Continuous infusion fluorouracil in the management of advanced breast cancer: a phase II study.
The evaluation of unconventional schedules of well-known drugs represents a promising avenue in the search for new regimens with a better therapeutic index in metastatic breast cancer. In particular, protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has yielded interesting results in gastrointestinal malignancies and in breast cancer. From March 1996 30 consecutive patients with heavily pretreated breast cancer were treated with PCI 5-FU at a daily dose of 250 mg/m2 by means of disposable elastomeric pumps until progression or toxicity. The median age was 54 years (range, 28-71) and median performance status was 1 (range, 0-3). All patients but four were pretreated with anthracycline-containing regimens or taxanes; the median number of chemotherapy lines was 3 (range, 2-4). Metastatic sites were predominantly visceral in 60% of the patient population. All 30 patients were evaluable for response and toxicity. The median duration of PCI was 20 weeks (range, 2-36 weeks). Two complete responses (7%) and eight partial remissions (26%) were observed, giving an overall response rate of 33%. The median duration of response was six months (range, 4-9 months). Stabilization was observed in seven patients (23%) with a median duration of seven months (range, 3-9 months). The main toxic effects were grade I-II mucositis and hematologic toxicity, while grade 3 hand-foot syndrome was observed in eight patients (27%). This study confirms the efficacy and safety of 5-FU at this dosage and schedule in heavily pretreated women with advanced breast cancer. In order to improve on these results further studies are needed in a less advanced stage of the disease and together with other active drugs.


Effects of monosodium glutamate on apoptosis of germ cells in testicular tissue of adult rat: An experimental study.
Monosodium glutamate (MSG) is used as a flavoring and food seasoning. Some studies have reported the oxidative effects of using this substance on various tissues. This study has investigated the effects of MSG and the protective effect of vitamin C (vit C) on apoptosis of testicular germ cells and biochemical factors. In this experimental study, 24 adult male Wistar rats were randomly divided into four groups: control (received distilled water), vit C group (150 mg/kg), experimental group 1 (MSG 3 gr/kg), experimental group 2 (MSG 3 gr/kg + vit C 150 mg/kg). The rats were gavaged for 30 days, and then were sacrificed, the right testis was isolated for biochemical examinations for the glutathione, malondialdehyde, and left testis used in histological experiments. Tunnel staining was used to determine the number of apoptotic cells. The results showed that apoptotic cells in the MSG group had a significant increase compared to the control group (P = 0.001), but the number of these cells in the MSG co-administered with vit C and vit C groups were significantly lower than the MSG group. Germinal epithelial thickness also decreased in MSG group compared to the control group. MSG can lead to increase apoptotic changes in the germinal epithelial of the testicle, and vit C as an antioxidant can modify the pathological and biochemical changes induced by MSG.


Effect of tongue-hold swallow on posterior pharyngeal wall using dynamic area detector computed tomography.
The purpose of this study was to elucidate the effects of the tongue-hold swallow (THS) on the pharyngeal wall by quantifying posterior pharyngeal wall (PPW) anterior bulge during the THS. In addition, the effect of tongue protrusion length on the extent of pharyngeal wall anterior bulge was analysed. Thirteen healthy subjects (6 males and 7 females, 23-43 years) underwent 320-row area detector CT during saliva swallow (SS) and THS at two tongue protrusion lengths (THS1 protrude the tongue as much as 1/3 of premeasured maximum tongue protrusion length (MTP-L) and THS2 protrude the tongue as much as 2/3 of MTP-L). To acquire images of the pharynx at rest, single-phase volume scanning was performed three times during usual breathing with no tongue protrusion (rest), protrusion of the tongue at 1/3 of MTP-L (rTHS1) and protrusion of the tongue at 2/3 of MTP-L (rTHS2). Length from cervical spine to PPW (PPW-AP) and the volume of pharyngeal cavity was measured and was compared between rest, rTHS1 and rTHS2 and between SS, THS1 and THS2. Correlation between MTP-L and PPW-AP was calculated in three conditions, SS, THS1 and THS2. PPW-AP at rest, rTHS1 and rTHS2 was 2.9 ± 0.6 mm, 3.0 ± 0.5 mm and 3.0 ± 0.5 mm, respectively, showing no significant differences across swallows. PPW-AP at the maximum pharyngeal constriction was 8.1 ± 2.0 mm, 9.1 ± 2.4 mm and 8.7 ± 2.0 mm in SS, THS1 and THS2, respectively. Compared to SS, PPW-AP in THS1 was significantly larger (p = 0.04) and PPW-AP in THS2 was not significantly different (p = 0.09). Pharyngeal volume at rest, rTHS1 and rTHS2 was 16.4 ± 5.2 mm3 , 18.4 ± 4.5 mm3 and 21.3 ± 6.2 mm3 , respectively. It was significantly larger during rTHS2 compared with rest or rTHS1 (rTHS2-rest p = 0.007, rTHS2-rTHS1 p = 0.007). Pharyngeal volume was completely obliterated (zero volume) at maximum pharyngeal contraction in all except one subject. There was no correlation between MTP-L and PPW-AP in any of the three conditions (SS, THS1 and THS2). This study demonstrated that the expanded pharyngeal cavity due to the tongue protrusion was completely obliterated by the increase in anterior motion of pharyngeal wall during THS. It also became clear that the degree of tongue protrusion did not linearly correlate with the movement of PPW during THS. There was no relationship between PPW motion and the MTP-L, suggesting that the effect of tongue protrusion is better determined in each subject by analysing the motion of PPW using imaging tools.


