A comparison of optimization algorithms for localized in vivo B0 shimming.
To compare several different optimization algorithms currently used for localized in vivo B0 shimming, and to introduce a novel, fast, and robust constrained regularized algorithm (ConsTru) for this purpose. Ten different optimization algorithms (including samples from both generic and dedicated least-squares solvers, and a novel constrained regularized inversion method) were implemented and compared for shimming in five different shimming volumes on 66 in vivo data sets from both 7 T and 9.4 T. The best algorithm was chosen to perform single-voxel spectroscopy at 9.4 T in the frontal cortex of the brain on 10 volunteers. The results of the performance tests proved that the shimming algorithm is prone to unstable solutions if it depends on the value of a starting point, and is not regularized to handle ill-conditioned problems. The ConsTru algorithm proved to be the most robust, fast, and efficient algorithm among all of the chosen algorithms. It enabled acquisition of spectra of reproducible high quality in the frontal cortex at 9.4 T. For localized in vivo B0 shimming, the use of a dedicated linear least-squares solver instead of a generic nonlinear one is highly recommended. Among all of the linear solvers, the constrained regularized method (ConsTru) was found to be both fast and most robust. Magn Reson Med 79:1145-1156, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Incidence of chemotherapy-induced nausea and vomiting in Taiwan: physicians' and nurses' estimation vs. patients' reported outcomes.
The major objective of the study was to determine the incidence and prevalence of acute and delayed chemotherapy-induced nausea and vomiting (CINV) among patients receiving chemotherapy and assess the accuracy with which medical providers perceive the incidence of CINV in their practice. Specialists, residents and nurses (medical providers) from two cancer centers in Taiwan estimated the incidence of acute and delayed CINV. Chemotherapy-naive patients from the same centers then completed a 5-day nausea and vomiting diary following highly and moderately emetogenic chemotherapy (HEC and MEC) to determine the actual incidence of acute and delayed CINV. Daily nausea ratings were recorded on a 100-mm visual analogue scale (VAS). No nausea was defined as a nausea VAS score <5 mm. Vomiting episodes were also recorded. Nausea and vomiting were defined as acute and delayed based on whether they occurred during the first 24 h after chemotherapy, or during days 2-5 after chemotherapy, respectively. In the two oncology centers, 37 medical providers (13 specialists, 4 residents, 20 nurses) and 107 patients were enrolled. The mean patient age was 49.2 years with 76% female and 74% having breast cancer. Of the 107 patients, 39% received HEC and 61% received MEC, and 77% received a 5-HT3 receptor antagonist and 94% received dexamethasone. There were no significant differences between patients with acute CINV and delayed CINV in terms of demographics, chemotherapy treatment or antiemetic treatment. The proportion of patients without alcohol use was significantly higher among patients with delayed CINV than among those with non-delayed CINV. Good control of CINV during the acute period correlated with the control of delayed emesis. There were no significant differences between specialists', residents', and nurses' estimations of the incidence rates of CINV. For HEC given to chemotherapy-naïve patients, the medical providers estimated acute CINV to be 44/41% and delayed CINV to be 61/53%, respectively. However, patient diaries revealed acute CINV to be 43/21% and delayed CINV to be 64/60%, respectively. For MEC given to chemotherapy-naive patients, medical providers estimated acute CINV to be 39/36% and delayed CINV to be 44/39%, respectively. However, patient diaries revealed acute CINV to be 55/18% and delayed CINV to be 74/55%, respectively. Medical providers significantly overestimated the incidence of acute vomiting by 20% and 18% in HEC and MEC patients, respectively. While they correctly estimated the rate of delayed vomiting in HEC patients, they underestimated it by 16% in MEC patients. With respect to nausea, medical providers correctly estimated rates of both acute and delayed nausea in HEC patients, but significantly underestimated rates of acute and delayed nausea by 16% and 30%, respectively, in MEC patients.


Evaluation of a brief anti-stigma campaign in Cambridge: do short-term campaigns work?
In view of the high costs of mass-media campaigns, it is important to understand whether it is possible for a media campaign to have significant population effects over a short period of time. This paper explores this question specifically in reference to stigma and discrimination against people with mental health problems using the Time to Change Cambridge anti-stigma campaign as an example. 410 face-to-face interviews were performed pre, during and post campaign activity to assess campaign awareness and mental health-related knowledge, attitudes and behaviours. Although campaign awareness was not sustained following campaign activity, significant and sustained shifts occurred for mental health-related knowledge items. Specifically, there was a 24% (p < 0.001) increase in persons agreeing with the statement: If a friend had a mental health problem, I know what advice to give them to get professional help, following the campaign. Additionally, for the statement: Medication can be an effective treatment for people with mental health problems, there was a 10% rise (p = 0.05) in the proportion of interviewees responding 'agree' or 'strongly agree' following the campaign. These changes, however, were not evident for attitudinal or behaviour related questions. Although these results only reflect the impact of one small scale campaign, these preliminary findings suggest several considerations for mass-media campaign development and evaluation strategies such as: (1) Aiming to influence outcomes pertaining to knowledge in the short term; (2) Planning realistic and targeted outcomes over the short, medium and long term during sustained campaigns; and (3) Monitoring indirect campaign effects such as social discourse or other social networking/contact in the evaluation.


Assessing the cross contamination and transfer rates of Salmonella enterica from chicken to lettuce under different food-handling scenarios.
Cross contamination of foodborne pathogens from raw meats to ready-to-eat foods has caused a number of foodborne outbreaks. The cross contamination and transfer rates of Salmonella enterica from chicken to lettuce under various food-handling scenarios were determined. The following scenarios were tested: in scenario 1, cutting board and knife used to cut chicken (10(6) CFU/g) were also used for cutting lettuce, without washing; in scenario 2, cutting board and knife were washed with water separately after cutting chicken, and subsequently used for cutting lettuce; and in scenario 3, cutting board and knife were thoroughly washed with soap and hot water after cutting chicken, and before cutting lettuce. In each scenario, cutting board, knife, chicken and lettuce were sampled for population of S. enterica. For scenario 1, both before and after cutting lettuce, the cutting board and knife each had about 2 logs CFU/cm(2) of S. enterica, respectively. The cut lettuce had about 3 logs CFU/g of S. enterica. In scenario 2, fewer organisms (0.5-2.4 logs CFU/g or cm(2)) were transferred. The transfer rates in both scenarios ranged from 0.02 to 75%. However, in scenario 3, <1 log CFU/g or cm(2) organisms were detected on lettuce, cutting board or knife, after washing and cutting lettuce. This shows that the FDA recommended practice for cleaning cutting boards is effective in removing S. enterica and preventing cross contamination.


Identification of multiple muscarinic binding site subtypes in cat and human cerebral vasculature.
The binding characteristics of the nonselective muscarinic antagonist [3H]N-methyl scopolamine ([3H]NMS) have been studied in membrane fractions of cat and human cerebral blood vessels. A computer-fitting method was used to analyze the data obtained from association/dissociation, saturation and competition experiments. Specific binding of [3H]NMS to membrane preparations from cat and human pia-arachnoid vessels was found to be saturable (respective Bmax values of 98 +/- 15 and 67 +/- 7 fmol/mg protein) and of high affinity (KD values of 165 +/- 28 and 125 +/- 12 pM, respectively). Competition studies, in the presence of various well-characterized M1, M2 or M3 putative muscarinic antagonists, performed against the binding of [3H]NMS, revealed the heterogeneity of muscarinic binding sites in these vascular tissues. A population of M1 sites was clearly identified in both human and cat pial vessel membranes and accounted for approximately 40 (human) and 20% (cat) of the total population of cerebrovascular muscarinic binding sites labeled with [3H]NMS. Such observation was further supported by saturation studies of [3H]NMS binding performed under M1 blocking conditions (75 nM pirenzepine). Competition and saturation (in the presence of M2 antagonists) studies suggested the presence of M2 sites (approximately 35% of total sites) in cat pial vessels. However, under the same conditions, no M2 binding sites could be detected in human cerebrovascular membranes. A small population of M3 sites (approx. 20%) was found in both human and cat cerebrovascular membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


Mating changes the subcellular distribution and the functionality of estrogen receptors in the rat oviduct.
Mating changes the mode of action of 17beta-estradiol (E2) to accelerate oviductal egg transport from a nongenomic to a genomic mode, although in both pathways estrogen receptors (ER) are required. This change was designated as intracellular path shifting (IPS). Herein, we examined the subcellular distribution of ESR1 and ESR2 (formerly known as ER-alpha and ER-beta) in oviductal epithelial cells of rats on day 1 of cycle (C1) or pregnancy (P1) using immunoelectron microscopy for ESR1 and ESR2. The effect of mating on intraoviductal ESR1 or ESR2 signaling was then explored comparing the expression of E2-target genes c-fos, brain creatine kinase (Ckb) and calbindin 9 kDa (s100g) in rats on C1 or P1 treated with selective agonists for ESR1 (PPT) or ESR2 (DPN). The effect of ER agonists on egg transport was also evaluated on C1 or P1 rats. Receptor immunoreactivity was associated with the nucleus, cytoplasm and plasma membrane of the epithelial cells. Mating affected the subcellular distribution of both receptors as well as the response to E2. In C1 and P1 rats, PPT increased Ckb while both agonists increased c-fos. DPN increased Ckb and s100g only in C1 and P1 rats, respectively. PPT accelerated egg transport in both groups and DPN accelerated egg transport only in C1 rats. Estrogen receptors present a subcellular distribution compatible with E2 genomic and nongenomic signaling in the oviductal epithelial cells of C1 and P1 although IPS occurs independently of changes in the distribution of ESR1 and ESR2 in the oviductal epithelial cells. Mating affected intraoviductal ER-signaling and induced loss of functional involvement of ESR2 on E2-induced accelerated egg transport. These findings reveal a profound influence on the ER signaling pathways exerted by mating in the oviduct.


