, particularly when there are relatively few data points available. However, under such sparse data scenarios it is often difficult to identify the most suitable model. The process of falsifying inappropriate candidate models is called model discrimination. We propose here a formal method of discrimination between competing Bayesian mixture-type longitudinal models that is both sensitive and sufficiently flexible to account for the complex variability of the longitudinal molecular data. The ideas from the field of Bayesian analysis of computer model validation are applied, along with modern Markov Chain Monte Carlo (MCMC) algorithms, in order to derive an appropriate Bayes discriminant rule. We restrict attention to the two-model comparison problem and present the application of the proposed rule to the mRNA data in the de-differentiation network of three mRNA concentrations in mammalian salivary glands as well as to a large synthetic dataset derived from the model used in the recent DREAM6 competition.


Aspects of the ecology of phlebotomines (Diptera: Psychodidae: Phlebotominae) in an area of cutaneous leishmaniasis occurrence, municipality of Angra dos Reis, coast of Rio de Janeiro State, Brazil.
Over a complete two-year period, phlebotomine specimens were caught in an area of cutaneous leishmaniasis occurrence in the municipality of Angra dos Reis. A manual suction tube was used to catch phlebotomines on house walls, and also light traps in domestic and peridomestic settings and in the forest. This yielded 14,170 specimens of 13 species: two in the genus Brumptomyia and eleven in the genus Lutzomyia. L. intermedia predominantly in domestic and peridomestic settings, with little presence in the forest, with the same trend being found in relation to L. migonei, thus proving that these species have adapted to the human environment. L. fischeri appeared to be eclectic regarding location, but was seen to be proportionally more endophilic. L. intermedia and L. migonei were more numerous in peridomestic settings, throughout the year, while L. fischeri was more numerous in domestic settings except in March, April, May and September. From the prevalence of L. intermedia, its proven anthropophily and findings of this species naturally infected with Leishmania (Viannia) braziliensis, it can be incriminated as the main vector for this agent of cutaneous leishmaniasis in the study area, especially in the peridomestic environment. L. fischeri may be a coadjuvant in carrying the parasite.


How well do farmers know their badgers? Relating farmer knowledge to ecological survey data.
Knowledge of badger distribution is important for the management of bovine tuberculosis. At the farm level, typically the only information on badger activity available is from the farmers themselves. This study compares how well farmer perceptions of badger activity match data obtained from ecological surveys. Farmer estimates of numbers of badger setts (burrows) surrounding their farms were generally correlated with field survey results, but tended to be underestimates. Farmers correctly recorded 50 per cent of setts recorded in surveys, with larger setts and active setts more likely to be correctly recorded. Badger visits to farm buildings and yards were also monitored using surveillance cameras. The majority of farmers were aware of badger visits to their farm buildings, but in 22 per cent of cases farmers were not aware of badger visits. At the farm level, knowledge of badger activity will be useful in informing vets and animal health professionals of the potential risks of disease transmission, and hence directing management interventions. However, the tendency to underestimate activity, combined with a lack of detailed knowledge of sett locations, means that farmer estimates of badger activity should be interpreted with caution and in isolation may not be sufficient to inform management interventions.


Thyroid function studies in normal pregnant Tanzanian women.
Iodine deficiency is well known as a cause of several disorders such as endemic goiter and cretinism, along with a wide spectrum of psychoneurologic development disorders including endemic mental deficiency, which are generally correlated with damage to the fetus. Since as much as 40% of the Tanzanian population is at risk for iodine deficiency disorders (IDD) because they live in iodine-deficient areas, and although the effects of iodine deficiency on human reproduction in Tanzania have not been objectively studied, it is estimated that there are approximately 600,000 cretins and cretinoids in the country as a result of IDD. As a baseline study for future research on iodine deficiency and its effects on human reproduction in Tanzania, we assayed serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and free thyroxine (FT4) in 93 clinically euthyroid pregnant women and 34 nonpregnant women as controls. Pregnancy was accompanied by significantly increased levels of total T3 and T4, decreased FT4, and increased TSH concentration in serum. However, biochemical euthyroidism (assessed by FT4 and basal TSH) was demonstrated in almost all (99%) of the pregnant subjects in conformity with most of the previous findings elsewhere. We conclude that pregnant Tanzanian women residing in areas without iodine deficiency experience changes in biochemical parameters of thyroid function similar to their counterparts in other places.