Chromatin Landscape Dynamics in the Early Development of the Plant Parasitic Nematode Meloidogyne incognita.
In model organisms, epigenome dynamics underlies a plethora of biological processes. The role of epigenetic modifications in development and parasitism in nematode pests remains unknown. The root-knot nematode Meloidogyne incognita adapts rapidly to unfavorable conditions, despite its asexual reproduction. However, the mechanisms underlying this remarkable plasticity and their potential impact on gene expression remain unknown. This study provides the first insight into contribution of epigenetic mechanisms to this plasticity, by studying histone modifications in M. incognita. The distribution of five histone modifications revealed the existence of strong epigenetic signatures, similar to those found in the model nematode Caenorhabditis elegans. We investigated their impact on chromatin structure and their distribution relative to transposable elements (TE) loci. We assessed the influence of the chromatin landscape on gene expression at two developmental stages: eggs, and pre-parasitic juveniles. H3K4me3 histone modification was strongly correlated with high levels of expression for protein-coding genes implicated in stage-specific processes during M. incognita development. We provided new insights in the dynamic regulation of parasitism genes kept under histone modifications silencing. In this pioneering study, we establish a comprehensive framework for the importance of epigenetic mechanisms in the regulation of the genome expression and its stability in plant-parasitic nematodes.


Camptothecin enhances 131I-rituximab-induced G1-arrest and apoptosis in Burkitt lymphoma cells.
Rituximab is a chimeric monoclonal antibody against CD20. It is an established immunotherapeutic agent for non-Hodgkin's lymphoma. Even though rituximab has been used in clinics for decades, only 50% of the patients respond to rituximab therapy. To enhance the in vitro effect of rituximab, it was labeled with Iodine-131 (131I) and combined effect of 131I-rituximab and camptothecin (CPT) was studied on a tumor cell line expressing CD20. The aim is to study the magnitude of cell killing and the underlying mechanism responsible for enhancing in vitro therapeutic efficacy. Rituximab was labeled with 131I by the iodogen method. Raji cells were pretreated with CPT (250 nM) for an hour followed by 131I-rituximab (0.37 and 3.7 MBq) and incubated for 24 h in a humidified atmosphere of CO2 incubator at 37°C. Subsequently, Raji cells were harvested and thoroughly washed to carry out studies of cellular toxicity, apoptosis, cell cycle, and mitogen-activated protein kinase (MAPK) pathways. Maximal inhibition of cell proliferation and enhancement of apoptotic cell death was observed in the cells treated with the combination of CPT and 131I-rituximab, compared to controls of CPT-treated and 131I-rituximab-treated cells. Raji cells undergo G1 arrest after 131I-rituximab treatment, which leads to apoptosis and was confirmed by the downregulation of bclxl protein. Expression of p38 was decreased while an increase in phosphorylation of p38 was observed in the combination treatment of CPT and 131I-rituximab. It was concluded from the findings that CPT enhanced 131I-rituximab-induced apoptosis, G1 cell cycle arrest and p38 MAPK phosphorylation in Raji cells.