[Update on proteomic use in hemodialysis].
Application of proteomics has become one of the leading experimental disciplines for increased understanding of the key role played by proteins and protein-protein interactions in all aspects of cell function. There is an increasing use of proteomic technologies for investigation into renal replacement therapy such as hemodialysis. In the last 10 years, the application of shotgun bottom-up liquid chromatography-mass spectrometry/mass spectrometry approaches has been successfully applied to research in uremic toxicity, with the discovery of novel uremic toxins and the potential to delineate a precise molecular approach to defining the biochemical nature of uremia. Major investigations of proteomics in hemodialysis therapy include molecular definition of uremic toxicity, identification of prognostic biomarkers, blood purification efficiency testing, and biocompatibility assessment of the dialyzer membrane materials. In this article, we review the results of recent proteoic investigations in the setting of chronic hemodialysis therapy.


The Efficacy of Topical Hyaluronic Acid 0.2% in the Management of Symptomatic Oral Lichen Planus.
Oral lichen planus (OLP) is a condition frequently referred to the specialist dental clinic for diagnosis and management. It is a disease of the skin and mucous membranes with oral manifestations too. It varies in appearance from keratotic to erythematous and ulcerative form. Immunosuppressants are frequently used for patients but some of these drugs could be implicated in malignant transformation, thus there is a clear need to find an alternative therapy for OLP. To evaluate the relief of symptoms and reduction in the size of the lesions of lichen planus with 0.2% hyaluronic acid topical application and to compare the efficacy of topical hyaluronic acid (0.2%) with that of patients on placebo. A randomized controlled study was conducted on 50 symptomatic and biopsy proven patients with lichen planus. The subjective symptoms like Visual Analogue Scale (VAS) and the objective symptoms like degree of erythema and mean area of the lesion were recorded preoperatively and on day 7, day 14, day 21 and day 28. The selected patients were divided randomly into group-I comprising of 25 patients who received topical 0.2% hyaluronic acid therapy for 14 days and group-II comprising of 25 patients who received topical application of placebo for 14 days. The statistical tests used were Mann-Whitney U test, t-test, Wilcoxon matched pairs test by ranks and paired t-test. Symptomatic effect of soreness evaluation- there was a significant reduction in VAS scores in the test group as compared to placebo, similarly there was also significant reduction in the degree of erythema, change in the size of the lesion and area of the lesion in the test group. There was significant improvement in relief of symptoms, in the degree of erythema and mean area of the lesion in Group-I when compared with group-II. Topical application of 0.2% Hyaluronic acid showed a significant clinical response when compared to topical placebo. It is easy to use; hence a frequent application scheme should be advised to improve the efficacy of hyaluronic acid.


Dexmedetomidine as an Adjuvant to Pre-Emptive Caudal Epidural Ropivacaine for Lumbosacral Spine Surgeries.
Pre-emptive caudal epidural is a proven technique for providing analgesia for spinal surgeries. Prolonged pain relief with no motor blockade is desired for early mobilisation. Present study aimed to evaluate the effect of addition of Inj dexmedetomidine to caudal ropivacaine on the duration of analgesia, haemodynamic profile and the associated side effects. In this prospective double-blind study a total of 60 patients undergoing lumbosacral spine surgery were randomised to receive 20 cc of pre-emptive caudal epidural injection of either inj ropivacaine 0.2% (Group R, n =30) or a mixture of Inj ropivacaine 0.2% and Inj dexmedetomidine 1 μg/kg (Group RD, n =30) under general anaesthesia after the patient was positioned prone for surgery. VAS scores, heart rate, blood pressures and time to rescue analgesia were recorded at regular intervals for the first 24 hours. Data analysis was carried out using Statistical Package for Social Science (SPSS, V 10.5 package). Mean VAS scores were significantly lower in the RD group for up to 12 hours following the caudal block. No clinically significant haemodynamic changes were noted in either of the groups. No other side effects were seen in both the groups. These results suggest that inj dexmedetomidine is an effective additive to inj ropivacaine for pre-emptive caudal epidural analgesia in lumbosacral spine surgeries.


Long-term expressing of breastmilk.
This article focuses on the breastfeeding experience of a midwife after the birth of her first child. He was born with a bilateral cleft lip and palate and despite attempting to breastfeed it was not possible physiologically. The decision was made to express breastmilk long-term and feed the baby by Chu Chu teat and squeeze bottle. This article describes the hints and ideas found along the way to make long-term expressing of breastmilk easier. It comes from personal experience, literature and asking other women in similar situations how they managed.


Apparent digestibility and proteic quality of the basic diet of Rio de Janeiro State complemented with multimixture.
Some factors in food can influence the protein digestibility positively or negatively. The protein quality is related to the protein synthesis capacity, growth, maintenance, reproduction and reconstitution of an organism. This work aims to determine the apparent digestibility coefficient and the protein quality of the standard basic diet of Rio de Janeiro State (HERJ), complemented with 2% of the multimixture (HERJ + MM), during rats' gestation and lactation periods. The results indicated a lower apparent digestibility coefficient (P < 0.05) during the gestation and lactation periods in HERJ diets (82.4% +/- 0.55; 80.64% +/- 1.7) and HERJ + MM (80.9% +/- 3.28; 81.7% +/- 1.2), in comparison to the casein diet (91.8% +/- 0.6; 93.9% +/- 0.4). There was no significant difference (P < 0.05) between HERJ diet (2.75 +/- 0.14) and HERJ + MM diet (2.53 +/- 0.18). However, the casein diet has showed a higher lactation value (3.27 +/- 0.3) in comparison with the two above mentioned groups. Therefore the use of the multimixture at 2% level neither impairs the apparent digestibility coefficient nor does it change the protein quality of the standard diet of Rio de Janeiro State.


Prediction uncertainty of density functional approximations for properties of crystals with cubic symmetry.
The performance of a method is generally measured by an assessment of the errors between the method's results and a set of reference data. The prediction uncertainty is a measure of the confidence that can be attached to a method's prediction. Its estimation is based on the random part of the errors not explained by reference data uncertainty, which implies an evaluation of the systematic component(s) of the errors. As the predictions of most density functional approximations (DFA) present systematic errors, the standard performance statistics, such as the mean of the absolute errors (MAE or MUE), cannot be directly used to infer prediction uncertainty. We investigate here an a posteriori calibration method to estimate the prediction uncertainty of DFAs for properties of solids. A linear model is shown to be adequate to address the systematic trend in the errors. The applicability of this approach to modest-size reference sets (28 systems) is evaluated for the prediction of band gaps, bulk moduli, and lattice constants with a wide panel of DFAs.


Identification of novel NFKB1 and ICOS frameshift variants in patients with CVID.
Common variable immunodeficiency (CVID) is a 'late-onset' primary immunodeficiency characterized by variable manifestations and genetic heterogeneity. A monogenic cause of CVID has been reported in 10% of patients. In this study, we identified two novel pathogenic variants implicated in monogenic CVID by whole exome sequencing (WES) analysis: a heterozygous nuclear factor κB subunit 1 (NFKB1) p.G686fs mutation and a homozygous inducible T-cell co-stimulator (ICOS) p.L96Sfs mutation. The predicted crystal models indicated premature truncation of the two mutated proteins. Both variants were demonstrated as loss-of-function mutations and were associated with overlapped manifestations of respiratory fungal infection and splenomegaly. We further performed a detailed assessment of immunologic phenotypes and impaired lymphocyte functions in patients. Moreover, we discovered an association between monoclonal T-large granular lymphocyte proliferation and ICOS-deficient CVID for the first time. These observations lead to a new perspective on the underlying genetic heterogeneity of CVID.


Utility of heating pattern with variable air temperature in drying; effects on drying time, energy consumption, and product quality.
Drying with variable air temperature is a technique to decrease the drying time, preserve quality and maintain the nutritional components of products. The aim of this study was to find the effect of different heating patterns with variable air temperatures on the drying time, energy consumption and the quality of garlic as well as investigate the critical times to change the air temperature. The constant air temperatures were 50, 60, and 70 °C, and the variable air temperature included three patterns of 60 °C → 50 °C (I), 70 °C→50 °C (II), and 70 °C (30 minutes) →50 °C (III). Despite preventing garlic slices' color changes in the constant air temperature of 50 °C, the antioxidant contents of the samples reduced significantly (45%), and the drying time was 136 minutes. At the air temperature of 70 °C, the color changes peaked, and the drying time was 65 minutes. The best drying condition was observed among the variable air temperature by pattern III. The drying time and loss of antioxidants were 24% and 45% lower than the one in the constant air temperature of 50 °C; besides, the effective moisture diffusivity was 24% higher. The color changes of these samples were lower compared to other patterns and the final product had acceptable quality and was produced in an optimal time.


The aging kidney. Defending a delicate balance of fluid and electrolytes.
The aging kidney is characterized by reduced glomerular filtration rate, loss of tubular volume, and narrowed homeostatic control of water and electrolyte balance. It is unclear whether these physiologic changes represent normal aging or subclinical disease. With aging, there is an increased risk of hyper- or hypovolemia. Sluggish control of potassium concentration also makes hyperkalemia more common, particularly when the patient is using certain drugs. Water metabolism is particularly vulnerable in older patients, resulting in a frequent tendency toward dehydration and hyperosmolality. Understanding these limitations on fluid and electrolyte homeostasis can help the clinician recognize and prevent complications when caring for older patients.