Cell biology of transcription and pre-mRNA splicing: nuclear architecture meets nuclear function.
Gene expression is a fundamental cellular process. The basic mechanisms involved in expression of genes have been characterized at the molecular level. A major challenge is now to uncover how transcription, RNA processing and RNA export are organized within the cell nucleus, how these processes are coordinated with each other and how nuclear architecture influences gene expression and regulation. A significant contribution has come from cell biological approaches, which combine molecular techniques with microscopy methods. These studies have revealed that the mammalian cell nucleus is a complex but highly organized organelle, which contains numerous subcompartments. I discuss here how two essential nuclear processes - transcription and pre-mRNA splicing - are spatially organized and coordinated in vivo, and how this organization might contribute to the control of gene expression. The dynamic nature of nuclear proteins and compartments indicates a high degree of plasticity in the cellular organization of nuclear functions. The cellular organization of transcription and splicing suggest that the morphology of nuclear compartments is largely determined by the activities of the nucleus.


A Novel, Highly Related Jumbo Family of Bacteriophages That Were Isolated Against Erwinia.
Erwinia amylovora is a plant pathogen from the Erwiniaceae family and a causative agent of the devastating agricultural disease fire blight. Here we characterize eight lytic bacteriophages of E. amylovora that we isolated from the Wasatch front (Utah, United States) that are highly similar to vB_EamM_Ea35-70 which was isolated in Ontario, Canada. With the genome size ranging from 271 to 275 kb, this is a novel jumbo family of bacteriophages. These jumbo bacteriophages were further characterized through genomic and proteomic comparison, mass spectrometry, host range and burst size. Their proteomes are highly unstudied, with over 200 putative proteins with no known homologs. The production of 27 of these putative proteins was confirmed by mass spectrometry analysis. These bacteriophages appear to be most similar to bacteriophages that infect Pseudomonas and Ralstonia rather than Enterobacteriales bacteria by protein similarity, however, we were only able to detect infection of Erwinia and the closely related strains of Pantoea.


Changes in the nasal mucosa of furniture workers. A pilot study.
The present study was carried out in order to evaluate whether precancerous lesions could be detected in the nasal mucosa of furniture workers. Histological examination of nasal biopsies from 113 workers (103 active and 10 retired) and 54 referents was performed. The histological sections were evaluated blindly according to a numerical classification scale, and the results were compared, by means of multiple regression analysis, to age, type and duration of exposure to wood dust, smoking habits, nasal allergy, and rhinoscopic findings. Nasal stenosis and mechanical wood preparation were significantly related to the histological findings by the partial correlation coefficients. Fourteen cases (12%) of dysplasia were found among the furniture workers, preferentially among those performing mechanical wood preparation, and among the referents there was one (2%). The evaluation of the importance of exposure to dust of individual types of wood was not possible. Nasal epithelial dysplasia should probably be interpreted as a preneoplastic lesion and may be of significance in the pathogenesis of nasal adenocarcinoma. Standard nasal biopsies appear to be valuable in identifying groups of persons with an increased incidence of nasal carcinoma.


Multiple osseous involvements in a case of disseminated cryptococcosis.
Osseous involvement occurs in 5-10% of patients with disseminated cryptococcosis. We are reporting an unusual case of disseminated cryptococcosis involving the sternum and lumbar vertebra with the formation of psoas abscess with pulmonary tuberculosis. The patient presented with fever for 3 months. A diagnosis of pulmonary tuberculosis was made on thoracic contrast-enhanced computerized tomography and she was put on antituberculosis treatment. She was immunocompetent with negative human immunodeficiency virus. She conceived subsequently and had complaints of backache and swelling over the sternum. Magnetic resonance imaging showed destruction of L5 vertebra with psoas abscess. Vertebral cryptococcosis may mimic tuberculosis and malignancy. She had a bad obstetric history and experienced five, first-trimester spontaneous abortions in each successive year since 2001. This pregnancy again resulted in spontaneous abortion. Cryptococcus neoformans was isolated from two different sites: pus-involving the sternum and ultrasound-guided psoas abscess aspirate. Serum latex agglutination test for cryptococcal capsular polysaccharide antigen was positive. The diagnosis of cryptococcosis was delayed because the patient was diagnosed as a case of pulmonary tuberculosis, wherein clinical signs, symptoms and radiological findings in both the conditions are similar. Amphotericin B was started but she developed varicella infection and expired due to cardiac failure.