Socioeconomic determinants of childhood overweight and obesity in China: the long arm of institutional power.
Previous studies have widely reported that the association between socioeconomic status (SES) and childhood overweight and obesity in China is significant and positive, which lends little support to the fundamental-cause perspective. Using multiple waves (1997, 2000, 2004 and 2006) of the China Health and Nutrition Survey (CHNS) (N = 2,556, 2,063, 1,431 and 1,242, respectively) and continuous BMI cut-points obtained from a polynomial method, (mixed-effect) logistic regression analyses show that parental state-sector employment, an important, yet overlooked, indicator of political power during the market transformation has changed from a risk factor for childhood overweight/obesity in 1997 to a protective factor for childhood overweight/obesity in 2006. Results from quantile regression analyses generate the same conclusions and demonstrate that the protective effect of parental state sector employment at high percentiles of BMI is robust under different estimation strategies. By bridging the fundamental causes perspective and theories of market transformation, this research not only documents the effect of political power on childhood overweight/obesity but also calls for the use of multifaceted, culturally-relevant stratification measures in testing the fundamental cause perspective across time and space.


Harmine and imipramine promote antioxidant activities in prefrontal cortex and hippocampus.
A growing body of evidence has suggested that reactive oxygen species (ROS) may play an important role in the physiopathology of depression. Evidence has pointed to the β-carboline harmine as a potential therapeutic target for the treatment of depression. The present study we evaluated the effects of acute and chronic administration of harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) or saline in lipid and protein oxidation levels and superoxide dismutase (SOD) and catalase (CAT) activities in rat prefrontal cortex and hippocampus. Acute and chronic treatments with imipramine and harmine reduced lipid and protein oxidation, compared to control group in prefrontal cortex and hippocampus. The SOD and CAT activities increased with acute and chronic treatments with imipramine and harmine, compared to control group in prefrontal cortex and hippocampus. In conclusion, our results indicate positive effects of imipramine antidepressant and β-carboline harmine of oxidative stress parameters, increasing SOD and CAT activities and decreasing lipid and protein oxidation.


Efficacy of liquid biopsy for disease monitoring and early prediction of tumor progression in EGFR mutation-positive non-small cell lung cancer.
15-40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations.


Sensory deprivation stress and supplemental stimulation in the rat pup and preterm human neonate.
This article reviews the literature and presents data from our laboratories on sensory deprivation stress and supplemental stimulation of the rat pup and the preterm neonate. The data suggest that the effects of maternal deprivation in the rat pup (suppression of growth hormone release and protein synthesis) are regulated by a specific form of tactile stimulation: only brush stroking of maternally deprived rat pups returned growth parameters to normal; other forms of stimulation, including kinesthetic and vestibular stimulation, were ineffective in restoring normal functions. Other data are presented demonstrating that very small preterm neonates given tactile-kinesthetic stimulation gain more weight per day, spend more time awake and active, and show more mature habituation, orientation, motor, and range of state behaviors on the Brazelton assessment.


The meaning of family routines in a homeless shelter.
This exploratory investigation sought to understand what meaning parents, living in a homeless shelter, attribute to family routines and the nature of those routines. In-depth interviews were conducted with 12 parents living in a homeless shelter. Thematic analysis was employed to develop descriptive codes and themes from transcribed data and field notes. Parents described family routines focused on three features: promoting intimacy, maintaining or developing a legacy, and connections with the community. These routines seemed to preserve family integrity while homeless and to provide hope for the family to continue into the future. Homeless parents, in this investigation, seemed to expend a substantial amount of energy to create or maintain family routines while living in a homeless shelter. Findings suggest that occupational therapy services may help support homeless parents as they exercise their role as the organizer of family routines.


Automatic and Quantitative Measurement of Collagen Gel Contraction Using Model-Guided Segmentation.
Quantitative measurement of collagen gel contraction plays a critical role in the field of tissue engineering because it provides spatial-temporal assessment (e.g., changes of gel area and diameter during the contraction process) reflecting the cell behaviors and tissue material properties. So far the assessment of collagen gels relies on manual segmentation, which is time-consuming and suffers from serious intra- and inter-observer variability. In this study, we propose an automatic method combining various image processing techniques to resolve these problems. The proposed method first detects the maximal feasible contraction range of circular references (e.g., culture dish) and avoids the interference of irrelevant objects in the given image. Then, a three-step color conversion strategy is applied to normalize and enhance the contrast between the gel and background. We subsequently introduce a deformable circular model (DCM) which utilizes regional intensity contrast and circular shape constraint to locate the gel boundary. An adaptive weighting scheme was employed to coordinate the model behavior, so that the proposed system can overcome variations of gel boundary appearances at different contraction stages. Two measurements of collagen gels (i.e., area and diameter) can readily be obtained based on the segmentation results. Experimental results, including 120 gel images for accuracy validation, showed high agreement between the proposed method and manual segmentation with an average dice similarity coefficient larger than 0.95. The results also demonstrated obvious improvement in gel contours obtained by the proposed method over two popular, generic segmentation methods.


Discovering charge density functionals and structure-property relationships with PROPhet: A general framework for coupling machine learning and first-principles methods.
Modern ab initio methods have rapidly increased our understanding of solid state materials properties, chemical reactions, and the quantum interactions between atoms. However, poor scaling often renders direct ab initio calculations intractable for large or complex systems. There are two obvious avenues through which to remedy this problem: (i) develop new, less expensive methods to calculate system properties, or (ii) make existing methods faster. This paper describes an open source framework designed to pursue both of these avenues. PROPhet (short for PROPerty Prophet) utilizes machine learning techniques to find complex, non-linear mappings between sets of material or system properties. The result is a single code capable of learning analytical potentials, non-linear density functionals, and other structure-property or property-property relationships. These capabilities enable highly accurate mesoscopic simulations, facilitate computation of expensive properties, and enable the development of predictive models for systematic materials design and optimization. This work explores the coupling of machine learning to ab initio methods through means both familiar (e.g., the creation of various potentials and energy functionals) and less familiar (e.g., the creation of density functionals for arbitrary properties), serving both to demonstrate PROPhet's ability to create exciting post-processing analysis tools and to open the door to improving ab initio methods themselves with these powerful machine learning techniques.


Diversified Biomineralization Roles of Pteria penguin Pearl Shell Lectins as Matrix Proteins.
Previously, we isolated jacalin-related lectins termed PPL2, PPL3 (PPL3A, 3B and 3C) and PPL4 from the mantle secretory fluid of Pteria penguin (Mabe) pearl shell. They showed the sequence homology with the plant lectin family, jacalin-related β-prism fold lectins (JRLs). While PPL3s and PPL4 shared only 35%-50% homology to PPL2A, respectively, they exhibited unique carbohydrate binding properties based on the multiple glycan-binding profiling data sets from frontal affinity chromatography analysis. In this paper, we investigated biomineralization properties of these lectins and compared their biomineral functions. It was found that these lectins showed different effects on CaCO3 crystalization, respectively, although PPL3 and PPL2A showed similar carbohydrate binding specificities. PPL3 suppressed the crystal growth of CaCO3 calcite, while PPL2A increased the number of contact polycrystalline calcite composed of more than one crystal with various orientations. Furthermore, PPL4 alone showed no effect on CaCO3 crystalization; however, PPL4 regulated the size of crystals collaborated with N-acetyl-D-glucosamine and chitin oligomer, which are specific in recognizing carbohydrates for PPL4. These observations highlight the unique functions and molecular evolution of this lectin family involved in the mollusk shell formation.


Sacro-iliac joint arthroscopy for arthrodesis after traumatic dislocation. Cadaver and clinical feasibility study.
Sacro-iliac arthrodesis usually requires an extended posterior approach, which is associated with a number of dreaded complications. Here, we assessed the feasibility of arthroscopic exploration of the dislocated sacro-iliac joint. In the first step of our study, we used ligament section to induce loss of sacro-iliac joint coaptation in a cadaver. We then studied 5 patients with Tile C pelvic ring injuries. Arthroscopy was used to clear the joint of fibrous tissue and to roughen the bone to subchondral level in order to induce sacro-iliac arthrodesis. In addition, posterior fixation was performed using a hinge system or an ilio-sacral screw. The cadaver study confirmed the feasibility of sacro-iliac arthroscopy after disruption of the strong posterior inter-osseous ligament. In the clinical part of the study in 5 patients with Tile C pelvic ring injuries, arthroscopy allowed direct visualisation extending to the anterior part of the joint space. A power burr and synovial knife were introduced to remove the interposed fibrous tissue and to roughen the bone to subchondral level in order to induce joint fusion. In addition, percutaneous or open posterior fixation was performed in all 5 patients. No infectious complications were recorded. An arthroscope cannot be introduced into the normal sacro-iliac joint. In contrast, after traumatic sacro-iliac dislocation, arthroscopy can be used to evaluate the intra-articular injuries and to roughen the bone to subchondral level.