Social support from family and friends as a buffer of low spousal support among mothers of critically ill children: A multilevel modeling approach.
To investigate whether social support from family and friends (family/friend support) attenuated ("buffered") adverse effects of having low spouse support (spousal support) among mothers of children undergoing hematopoietic stem cell transplantation (HSCT). One hundred sixty-three married mothers who were their child's primary caregiver during treatment completed assessments during the child's hospitalization for HSCT and 3-, 6-, and 12-months post-HSCT. Family/friend support and spousal support were assessed during hospitalization. Maternal physical and mental health-related functioning (the main outcome measures) were assessed at all timepoints. Multilevel modeling was used to analyze trajectories of maternal functioning. Findings indicated that mothers with low spousal support and low family/friend support demonstrated the worst functioning across all timepoints. Mothers with low spousal support and high family/friend support demonstrated significantly better functioning, supporting the hypothesized buffering effect. Their functioning compared to the functioning of mothers with high spousal support. Moreover, mothers with high family/friend support demonstrated trajectories of physical health-related functioning that were more stable than the trajectories of mothers with low family/friend support. These findings have clinical implications in addition to advancing knowledge of social support processes among couples coping with the shared stressor of a child's life-threatening illness and treatment.


Comparison of the upper lip bite test with measurement of thyromental distance for prediction of difficult intubations.
The upper lip bite test (ULBT) introduced in 2003 is a simple method for predicting difficult intubations. According to this test, the higher a patient can bite the upper lip with the lower incisors, the lower the risk of difficult intubation. Given the necessity for evaluation and re-evaluation of a newer predictive method, this study was conducted to compare the ULBT with another method for difficult airway prediction, the measurement of thyromental distance (TMD). In this prospective, observational, single-blind study, 350 patients who required inhaled general anesthesia with endotracheal intubation for elective surgery were enrolled for evaluation of the accuracy in predicting difficult intubation by TMD measurement and ULBT. In the ULBT, the capacity of biting the upper lip is categorized into three classes: class I, a patient is able to raise the lower incisors above the vermilion line; class II, a patient is able to bite the upper lip below the vermilion line; and class III, a patient is unable to bite the upper lip. After induction of anesthesia with a standard protocol, the patient's grade of laryngeal view by the Cormack-Lehane classification was documented by an anesthesiologist with at least 3 years' experience who was unaware of prior evaluations. A TMD equal to or less than 4 cm and a class III ULBT were considered to be predictive of difficult intubation. A Cormack-Lehane class III or IV was considered a difficult intubation. Only 20 (5.7%) of the patients were considered to have difficult intubations. Sensitivity, specificity, positive and negative predictive values, and accuracy were 70%, 93.3%, 39%, 98.1%, and 92.6%, respectively, for the ULBT, and 55%, 88%, 22%, 97%, and 86.3%, respectively, for TMD. Specificity and positive predictive value were found to be significantly higher for the ULBT than for TMD (p < 0.05). The sensitivity, negative predictive value, and accuracy were not significantly different between the two methods. The findings suggest that the sensitivity of the ULBT and TMD for predicting difficult intubations may not be significantly different, but the specificity of the ULBT is significantly higher. The positive predictive value of the ULBT was significantly higher than that of TMD, signifying that a positive ULBT is more predictive of a difficult airway than is a positive TMD.


Genetic Diversity and Conservation Status of Helianthus verticillatus, an Endangered Sunflower of the Southern United States.
Evaluating species diversity and patterns of population genetic variation is an essential aspect of conservation biology to determine appropriate management strategies and preserve the biodiversity of native plants. Habitat fragmentation and potential habitat loss are often an outcome of a reduction in naturally occurring wildfires and controlled prescribed burning, as seen in Helianthus verticillatus (whorled sunflower). This endangered, wild relative of the common sunflower, Helianthus annuus, is endemic to four locations in Alabama, Georgia, and Tennessee, United States. Despite its endangered status, there is no recovery plan for H. verticillatus, and knowledge related to its basic plant biology and importance in ecosystem services is mostly unknown. In this study, we utilized 14 microsatellite loci to investigate fine-scale population structure and genetic diversity of H. verticillatus individuals found on two sampling sites within the Georgia population. Our results indicated moderate genetic diversity and the presence of two distinct genetic clusters. Analyses of molecular variance indicated that the majority of variance was individually based, thus confirming high genetic differentiation and limited gene flow between H. verticillatus collection sites. The evidence of a population bottleneck in these sites suggests a recent reduction in population size that could be explained by habitat loss and population fragmentation. Also, high levels of linkage disequilibrium were detected, putatively suggesting clonal reproduction among these individuals. Our study provides a better understanding of fine-scale genetic diversity and spatial distribution of H. verticillatus populations in Georgia. Our results can underpin an original recovery plan for H. verticillatus that could be utilized for the conservation of this endangered species and to promote its persistence in the wild.