GROWTH CHARACTERISTICS OF THE BLUE-GREEN ALGAL VIRUS LPP-1.
Safferman, Robert S. (Robert A. Taft Sanitary Engineering Center, Cincinnati, Ohio), and Mary-Ellen Morris. Growth characteristics of the blue-green algal virus LPP- 1. J. Bacteriol. 88:771-775. 1964.-The blue-green algal (BGA) virus, strain LPP-1, formed two distinct plaque variants. During subsequent propagation, each of the isolated variants eventually reverted to a mixture of both plaque types. The large-plaque-former, multiplying at a somewhat faster rate, showed maximal virus production within 60 hr after infection; maximal titer of the small-plaque mutant was reached after a 76-hr incubation period. No differences were observed in either their host spectra or their pH and thermal stability. Evidence was presented which demonstrated that BGA virus samples could be assayed with reasonable accuracy from plaque counts. Variations resulting from this plating technique were within the range of experimental error that has been generally reported for such a system.


The effects of nutrients on the survival of Escherichia coli in lake water.
Escherichia coli was shown to survive without decline in viable counts for at least 12 d in filtered-autoclaved lake water. In unfiltered lake water there was a rapid decline in the viable count of E. coli. The addition of synthetic sewage to filtered-autoclaved lake water led to an increase in the viable count of E. coli at 15 degrees C and 37 degrees C and to an increase in the survival time of the E. coli in unfiltered water. The addition of phosphate and carbon sources (glucose, glycerol, succinate, acetate and lactose) did not significantly increase the survival time of E. coli in unfiltered water over the controls. The addition of ammonium sulphate and some amino acids (as nitrogen sources) to the unfiltered lake water did lead to an increase in the survival times for E. coli and this increase was proportional to the concentration of the added nitrogen source.


Individuals Who Believe in the Paranormal Expose Themselves to Biased Information and Develop More Causal Illusions than Nonbelievers in the Laboratory.
In the reasoning literature, paranormal beliefs have been proposed to be linked to two related phenomena: a biased perception of causality and a biased information-sampling strategy (believers tend to test fewer hypotheses and prefer confirmatory information). In parallel, recent contingency learning studies showed that, when two unrelated events coincide frequently, individuals interpret this ambiguous pattern as evidence of a causal relationship. Moreover, the latter studies indicate that sampling more cause-present cases than cause-absent cases strengthens the illusion. If paranormal believers actually exhibit a biased exposure to the available information, they should also show this bias in the contingency learning task: they would in fact expose themselves to more cause-present cases than cause-absent trials. Thus, by combining the two traditions, we predicted that believers in the paranormal would be more vulnerable to developing causal illusions in the laboratory than nonbelievers because there is a bias in the information they experience. In this study, we found that paranormal beliefs (measured using a questionnaire) correlated with causal illusions (assessed by using contingency judgments). As expected, this correlation was mediated entirely by the believers' tendency to expose themselves to more cause-present cases. The association between paranormal beliefs, biased exposure to information, and causal illusions was only observed for ambiguous materials (i.e., the noncontingent condition). In contrast, the participants' ability to detect causal relationships which did exist (i.e., the contingent condition) was unaffected by their susceptibility to believe in paranormal phenomena.


Enzymatic and Non-Enzymatic Virulence Activities of Dermatophytes on Solid Media.
Dermatophytes are keratinophilic fungi causing superficial cutaneous infections that account 20-25% of the global population. As per literature search, there is a dearth in the study on virulence factors of dermatophytes from the Indian sub-continent and moreover the association of the virulence factors and the host tissue in vitro helps in understanding the host-pathogen interaction. To analyse the enzymatic and non-enzymatic virulence activities of dermatophytes on solid media. A total of 11 isolates, three standard American Type Culture Collection (ATCC) strains- Trichophyton rubrum- 28188, Trichophyton mentagrophytes- 9533, Trichophyton tonsurans- 28942, one CBS KNAW Fungal Biodiversity Centre strain- Arthroderma grubyi- 243.66, five clinical isolates- T. rubrum, T. mentagrophytes, Trichophyton rubrum var. raubitschekii, Trichophyton interdigitale, Epidermophyton floccosum, and two laboratory isolates - Microsporum gypseum and Microsporum canis were screened for the production of virulence enzymes such as phospholipase, lipase, protease, gelatinase and non-enzyme virulence factors (haemolytic activity) of dermatophytes. The clinical isolates were identified from a tertiary care hospital, Chennai. These dermatophytes were tested upon specific substrates on solid media such as egg yolk, tween 80, bovine serum albumin, gelatin powder and sheep blood respectively. The virulence activity of phospholipase, lipase, protease and gelatinase was observed from all the dermatophyte species. T. rubrum, T. rubrum ATCC strain, T. rubrum var. raubitschekii, T. mentagrophytes, T. mentagrophytes ATCC strain, T. interdigitale and A. grubyi CBS strain produced complete haemolysis, whereas other dermatophytes showed no haemolytic activity. Phospholipase, lipase, protease and gelatinase act as enzymatic virulence marker and the T. rubrum complex, T. mentagrophytes complex and A. grubyi showed complete haemolysis and hence they may also act as a non-enzymatic virulence marker for dermatophytes.


[Study on mitoxantrone albumin microspheres for liver targeting].
An optimum procedure was established for preparing mitoxantrone albumin microspheres (DHAQ-BSA-MS) with emulsion-heating solidification. The morphology, diameters, drug loading, release characteristics, stability and its distribution in vivo of the drug-loaded albumin microspheres were studied. The results showed that the surface was regular, the average diameter was 0.99 micron, mean surface diameter was 1.24 microns and mean volume diameter was 1.44 microns, apparent drug loading was 2.558 +/- 0.101 micrograms.mg-1 (n = 5), effective drug loading was 1.503% +/- 0.127% (n = 5), embedding ratio was 92.82% +/- 6.48% (n = 5), and the release characteristics were in accord with "biphase kinetics equation": 1 - Q = 0.6428e-0.2132t + 0.3988e-0.00150t (gamma 1 = -0.9951, gamma 2 = -0.9982); T1/2 alpha = 3.250 h, T1/2 beta = 461.7 h. The stability of the drug-loaded albumin microspheres was good after three months storage at room temperature. The results determined by HPLC showed that the drug accumulated about 77.6% +/- 1.38% of the dose in the liver 20 minutes after intravenous injection to mice. This indicates that DHAQ-BSA-MS showed remarkable targeting for liver, and it seems to have important value for increasing the antihepatoma effect and decreasing the toxicity of mitoxantrone.


The DNA helicase recql4 is required for normal osteoblast expansion and osteosarcoma formation.
RECQL4 mutations are associated with Rothmund Thomson Syndrome (RTS), RAPADILINO Syndrome and Baller-Gerold Syndrome. These patients display a range of benign skeletal abnormalities such as low bone mass. In addition, RTS patients have a highly increased incidence of osteosarcoma (OS). The role of RECQL4 in normal adult bone development and homeostasis is largely uncharacterized and how mutation of RECQL4 contributes to OS susceptibility is not known. We hypothesised that Recql4 was required for normal skeletal development and both benign and malignant osteoblast function, which we have tested in the mouse. Recql4 deletion in vivo at the osteoblastic progenitor stage of differentiation resulted in mice with shorter bones and reduced bone volume, assessed at 9 weeks of age. This was associated with an osteoblast intrinsic decrease in mineral apposition rate and bone formation rate in the Recql4-deficient cohorts. Deletion of Recql4 in mature osteoblasts/osteocytes in vivo, however, did not cause a detectable phenotype. Acute deletion of Recql4 in primary osteoblasts or shRNA knockdown in an osteoblastic cell line caused failed proliferation, accompanied by cell cycle arrest, induction of apoptosis and impaired differentiation. When cohorts of animals were aged long term, the loss of Recql4 alone was not sufficient to initiate OS. We then crossed the Recql4fl/fl allele to a fully penetrant OS model (Osx-Cre p53fl/fl). Unexpectedly, the Osx-Cre p53fl/flRecql4fl/fl (dKO) animals had a significantly increased OS-free survival compared to Osx-Cre p53fl/fl or Osx-Cre p53fl/flRecql4fl/+ (het) animals. The extended survival was explained when the Recql4 status in the tumors that arose was assessed, and in no case was there complete deletion of Recql4 in the dKO OS. These data provide a mechanism for the benign skeletal phenotypes of RECQL4 mutation syndromes. We propose that tumor suppression and osteosarcoma susceptibility are most likely a function of mutant, not null, alleles of RECQL4.


False-positive Candida and Aspergillus antigen testing in recipients of allogeneic haematopoietic cell transplantation due to administration of parenteral nutrition and fixed combinations of piperacillin-tazobactam.
False positivity of antigen immunoassays used as an early diagnostic tool to detect invasive fungal infections is known. Interpretation of the assay needs the identification of sources which could affect the specificity of the test. We focused on the influence of parenteral nutrition (PN) and piperacillin-tazobactam (TZP) on fungal immunoassays. Measurable amounts of Candida antigen mannan were detected in several compounds of PN and TZP in a previous in vitro study. In the current study, 84 patients undergoing allogeneic haematopoietic cell transplantation receiving either TZP, PN or both were monitored with Aspergillus and Candida antigen assay. Six patients were analysed closer in a kinetic analysis with more frequent blood sampling to detect mannan. PN in diverse compositions as well as TZP did not increase significantly the amount of mannan and the Aspergillus antigen in serum. We could not confirm the positive results of the in vitro study. Physicians should be aware that mannan antigenemia due to drug infusion could be a transient issue and should be considered in the interpretation of fungal immunoassays, although we could not find clinically relevant effects on mannan levels.


Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark.
Both morbidity and mortality resulting from Staphylococcus aureus endocarditis are known to be high, and the incidence of this disease seems to increase. The Statens Serum Institut, Copenhagen, Denmark, made it possible for us to analyze the clinical features of S aureus endocarditis in a nation-wide population of non-drug addicts. Almost all Danish cases of bacteremia due to S aureus are reported to the Staphylococcus laboratory, Statens Serum Institut. The medical records were reviewed in cases reported from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. A total of 260 patients, 145 males and 115 females, fulfilled the diagnostic criteria. The median age was 67.5 years. In 83 patients, the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46%. Among the subset of patients who received medical therapy only and appropriate antistaphylococcal treatment, mortality was significantly associated with late congestive heart failure, age, and involvement of the central nervous system. A raised awareness of the paucity of clinical findings and a more frequent use of echocardiography as a screening method seem essential to improve the prognosis of patients with S aureus endocarditis. Involvement of the central nervous system constitutes a relative indication of early valve replacement.


Role of mitochondrial aldehyde dehydrogenase in nitrate tolerance.
Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO from GTN. This enzyme has not conclusively been identified. However, the mitochondrial aldehyde dehydrogenase (ALDH2) is inhibited in GTN-tolerant tissues and produces NO2- from GTN, which is proposed to be converted to NO within mitochondria. To investigate the role of this enzyme in GTN tolerance, cumulative GTN concentration-response curves were obtained for both GTN-tolerant and -nontolerant rat aortic rings treated with the ALDH inhibitor cyanamide or the ALDH substrate propionaldehyde. Tolerance to GTN was induced using both in vivo and in vitro protocols. The in vivo protocol resulted in almost complete inhibition of ALDH2 activity and GTN biotransformation in hepatic mitochondria, indicating that long-term GTN exposure results in inactivation of the enzyme. Treatment with cyanamide or propionaldehyde caused a dose-dependent increase in the EC50 value for GTN-induced relaxation of similar magnitude in both tolerant and nontolerant aorta, suggesting that although cyanamide and propionaldehyde inhibit GTN-induced vasodilation, these inhibitors do not affect the enzyme or system involved in tolerance development to GTN. Treatment with cyanamide or propionaldehyde did not significantly inhibit 1,1-diethyl-2-hydroxy-2-nitrosohydrazine-mediated vasodilation in tolerant or nontolerant aorta, indicating that these ALDH inhibitors do not affect the downstream effectors of NO-induced vasodilation. Immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by ALDH2 plays a minor role in the overall vascular biotransformation of GTN by this enzyme.


Cethromycin-mediated protection against the plague pathogen Yersinia pestis in a rat model of infection and comparison with levofloxacin.
The Gram-negative plague bacterium, Yersinia pestis, has historically been regarded as one of the deadliest pathogens known to mankind, having caused three major pandemics. After being transmitted by the bite of an infected flea arthropod vector, Y. pestis can cause three forms of human plague: bubonic, septicemic, and pneumonic, with the latter two having very high mortality rates. With increased threats of bioterrorism, it is likely that a multidrug-resistant Y. pestis strain would be employed, and, as such, conventional antibiotics typically used to treat Y. pestis (e.g., streptomycin, tetracycline, and gentamicin) would be ineffective. In this study, cethromycin (a ketolide antibiotic which inhibits bacterial protein synthesis and is currently in clinical trials for respiratory tract infections) was evaluated for antiplague activity in a rat model of pneumonic infection and compared with levofloxacin, which operates via inhibition of bacterial topoisomerase and DNA gyrase. Following a respiratory challenge of 24 to 30 times the 50% lethal dose of the highly virulent Y. pestis CO92 strain, 70 mg of cethromycin per kg of body weight (orally administered twice daily 24 h postinfection for a period of 7 days) provided complete protection to animals against mortality without any toxic effects. Further, no detectable plague bacilli were cultured from infected animals' blood and spleens following cethromycin treatment. The antibiotic was most effective when administered to rats 24 h postinfection, as the animals succumbed to infection if treatment was further delayed. All cethromycin-treated survivors tolerated 2 subsequent exposures to even higher lethal Y. pestis doses without further antibiotic treatment, which was related, in part, to the development of specific antibodies to the capsular and low-calcium-response V antigens of Y. pestis. These data demonstrate that cethromycin is a potent antiplague drug that can be used to treat pneumonic plague.


Targeted tumor therapies at a glance.
Conventional tumor therapy is usually based on surgery, radiation and chemotherapy. Treatment with chemotherapeutics is often impeded by dose-limiting toxicities. Therefore, medical scientists sought for tools to improve chemotherapy by directly coupling targeting molecules to cytotoxic substances. This review provides a general overview on the development of targeted drugs designed for tumor therapy. Further carrier-based delivery systems of anti-tumorigenic drugs will not be described here. The targeting moiety is usually an antibody or a fragment thereof. Growth factors, cytokines and ligands are also used as targeting moiety. The targeting moiety is coupled to the toxic moiety either chemically or both components were combined as fusion proteins. In addition to those targeted molecules containing conventional chemotherapeutics, more sophisticated targeted drugs were developed containing protein toxins, such as diphtheria toxin or Pseudomonas exotoxin. Only a small number of these protein toxins inside tumor cells results in efficient killing of the target cell. Several of these targeted toxins are currently in clinical trials. Another targeting mechanism utilizes the activation of formerly harmless substances in the vicinity of tumor cells. This mechanism is referred to as directed enzyme prodrug therapy.


N-Aryl iminochromenes inhibit cyclooxygenase enzymes via π-π stacking interactions and present a novel class of anti-inflammatory drugs.
Cyclooxygenase enzymes (COX1/2) have been widely studied and noted for their role in the biosynthesis of inflammation-induced proteins, prostaglandins and thromboxane. Multiple anti-inflammatory drugs have been developed to target these two enzymes, but most of them appeared to have notable adverse effects, especially on the cardiovascular system and lower gastrointestinal tract, suggesting an urgent need for new potent anti-inflammatory drugs. In this study, we screened twenty-two previously synthesized N-aryl iminochromenes (NAIs) for their anti-inflammatory activity by performing COX-1/2 inhibitory assays. Five compounds (1, 10, 14, 15, and 20) that gave the best in vitro anti-inflammatory results were subjected to an in vivo anti-inflammatory assay using the formalin-induced hind rat paw oedema method, followed by in silico studies using indomethacin and celecoxib as standard drugs. Among them, compound 10 stood out as the best candidate, and the percentage reduction in paw oedema at the dose of 20 mg kg-1 body weight was found to be substantially higher with compound 10 than that with indomethacin. This is mostly due to the excellent suitability of the chromene-phenyl scaffold with a highly concentrated area of aromatic residues, which produced good π-π stacking interactions. Taken together, this study strongly suggests compound 10 as a potential candidate for anti-inflammatory drug research.


Synthesis of copper nanoparticles mediated by photogenerated free radicals: catalytic role of chloride anions.
The photodecomposition of ketones by the Norrish Type I reaction, leading to the efficient release of reducing ketyl or alpha-amino alkyl radicals, provides a facile route for the synthesis of copper nanoparticles (CuNP) in both aqueous and organic solvents. The role of different counterions (especially halides) and surfactants has been used to 'tune' the morphology and size of the nanostructures formed. In aqueous solutions chloride ions catalyze the disproportionation that mediates the Cu(I) --> Cu(0) --> CuNP conversion. This article concentrates on spherical nanoparticles and offers some insights into the routes to other nanostructures.


Association of glomerular C4d deposition with various demographic data in IgA nephropathy patients; a preliminary study.
IgA nephropathy (IgAN) is the most prevalent primary chronic glomerulopathy worldwide. Thus, it is of vital importance to search for factors aggravating the disease progress, monitor disease activity and predict disease-specific therapy. C4d is a well-known biomarker of the complement cascade with a potential to meet the above needs. The aim of our study was, therefore, to determine whether C4d staining at the time of kidney biopsy had any correlation with the demographic, clinical and biochemical variables in IgAN. The definition of IgAN requires the presence of diffuse and global IgA deposits which were graded ≥2+ and weak C1q deposition. C4d immunohistochemical staining was conducted retrospectively on 29 renal biopsies of patients with IgAN, which were selected randomly from all biopsies. C4d immunohistochemical staining was performed on 3-μm deparaffinized and rehydrated sections of formaldehyde-fixed, paraffin-embedded renal tissues. Of 29 selected patients, 68% were male. In this study, 54.2±25 percent of glomeruli in all biopsies were positive for C4d. The mean and standard deviation (SD) of serum creatinine and the magnitude of proteinuria were 1.72±1.2 mg/dl and 1582±1214 mg/day, respectively. In this study, we observed statistically significant correlations of percent C4d positivity with the serum creatinine (r=0.61, p=0.0005), magnitude of proteinuria (r=0.72, p=0.0001), the proportion of globally sclerotic glomeruli (r=0.43, p=0.02) and the proportion of tubulointerstitial fibrosis (r=0.54, p=0.0023). The results from our investigation on C4d positivity in biopsy-proven cases of IgAN are in accord with some of the previous studies. These findings, however, require further validation in larger samples.