Investigating Biochemical and Developmental Dependencies of Lignification with a Click-Compatible Monolignol Analog in Arabidopsis thaliana Stems.
Lignin is a key structural component of plant cell walls that provides rigidity, strength, and resistance against microbial attacks. This hydrophobic polymer also serves a crucial role in water transport. Despite its abundance and essential functions, several aspects of lignin biosynthesis and deposition remain cryptic. Lignin precursors are known to be synthesized in the cytoplasm by complex biosynthetic pathways, after which they are transported to the apoplastic space, where they are polymerized via free radical coupling reactions into polymeric lignin. However, the lignin deposition process and the factors controlling it are unclear. In this study, the biochemical and developmental dependencies of lignification were investigated using a click-compatible monolignol analog, 3-O-propargylcaffeyl alcohol (3-OPC), which can incorporate into both in vitro polymerized lignin and Arabidopsis thaliana tissues. Fluorescence labeling of 3-OPC using click chemistry followed by confocal fluorescence microscopy enabled the detection and imaging of 3-OPC incorporation patterns. These patterns were consistent with endogenous lignification observed in different developmental stages of Arabidopsis stems. However, the concentration of supplied monolignols influenced where lignification occurred at the subcellular level, with low concentrations being deposited in cell corners and middle lamellae and high concentrations also being deposited in secondary walls. Experimental inhibition of multiple lignification factors confirmed that 3-OPC incorporation proceeds via a free radical coupling mechanism involving peroxidases/laccases and reactive oxygen species (ROS). Finally, the presence of peroxide-producing enzymes determined which cell walls lignified: adding exogenous peroxide and peroxidase caused cells that do not naturally lignify in Arabidopsis stems to lignify. In summary, 3-OPC accurately mimics natural lignification patterns in different developmental stages of Arabidopsis stems and allows for the dissection of key biochemical and enzymatic factors controlling lignification.


The role of public biological resource centers in providing a basic infrastructure for microbial research.
Public collections of microorganisms have been established since the late 19th century, and currently 573 service collections are registered at the World Data Center for Microorganisms (www.wdcm.org). All together, they hold more than 1.5 million microorganisms. By implementing guidelines compiled by the Organisation for Economic Co-operation and Development (OECD), many public service collections evolve into professional ex situ repositories of biodiversity and distribution nodes for known, validated and precisely identified microbial resources and associated information to legitimate end-users. These Biological Resource Centers (BRCs) may be the preferred mechanism for the appropriate exploitation of microbial resources by offering the guarantee of accessibility and of transparency of supply, taking into account all relevant regulations and stakeholders' rights, as required by the Convention on Biological Diversity (CBD). Scientists are encouraged to deposit researched microbial material at public BRCs to contribute to the Science (semi-) Commons and maximize the impact of prior knowledge. BRCs are essential infrastructures supporting the future of life sciences and biotechnology.


Indications for bilateral modified radical neck dissection in patients with papillary carcinoma of the thyroid.
After subtotal thyroidectomy with modified radical neck dissection of the affected side, nodal recurrence at the contralateral cervical side indicates a poor prognosis for patients with papillary thyroid cancer. Bilateral modified radical neck dissection is beneficial for patients at high risk for contralateral nodal recurrence. Retrospective study of patients with papillary cancer who were treated surgically from January 1, 1970, through December 31, 1995, at the Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan. Patients (N = 1776) had primary tumors greater than 10 mm in maximum diameter and underwent thyroidectomy and ipsilateral modified radical neck dissection with curative intent. Thirty-two patients (1.8%) developed contralateral lymph node metastases during the mean follow-up period of 12.1 years. The risk factors for contralateral nodal recurrence were male sex, large primary tumor, tumor extension over the isthmus, extracapsular adhesion or invasion to surrounding tissues, and the presence of gross nodal metastasis at initial surgery. These patients had a greater number of distant metastases (31.1% vs 0.7%; P<.001) and a lower 10-year survival rate (83.7% vs 99.3%; P<.001) than patients without nodal recurrence. Bilateral modified radical neck dissection should be considered for patients with papillary carcinoma who show risk factors for contralateral nodal recurrence, as it could prevent a second operation and may improve their outcome.