20-kDa accessory protein (P20) from Bacillus thuringiensis subsp. israelensis ISPC-12: Purification, characterization, solution scattering and structural analysis.
The 20-kDa accessory protein (P20) from Bacillus thuringiensis subsp. israelensis (Bti) has been identified as an essential molecular chaperone in the enhancement of Cry11Aa and Cyt1Aa toxins production and their bio-crystallization. Additionally, P20 plays a vital role in suppressing the toxic effect of Cyt toxin on the host bacterium and also enhances insecticidal activity of Cry1Ac protein. Thus, the function of P20 is more specific than that of the chaperones. However, P20 is poorly investigated and insufficiently characterized. In the present study, we recombinantly expressed p20 from local isolate Bti ISPC-12 in heterologous bacterium E. coli and P20 protein was purified to homogeneity. Detailed biochemical and biophysical characterization provides crucial insights about in-vitro behavior as well as spatial conformations of P20 protein. Further, structural modelling and analysis provides insights into three-dimensional organization of the protein and shows that P20 is a non-toxic member of cytolytic (Cyt) toxin family similar to Cyt1Ca, with presence of conserved cytolysin fold. Additionally, solution scattering reveals that P20 is present as a dimer in the solution and probable dimeric assembly of P20 is presented. The findings reported here reveal engaging facts about P20 thereby advancing our understanding about this protein, which will expedite future studies.


Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.
A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.


Antiviral strategies in chronic hepatitis B virus infection: II. Inhibition of duck hepatitis B virus in vitro using conventional antiviral agents and supercoiled-DNA active compounds.
Primary duck hepatocyte (PDH) cultures, congenitally infected with the duck hepatitis B virus (DHBV), were grown on feeder cell layers of irradiated human embryonic lung fibroblasts and then exposed to a number of compounds with recognized or potential antiviral activity. These compounds included conventional antiviral agents, reverse transcriptase inhibitors, compounds with activity to supercoiled-DNA, and DNA-binding agents. Twenty-three compounds were evaluated, and 13 were found to inhibit significantly viral DNA replication. Seven of these compounds (ellipticine, amsacrine, coumermycin A1, Adriamycin, mitozantrone, chloroquine, and neocarzinostatin) acted at the level of viral SC DNA and significantly inhibited production of duck hepatitis B surface antigen (DHBsAg). Conventional agents that inhibited DHBV DNA replication included ganciclovir, acyclovir, bromovinyldeoxyuridine, ribavirin, phosphonoformate, and dideoxyadenosine. Except for dideoxyadenosine, these inhibitors of viral DNA synthesis did not significantly inhibit DHBsAg production. Two additional compounds, novobiocin and nalidixic acid, altered the pattern of viral DNA replication, especially the generation and processing of viral SC DNA, and also inhibited the production of DHBsAg. Several compounds acting at the level of viral SC DNA have now been identified and may offer potential for the management of chronic hepatitis B virus infection.


Colorectal cancer in the elderly: characteristics and short term results.
to analyse the characteristics of colorectal cancer in elderly patients and to assess the outcomes of treatment. the study included 1,924 patients diagnosed with colorectal cancer during a 22 year period (1985-2007). We analysed patient clinical and demographic characteristics as well as their treatment and its outcome. there was an increase in emergency surgery with age, increasing from 13% among patients under 80 years of age to 47% in those over 90 years of age (p = 0.0001). On the other hand, the overall percentage of patients who underwent surgical treatment decreased from 96% in patients younger than 80 years of age, to 85% and 59% in octogenarians and nonagenarians, respectively (p = 0.0001), and there was a similar pattern in the rates of curative surgery among patients who underwent surgery. The overall mortality of patients who underwent surgery was 8% (141 out of 1,769), increasing from 4% in patients younger than 70 years of age to 25% in those over 90 (p = 0.0001). Multivariate analysis showed that the factors associated with mortality were the emergency nature of the surgery (p = 0.001), the ASA grade (p = 0.0001), and the presence of systemic complications (p = 0.0001), the weight of age decreasing significantly with respect to the univariate analysis (p = 0.013). there is an increase in the rate of complicated forms of colorectal cancer with increasing age of patients. In addition, there is a dramatic decrease in the rate of curative tumour resection with increasing age. Intraoperative mortality for colorectal cancer in octogenarians and nonagenarians is more closely related to the nature and intent of the surgery (elective or emergency; palliative or curative), the perioperative risk (ASA grade), and severe systemic complications, than to age.


A Systematic Review of Evidence for the Clubhouse Model of Psychosocial Rehabilitation.
The Clubhouse Model has been in existence for over sixty-five years; however, a review that synthesizes the literature on the model is needed. The current study makes use of the existing research to conduct a systematic review of articles providing a comprehensive understanding of what is known about the Clubhouse Model, to identify the best evidence available, as well as areas that would benefit from further study. Findings are summarized and evidence is classified by outcome domains. Fifty-two articles met the selection criteria of Randomized Clinical Trials (RCT's), quasi-experimental studies, or observational studies for domains of employment (N = 29); quality of life/satisfaction (N = 10); reductions in psychiatric hospitalization(s) (N = 10); social relationships (N = 10); education (N = 3); and health promotion activities (N = 2). RCT results support the efficacy of the Clubhouse Model in promoting employment, reducing hospitalization(s), and improving quality of life. Quasi-experimental and observational studies offer support in education and social domains. The findings from this review indicate that Clubhouses are a promising practice but additional studies using rigorous methods that report the strength of the outcomes are needed to evaluate Clubhouse programs with fidelity to the Clubhouse Model.


Glucose metabolism and kinetics of phosphorus removal by the fermentative bacterium Microlunatus phosphovorus.
Phosphorus and carbon metabolism in Microlunatus phosphovorus was investigated by using a batch reactor to study the kinetics of uptake and release of extracellular compounds, in combination with (31)P and (13)C nuclear magnetic resonance (NMR) to characterize intracellular pools and to trace the fate of carbon substrates through the anaerobic and aerobic cycles. The organism was subjected to repetitive anaerobic and aerobic cycles to induce phosphorus release and uptake in a sequential batch reactor; an ultrafiltration membrane module was required since cell suspensions did not sediment. M. phosphovorus fermented glucose to acetate via an Embden-Meyerhof pathway but was unable to grow under anaerobic conditions. A remarkable time shift was observed between the uptake of glucose and excretion of acetate, resulting in an intracellular accumulation of acetate. The acetate produced was oxidized in the subsequent aerobic stage. Very high phosphorus release and uptake rates were measured, 3.34 mmol g of cell(-1) h(-1) and 1.56 mmol g of cell(-1) h(-1), respectively, values only comparable with those determined in activated sludge. In the aerobic period, growth was strictly dependent on the availability of external phosphate. Natural abundance (13)C NMR showed the presence of reserves of glutamate and trehalose in cell suspensions. Unexpectedly, [1-(13)C]glucose was not significantly channeled to the synthesis of internal reserves in the anaerobic phase, and acetate was not during the aerobic stage, although the glutamate pool became labeled via the exchange with intermediates of the tricarboxylic acid cycle at the level of glutamate dehydrogenase. The intracellular pool of glutamate increased under anaerobic conditions and decreased during the aerobic period. The contribution of M. phosphovorus for phosphorus removal in wastewater treatment plants is discussed on the basis of the metabolic features disclosed by this study.


Anti-tumour effects and pharmacokinetic profile of 17-(5'-isoxazolyl)androsta-4,16-dien-3-one (L-39) in mice: an inhibitor of androgen synthesis.
17-(5'-Isoxazolyl)androsta-4,16-dien-3-one (L-39), a novel androstene derivative, was synthesized and evaluated in vitro and in vivo. L-39 showed potent and non-competitive inhibition of human testicular microsomal 17alpha-hydroxylase/C(17,20)-lyase with an IC50 value of 59 nM and Ki of 22 nM. L-39 also showed potent and competitive inhibition of 5alpha-reductase in human prostatic microsomes with IC50 and Ki values of 33 and 28 nM respectively. L-39 (5 microM) has also been shown to manifest anti-androgenic activity in cultures of human prostate cancer cell lines (LNCaP) by preventing the labelled synthetic androgen R1881 (5 nM) from binding to the androgen receptors. Androgen-dependent human prostate cancer xenografts (PC-82) were grown in nude mice and the effects of L-39 (50 mg kg(-1) day(-1)) on tumour growth and prostate-specific antigen (PSA) levels were determined after 28 days. L-39 significantly (P < 0.01) diminished tumour growth and wet weights to a similar extent as castration or flutamide treatment. L-39 also significantly (P < 0.01) reduced serum PSA levels by more than 80% in the mice bearing human prostate cancer xenografts. Pharmacokinetic studies were also conducted in male Balb/c mice. After subcutaneous administration of a single bolus dose, L-39 was rapidly absorbed into the systemic circulation. Peak plasma levels occurred at 0.75 h and then declined with a t(1/2) of 1.51 h. The bioavailability of L-39 after subcutaneous administration was 28.5%. These results demonstrate that L-39 is a potent inhibitor of androgen synthesis and is effective in reducing the growth of human prostate cancer xenografts in nude mice. Although improvements in the bioavailability are necessary, L-39 is a potential lead compound with this profile as an inhibitor of prostate cancer growth.