Effects of α-tocopherol on bone marrow mesenchymal cells derived from type II diabetes mellitus rats.
It is widely accepted that vitamin E (VE) acts as an antioxidant and is involved in various metabolic systems including the regulation of gene expression and inhibition of cell proliferation. The most predominant isoform of VE in the living body is α-tocopherol. However, the influence of α-tocopherol on bone marrow mesenchymal cells (BMMCs) in a background of type II diabetes mellitus (DM) has not been investigated. The focus of the present study was to clarify the effect of α-tocopherol on BMMCs derived from rats with type II DM and the underlying mechanisms involved. BMMCs were isolated from rats with type II DM. The BMMCs were either untreated or exposed to α-tocopherol at concentrations of 1.0, 10, and 100 μM, and the resulting effects of α-tocopherol on cell proliferation, H2O2 activity, and antioxidant and inflammatory cytokine production were examined. At 100 μM, α-tocopherol had no effect on cell proliferation, but H2O2 activity was significantly increased. At 10 μM, α-tocopherol increased the gene expression of IL-1β, and markedly promoted that of TNF-α. Expression of catalase in the presence of 100 μM α-tocopherol was lower than for the other concentrations. At a low concentration, α-tocopherol exerted good antioxidant and anti-inflammatory effects on BMMCs. The study suggests that maintaining α-tocopherol at a low concentration might promote the recovery of BMMCs from oxidative stress.


Ocean Wind Observation Based on the Mean Square Slope Using a Self-Developed Miniature Wave Buoy.
Real-time, continuous, and long-term marine monitoring data benefits ocean research. This study developed a low-cost, multi-parameter, miniature wave buoy. High spatial and temporal resolution of sea surface parameters, including wind, waves, and current, can be obtained at low cost through the deployment of numerous buoys, thus forming an observation array. Tested in the laboratory water tank, the relative error of water surface slope measurement of the buoy was approximately 5.6% when the slope angle was less than 15°. For frequencies between 0.1 and 1.0 Hz, the measurement of slope spectrum was almost identical to that of the wave gauge. The buoy underestimated the slope spectrum between 1.0−1.56 Hz. A good relationship (r2 = 0.75) was obtained between wind speed at 10 m above sea surface (U10) and the low-pass-filtered mean square slope (LPMSS). After incorporating the wave age into the U10 inversion process, the root mean square error (RMSE) and BIAS were reduced to 1.15 m/s and 0.02 m/s, respectively. The 2D distribution of buoy-measured slope components was used to detect the wind direction, with an RMSE of 23.7°. The spectral tail slope steepened with increasing wind speed at low wind speeds (<7 m/s). A technical flow chart of the miniature wave buoy is proposed to observe the sea surface parameters. This miniature buoy will play an essential complementary role in the growing demand for sea state monitoring, especially in nearshore oceans.


Saccharomyces cerevisiae engineered to produce D-xylonate.
Saccharomyces cerevisiae was engineered to produce D-xylonate by introducing the Trichoderma reesei xyd1 gene, encoding a D-xylose dehydrogenase. D-xylonate was not toxic to S. cerevisiae, and the cells were able to export D-xylonate produced in the cytoplasm to the supernatant. Up to 3.8 g of D-xylonate per litre, at rates of 25-36 mg of D-xylonate per litre per hour, was produced. Up to 4.8 g of xylitol per litre was also produced. The yield of D-xylonate from D-xylose was approximately 0.4 g of D-xylonate per gramme of D-xylose consumed. Deletion of the aldose reductase encoding gene GRE3 in S. cerevisiae strains expressing xyd1 reduced xylitol production by 67%, increasing the yield of D-xylonate from D-xylose. However, D-xylose uptake was reduced compared to strains containing GRE3, and the total amount of D-xylonate produced was reduced. To determine whether the co-factor NADP+ was limiting for D-xylonate production the Escherichia coli transhydrogenase encoded by udhA, the Bacillus subtilis glyceraldehyde 3-phosphate dehydrogenase encoded by gapB or the S. cerevisiae glutamate dehydrogenase encoded by GDH2 was co-expressed with xyd1 in the parent and GRE3 deficient strains. Although each of these enzymes enhanced NADPH consumption on D-glucose, they did not enhance D-xylonate production, suggesting that NADP+ was not the main limitation in the current D-xylonate producing strains.