Variable extent of sex-biased dispersal in a strongly polygynous mammal.
For mammals with a polygynous mating system, dispersal is expected to be male-biased. However, with the increase in empirical studies, discrepancies are arising between the expected and observed direction/extent of the bias in dispersal. In this study, we assessed sex-biased dispersal in red deer (Cervus elaphus) on 13 estates from the Scottish Highlands. A total of 568 adult individuals were genotyped at 21 microsatellite markers and sequenced for 821 bp of the mitochondrial control region. Estimates of population structure with mitochondrial sequences were eight times larger than that obtained with microsatellite data (F(st'-mtDNA) = 0.831; F(st'-micros) = 0.096) indicating overall male-biased dispersal in the study area. Comparisons of microsatellite data between the sexes indicated a predominance of male-biased dispersal in the study area but values of F(ST) and relatedness were only slighter larger for females. Individual-based spatial autocorrelation analysis generated a similar pattern of relatedness across geographical distances for both sexes, with differences only significant at two distance intervals (25-30 and 70-112 km). Patterns of relatedness differed between estates, male biased-dispersal was detected in eight estates but no sex-biased dispersal was found in the remaining five. Neither population density nor landscape cover was found to be associated with the patterns of relatedness found across the estates. Differences in management strategies that could influence age structure, sex ratio and dispersal behaviour are proposed as potential factors influencing the relatedness patterns observed. This study provides new insights on dispersal of a strongly polygynous mammal at geographical scales relevant for management and conservation.


Augmented cerebral blood velocity in response to isometric handgrip exercise in women with a history of preeclampsia.
Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE (n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women (P < 0.05 for all). MCAv increased during IHG in both groups (P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP -2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.


Responding to reviewers' comments as part of writing for publication.
The aim of this paper is to provide a resource for authors to help them in getting their work published. The focus is on dealing with, and responding to, the comments of reviewers. The importance to research of nurses writing for publication is widely acknowledged. However, a number of significant barriers to nurses actively engaging in this form of dissemination has been identified. Ways in which nurses can avoid the pitfalls that would make their manuscripts more likely to be rejected have been the subjects of published articles. Significantly less attention has been devoted to providing authors with methods to assist them in responding when their manuscripts are rejected or major revisions are requested. This article provides a brief overview of the process of editorial review. It offers a practical but structured approach to responding to reviewers' comments when undertaking major revisions and to preparing a rejected manuscript for resubmission to another journal. Authors frequently respond negatively to reviewers' comments and this may result in their being dissuaded from writing for publication. A structured approach to dealing with reviewers' comments may help nurses in making the requested revisions and increase their chances of publication. The publication of research findings and other scholarly work are important for the professional advancement of nursing. Strategies to overcome the barriers to writing for publication are essential to achieving this goal. Helping authors to respond positively to reviewer critique and to make the necessary changes are important steps in this process.


Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.
Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.


A new statistical method for transfer coefficient calculations in the framework of the general multiple-compartment model of transport for radionuclides in biological systems.
A new and simple statistical procedure (STATFLUX) for the calculation of transfer coefficients of radionuclide transport to animals and plants is proposed. The method is based on the general multiple-compartment model, which uses a system of linear equations involving geometrical volume considerations. By using experimentally available curves of radionuclide concentrations versus time, for each animal compartment (organs), flow parameters were estimated by employing a least-squares procedure, whose consistency is tested. Some numerical results are presented in order to compare the STATFLUX transfer coefficients with those from other works and experimental data.


Family caregiver's willingness to care from the perspective of altruism.
The willingness of family members to take care of older relatives directly affects the quality of life of disabled older adults, so it is necessary to understand the status quo of willingness to care and its influencing factors. This has been extensively studied in other countries, but, it is rarely studied in China. Based on the theory of altruism, employing a unique sample from Shanghai, China in 2017 and 2022, we attempt to reveal the influencing factors of the care willingness of family caregivers during the transition period. To measure caregiver burden and functional disability of the care recipient, we employ the Zarit Burden Interview (ZBI) and the Barthel Index, respectively. Then we utilized the ordinary least squares (OLS) methodology and estimated four regression models. Models 1, 2, and 3 examined the impact of the variables of the caregiver burden, responsibility and love, and the quality of the caregiver-caregiver recipient relationship, respectively, on family caregivers' willingness to care. Model 4 was the full model. To testify whether the caregiver burden is likely to act as a mediator, path analysis was used, and the path was adjusted and verified. According to the survey, in Shanghai, only half of the caregivers had a very high care willingness to care for disabled older relatives, while nearly one-tenth of the caregivers had a low willingness. It was the caregiver burden rather than the functional disability of older adults that harms family caregivers' willingness to care. Responsibility and caring out of love were positively related to care willingness. Relationship quality was the most important influencing factor, explaining 10.2% of the variance in care willingness. Path analysis demonstrated that responsibility, caring out of love, and relationship quality directly and through the mediation of caregiver burden indirectly affected care willingness. Our results revealed that reciprocal altruism presented by the quality of the caregiver-care recipient relationship had a significantly positive impact on family caregivers' willingness to care. In addition, the caregiver burden was found not only directly affected care willingness, but also acted as a mediator. To promote the perfection of laws and policies, comprehensive samples of different types of cities should be included and the measurement of key variables could be further improved in future studies.


Preventing Excessive Noise Exposure in Infants, Children, and Adolescents.
Noise exposure is a major cause of hearing loss in adults. Yet, noise affects people of all ages, and noise-induced hearing loss is also a problem for young people. Sensorineural hearing loss caused by noise and other toxic exposures is usually irreversible. Environmental noise, such as traffic noise, can affect learning, physiologic parameters, and quality of life. Children and adolescents have unique vulnerabilities to noise. Children may be exposed beginning in NICUs and well-baby nurseries, at home, at school, in their neighborhoods, and in recreational settings. Personal listening devices are increasingly used, even by small children. Infants and young children cannot remove themselves from noisy situations and must rely on adults to do so, children may not recognize hazardous noise exposures, and teenagers generally do not understand the consequences of high exposure to music from personal listening devices or attending concerts and dances. Environmental noise exposure has disproportionate effects on underserved communities. In this report and the accompanying policy statement, common sources of noise and effects on hearing at different life stages are reviewed. Noise-abatement interventions in various settings are discussed. Because noise exposure often starts in infancy and its effects result mainly from cumulative exposure to loud noise over long periods of time, more attention is needed to its presence in everyday activities starting early in life. Listening to music and attending dances, concerts, and celebratory and other events are sources of joy, pleasure, and relaxation for many people. These situations, however, often result in potentially harmful noise exposures. Pediatricians can potentially lessen exposures, including promotion of safer listening, by raising awareness in parents, children, and teenagers. Noise exposure is underrecognized as a serious public health issue in the United States, with exposure limits enforceable only in workplaces and not for the general public, including children and adolescents. Greater awareness of noise hazards is needed at a societal level.


Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC.
Initial cell surface expression of the pre-B cell receptor induces proliferation. After 2 to 5 divisions, however, large pre-BII (Fraction C') cells exit cell cycle to become resting, small pre-BII cells (Fraction D). The mechanism by which pre-BII cells exit cell cycle, however, is currently unclear. The checkpoint at the Fraction C'-D transition is critical for immunoglobulin light chain gene recombination and to prevent malignant transformation into acute lymphoblastic leukemia. Here we demonstrate that inducible activation of pre-B cell receptor signaling induces cell-cycle exit through up-regulation of the transcriptional repressor BCL6. Inducible activation of BCL6 downstream of the pre-B cell receptor results in transcriptional repression of MYC and CCND2. Hence, pre-B cell receptor-mediated activation of BCL6 limits pre-B cell proliferation and induces cellular quiescence at the small pre-BII (Fraction D) stage.


Synchronous Malignancies Identified by PET-CT Scan in Breast Cancer Patients.
Breast cancer is a common malignancy and a common cause of cancer-related mortality in women. Pre-treatment workup of breast cancer does not routinely include positron emission tomography scans. We aimed to review cases of women with breast cancer and a synchronous second primary malignancy. We present three cases of women with non-metastatic cancer in whom a synchronous second primary malignancy was found. Synchronous, second primary malignancies which were identified included rectal cancer, gastrointestinal stromal tumor, and non-small cell lung cancer. All second primary malignancies were identified by a PET-CT scan. In conclusion, PET-CT may be used for detection of secondary primary malignancies in select breast cancer patients.


Sensory potential can be preserved in severe common peroneal neuropathy.
Neuropathy of Common Peroneal Nerve (CPN) is a frequent clinical condition, generally caused by compression at the fibula head. Three neurophysiological patterns were described: 1) segmental demyelination with conduction block; 2) axonal damage with loss of motor units and sensory potential; 3) a mixed pattern. We report 5 patients with foot drop in whom CPN neuropathy was identified. In 3 in spite of impressive abnormalities in various motor branches and fascicles of the nerve, the peroneus nerve sensory potential remained well preserved. Focal neuropathies can be remarkably selective in terms of motor and sensory deficits, the reason can rely on a different location of the fibres or be related to a distinct histological-biochemical constitution. A preserved SPSP should not exclude a CPN neuropathy.


Multifunctional Silk Fibroin/Carbon Nanofiber Scaffolds for In Vitro Cardiomyogenic Differentiation of Induced Pluripotent Stem Cells and Energy Harvesting from Simulated Cardiac Motion.
In this proof-of-concept study, cardiomyogenic differentiation of induced pluripotent stem cells (iPSCs) is combined with energy harvesting from simulated cardiac motion in vitro. To achieve this, silk fibroin (SF)-based porous scaffolds are designed to mimic the mechanical and physical properties of cardiac tissue and used as triboelectric nanogenerator (TENG) electrodes. The load-carrying mechanism, β-sheet content, degradation characteristics, and iPSC interactions of the scaffolds are observed to be interrelated and regulated by their pore architecture. The SF scaffolds with a pore size of 379 ± 34 μm, a porosity of 79 ± 1%, and a pore interconnectivity of 67 ± 1% upregulated the expression of cardiac-specific gene markers TNNT2 and NKX2.5 from iPSCs. Incorporating carbon nanofibers (CNFs) enhances the elastic modulus of the scaffolds to 45 ± 3 kPa and results in an electrical conductivity of 0.021 ± 0.006 S/cm. The SF and SF/CNF scaffolds are used as conjugate TENG electrodes and generate a maximum power output of 0.37 × 10-3 mW/m2, with an open-circuit voltage and a short circuit current of 0.46 V and 4.5 nA, respectively, under simulated cardiac motion. A novel approach is demonstrated for fabricating scaffold-based cardiac patches that can serve as tissue scaffolds and simultaneously allow energy harvesting.


Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.
The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.


Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity.
Mcm proteins play an essential role in eukaryotic DNA replication, but their biochemical functions are poorly understood. Recently, we reported that a DNA helicase activity is associated with an Mcm4-Mcm6-Mcm7 (Mcm4,6,7) complex, suggesting that this complex is involved in the initiation of DNA replication as a DNA-unwinding enzyme. In this study, we have expressed and isolated the mouse Mcm2, 4,6,7 proteins from insect cells and characterized various mutant Mcm4,6,7 complexes in which the conserved ATPase motifs of the Mcm4 and Mcm6 proteins were mutated. The activities associated with such preparations demonstrated that the DNA helicase activity is intrinsically associated with the Mcm4,6,7 complex. Biochemical analyses of these mutant Mcm4,6,7 complexes indicated that the ATP binding activity of the Mcm6 protein in the complex is critical for DNA helicase activity and that the Mcm4 protein may play a role in the single-stranded DNA binding activity of the complex. The results also indicated that the two activities of DNA helicase and single-stranded DNA binding can be separated.


Seasonal Variation in the Epidemiology of Asymptomatic Plasmodium falciparum Infections across Two Catchment Areas in Bongo District, Ghana.
Understanding the epidemiology of asymptomatic Plasmodium falciparum infections is critical for countries to move toward malaria elimination. Using different methods for parasite detection, we evaluated how seasonality, spatial location, and other factors affect the age-specific epidemiology of asymptomatic malaria in Bongo District, Ghana. Asymptomatic prevalence by microscopy decreased significantly from 42.5% at the end of the wet to 27.5% at the end of the dry season (P < 0.001). Using the 18S rRNA polymerase chain reactions (PCRs), all microscopy-negative samples were screened and prevalence of submicroscopic infections also decreased significantly from the wet (55.4%) to the dry (20.7%) season (P < 0.001). Combining detection methods, 74.4% and 42.5% of the population in the wet and dry seasons, respectively, had evidence of a P. falciparum infection. Interestingly in those > 20 years of age, we found evidence of infection in 64.3% of the population in the wet and 27.0% in the dry season. Using both microscopy and PCR, the asymptomatic P. falciparum reservoir peaks at the end of the wet season and infections in all age groups constitute the reservoir of malaria infection. At the end of the wet season, spatial heterogeneity in the prevalence and density of P. falciparum infections was observed between the two catchment areas surveyed in Bongo District. These results indicate that if elimination is to succeed, interventions will need to target not just P. falciparum infections in children but also in adults, and be implemented toward the end of the dry season in this area of West Africa.


Could reflex cough induced through nebulized capsaicin achieve airway clearance in patients with acute retention of lung secretions?
Nasotracheal suctioning (NTS) is a procedure commonly performed by respiratory physiotherapists and nurses to remove excess respiratory secretions from the tracheobronchial tree in a self-ventilating, non-intubated and non-tracheotomized patient. NTS is an important treatment modality for patients with acute secretion retention who are at high risk of progressive respiratory deterioration and arrest. However, NTS is a blind invasive procedure with risk of serious adverse events, and the patient experience of NTS is often extremely negative. Capsaicin, a substance extracted from cayenne pepper, elicits reflex coughs when inhaled. It is hypothesized that capsaicin-induced reflex cough may offer an alternative treatment option to NTS. It is suggested that repeated reflex cough bouts, elicited through inhalation of nebulized capsaicin via a facemask, could achieve clearance of retained secretions from the tracheobronchial tree to the oropharynx, thereby avoiding the need for NTS. This hypothesis is supported by preliminary cough flow data from a stroke trial. Stroke patients underwent assessments of peak cough flow (PCF, a measure of cough effectiveness) of both maximal volitional cough and capsaicin-induced reflex cough. In a sub-group of 20 stroke patients with weak volitional cough (mean PCF 220 L/min, SD 80), PCF of capsaicin-induced reflex cough was on average 184 L/min (SD 130) higher than PCF of subjects' maximal volitional cough effort. Cough flow traces indicate a pattern of cough augmentation during consecutive reflex cough bouts. It is suggested that the hypothesis may best be tested in a pragmatic applied clinical study, i.e. through the application of nebulized capsaicin in relevant clinical situations, as opposed to observational or experimental physiological studies.


Antimicrobial and antioxidant activities of the various extracts of Verbascum pinetorum Boiss. O. Kuntze (Scrophulariaceae).
The present study was performed to evaluate the in vitro antimicrobial and antioxidant properties of various extracts of Verbascum (V.) pinetorum, a member of Scrophulariaceae family. While the antimicrobial activity of various extracts of V. pinetorum was determined with agar-well diffusion method, the antioxidant activity was examined with two complementary test systems, namely 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and beta-carotene/linoleic acid test systems. The hexane extract exhibits antimicrobial activity against few microorganisms. However, dichloromethane, direct methanol and methanol/chloroform extracts are effective on a broad range of microorganisms. Among the tested bacteria Haemophilus influenzae was found to be the most sensitive bacterium. The 50% (IC50) inhibition activity of the methanolic extract of V. pinetorum on the free radical DPPH was determined as 13.04 mg/ml. In the case of the linoleic acid system, oxidation of linoleic acid was inhibited by methanolic extract of V. pinetorum, which showed 89.39% inhibition that is quite close to the value of the synthetic antioxidant reagent butylhydroxytoluene (BHT), 92.46%. Iridoid glycosides, flavonoids and saponins were determined as the major natural compounds in the methanolic extracts. The total phenolic components of V. pinetorum were found as 42.45 mg/g gallic acid equivalent. The results provide evidence that the extracts of V. pinetorum contained iridoid glycosides, flavonoids, saponins and phenolic compounds which may be responsible for the substantial antimicrobial and antioxidant activities.


Plasmalogens of high-density lipoproteins (HDL) are associated with coronary artery disease and anti-apoptotic activity of HDL.
Low high-density lipoprotein (HDL) cholesterol and loss of atheroprotective functions of HDL are associated with coronary artery disease (CAD). Here, we investigated the associations of HDL phospholipids with acute and stable CAD as well as with the anti-apoptotic activity of HDL. 49 species of phosphatidylcholines (PCs), lysophosphatidylcholines and sphingomyelins (SMs) as well as three species of sphingosine-1-phosphate (S1P) were quantified by liquid chromatography - mass spectrometry in HDL isolated from 22 healthy subjects as well as 23 and 22 patients with stable CAD and acute coronary syndrome (ACS), respectively. Native HDL and artificially reconstituted HDL (rHDL) were tested for their capacity to inhibit apoptosis of endothelial cells (ECs) induced by serum deprivation. HDL of CAD or ACS patients differed from HDL of healthy controls by the content in nine of the 52 quantified phospholipid species as well as reduced anti-apoptotic activity. The capacity of HDL to inhibit EC apoptosis correlated significantly with five of eleven odd-chain PC's (= plasmalogens), two S1P's, SM42:2, PC34:2, and PC32:0. An orthogonal partial least square - discriminant analysis revealed independent associations of stable CAD with HDL-associated PC34:2, PC33:3 and PC35:2 as well as anti-apoptotic activity of HDL and of ACS with HDL-associated PC33:3, PC35:2, SM42:1, PC34:2 and PC36:2. rHDL reconstituted with apoA-I, PC34:1, and PC35:2 inhibited apoptosis of EC's more effectively than rHDL containing only apoA-I and PC34:1. The inverse association of HDL-plasmalogen levels with both stable and acute CAD may reflect direct anti-apoptotic effects of plasmologens on ECs.


Molecular study of the rhodopsin gene in retinitis pigmentosa patients in the Basque Country.
Retinitis pigmentosa (RP) is a degenerative disorder affecting the outer segment of the retina and leading to night blindness and progressive visual field loss. The rhodopsin gene encodes a photolabile pigment located in the rod outer segments constituting around 80-90% of its protein content and is the initiation point for the visual cascade upon absorption of a single photon. Seventy-five unrelated, isolated RP families in the Basque Country, with at least one affected member, were diagnosed at our hospital after ophthalmic examination and electroretinogram analysis. The patients received genetic counselling according to their individual case based on their clinical diagnosis. The modes of inheritance found from pedigree studies were the following: 20% (15/75) were classified as autosomal dominant retinitis pigmentosa (ADRP), 17.33% (13/75) were autosomal recessive (ARRP), 2.66% (2/75) were unclassified (NC), and 60% (45/75) were sporadic cases (SCRP). From these families, 75 unrelated and affected index cases together with 22 affected relatives and 42 unaffected relatives were screened for mutations in the rhodopsin gene by GC clamped denaturing gradient gel electrophoresis. Our results showed that five ADRP, three ARRP, 15 SCRP, and one NC families had alterations in this gene. Only three of these alterations, that is 4% (3/75) (95% CL 0-8), appeared to be responsible for the disease. This represents a lower percentage than the 10% previously reported.