Temporal updating scheme for probabilistic neural network with application to satellite cloud classification.
In cloud classification from satellite imagery, temporal change in the images is one of the main factors that causes degradation in the classifier performance. In this paper, a novel temporal updating approach is developed for probabilistic neural network (PNN) classifiers that can be used to track temporal changes in a sequence of images. This is done by utilizing the temporal contextual information and adjusting the PNN to adapt to such changes. Whenever a new set of images arrives, an initial classification is first performed using the PNN updated up to the last frame while at the same time, a prediction using Markov chain models is also made based on the classification results of the previous frame. The results of both the old PNN and the predictor are then compared. Depending on the outcome, either a supervised or an unsupervised updating scheme is used to update the PNN classifier. Maximum likelihood (ML) criterion is adopted in both the training and updating schemes. The proposed scheme is examined on both a simulated data set and the Geostationary Operational Environmental Satellite (GOES) 8 satellite cloud imagery data. These results indicate the improvements in the classification accuracy when the proposed scheme is used.


Hepatitis C virus seropositivity at the time of renal transplantation in the United States: associated factors and patient survival.
National statistics for patient characteristics and survival of renal transplant recipients positive for hepatitis C virus (HCV+) at the time of renal transplant are presented. A historical cohort analysis of 33479 renal transplant recipients in the United States Renal Data System from 1 July, 1994 to 30 June, 1997 has been carried out. The medical evidence form was also used for additional variables, but because of fewer available values, this was analyzed in a separate model. Outcomes were patient characteristics and survival associated with HCV+. Of 28692 recipients with valid HCV serologies, 1624 were HCV+ at transplant (5.7% prevalence). In logistic regression analysis, HCV+ was associated with African-American race, male gender, cadaveric donor type, increased duration of pre-transplant dialysis, previous transplant, donor HCV+, recipient (but not donor) age, serum albumin, alcohol use, and increased all-cause hospitalizations. Diabetes and IgA nephropathy were less associated with HCV+. Total all-cause, unadjusted mortality was 13.1% in HCV+ vs. 8.5% in HCV- patients (p <0.01 by log rank test). In Cox regression, mortality was higher for HCV+ (adjusted hazard ratio = 1.23, 95% confidence interval = 1.01-1.49, p = 0.04). HCV+ recipients were more likely to be African-American, male, older, and to have received repeat transplants and donor HCV+ transplants. HCV+ recipients also had substantially longer waiting times for transplant. In contrast to recent studies, diabetes did not have an increased association with HCV+, perhaps due to limitations of the database. HCV+ recipients had increased mortality and hospitalization rates compared with other transplant recipients.


N-Linked glycosylation of a baculovirus-expressed recombinant glycoprotein in insect larvae and tissue culture cells.
The potential of insect cell cultures and larvae infected with recombinant baculoviruses to produce authentic recombinant glycoproteins cloned from mammalian sources was investigated. A comparison was made of the N-linked glycans attached to secreted alkaline phosphatase (SEAP) produced in four species of insect larvae and their derived cell lines plus one additional insect cell line and larvae of one additional species. These data survey N-linked oligosaccharides produced in four families and six genera of the order Lepidoptera. Recombinant SEAP expressed by recombinant isolates of Autographa californica and Bombyx mori nucleopolyhedroviruses was purified from cell culture medium, larval hemolymph or larval homogenates by phosphate affinity chromatography. The N-linked oligosaccharides were released with PNGase-F, labeled with 8-aminonaphthalene-1-3-6-trisulfonic acid, fractionated by polyacrylamide gel electrophoresis, and analyzed by fluorescence imaging. The oligosaccharide structures were confirmed with exoglycosidase digestions. Recombinant SEAP produced in cell lines of Lymantria dispar (IPLB-LdEIta), Heliothis virescens (IPLB-HvT1), and Bombyx mori (BmN) and larvae of Spodoptera frugiperda, Trichoplusia ni , H.virescens , B.mori , and Danaus plexippus contained oligosaccharides that were structurally identical to the 10 oligosaccharides attached to SEAP produced in T.ni cell lines. The oligosaccharide structures were all mannose-terminated. Structures containing two or three mannose residues, with and without core fucosylation, constituted more than 75% of the oligosaccharides from the cell culture and larval samples.


Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics.
Higher rates of sepsis have been reported in minorities. To explore racial differences in the incidence and associated case fatality of severe sepsis, accounting for clinical, social, health care service delivery, and geographic characteristics. Retrospective population-based cohort study using hospital discharge and U.S. Census data for all persons (n = 71,102,655) living in 68 hospital referral regions in six states. Age-, sex- and race-standardized severe sepsis incidence and inpatient case fatality rates, adjusted incidence rate ratios, and adjusted intensive care unit (ICU) admission and case fatality rate differences. Of 8,938,111 nonfederal hospitalizations, 282,292 had severe sepsis. Overall, blacks had the highest age- and sex-standardized population-based incidence (6.08/1,000 vs. 4.06/1,000 for Hispanics and 3.58/1,000 for whites) and ICU case fatality (32.1 vs. 30.4% for Hispanics and 29.3% for whites, P < 0.0001). Adjusting for differences in poverty in their region of residence, blacks still had a higher population-based incidence of severe sepsis (adjusted rate ratio, 1.44 [95% CI, 1.42-1.46]) than whites, but Hispanics had a lower incidence (adjusted rate ratio, 0.91 [0.90-0.92]). Among patients with severe sepsis admitted to the ICU, adjustments for clinical characteristics and the treating hospital fully explained blacks' higher ICU case fatality. Higher adjusted black incidence and the lower Hispanic incidence may reflect residual confounding, or it could signal biologic differences in susceptibility. Focused interventions to improve processes and outcomes of care at the hospitals that disproportionately treat blacks could narrow disparities in overall mortality from severe sepsis.


Effect of moisture content on radon emanation from uranium ore and tailings.
A study was made of the effect of moisture on the emanation coefficient and radon flux from uranium mill tailings. A sharp rise in emanation coefficient occurred as the moisture content was increased from the absolutely dry state to 2% water by weight. The emanation coefficients from water-saturated tailings were about four times those from absolutely dry materials. Radon flux was measured from columns of dry, moist and water-saturated tailings. The highest flux came from the column filled with moist tailings. This can be explained by the effect of moisture content on the emanation coefficient. Water-saturated tailings gave the lowest flux because of the much lower diffusion coefficient of radon through water.


Down-regulation of SP1 DNA binding activity in the process of radiation-induced pulmonary fibrosis.
To determine changes in the expression and function of the transcription factor SP1 in radiation-induced pulmonary fibrosis. The right lungs of female Fischer rats were irradiated with a fibrogenic single dose of 20 Gy gamma-irradiation. SP1 mRNA and protein expression was determined by Northern and Western blotting, respectively, between 30 min and 12 weeks after irradiation. Cellular localization of SP1 protein was characterized by immunohistochemistry (peroxidase labelling). SP1 DNA binding activity was studied with electrophoretic mobility shift assays (EMSA). Eight weeks after irradiation, pulmonary fibrosis was first observed. SP1 DNA binding activity showed a short-term increase from 30 min to 12 h after irradiation. Thereafter it remained quite stable until 1 month after irradiation. However, 2 months after irradiation, SP1 DNA binding activity was no longer detectable. The SP1 mRNA level was not reduced at this time, nor was there a reduction in its size. However, Western blotting revealed the occurrence of at least two slightly smaller additional bands 2 months after irradiation whereas the original SP1 band vanished. This suggests a degradation event of SP1 taking place near one or both ends of the protein. Most of the SP1 protein was found in type II pneumocytes and alveolar macrophages of the normal and fibrotic lung. Bronchial epithelial cells were also positive. In the fibrotic lung, proliferating fibroblasts also become positive. The functional knockout of the transcription factor SP1, in the process of irradiation-induced pulmonary fibrosis, is demonstrated. This should help elucidate the severe disturbances in transcriptional regulation, cellular proliferation and differentiation occurring in the lung at long intervals after irradiation.


Physiological responses to starvation in the marine oligotrophic ultramicrobacterium Sphingomonas sp. strain RB2256.
Sphingomonas sp. strain RB2256 is representative of the ultramicrobacteria that proliferate in oligotrophic marine waters. While this class of bacteria is well adapted for growth with low concentrations of nutrients, their ability to respond to complete nutrient deprivation has not previously been investigated. In this study, we examined two-dimensional protein profiles for logarithmic and stationary-phase cells and found that protein spot intensity was regulated by up to 70-fold. A total of 72 and 177 spots showed increased or decreased intensity, respectively, by at least twofold during starvation. The large number of protein spots (1,500) relative to the small genome size (ca. 1.5 Mb) indicates that gene expression may involve co- and posttranslational modifications of proteins. Rates of protein and RNA synthesis were examined throughout the growth phase and up to 7 days of starvation and revealed that synthesis was highly regulated. Rates of protein synthesis and cellular protein content were compared to ribosome content, demonstrating that ribosome synthesis was not directly linked to protein synthesis and that the function of ribosomes may not be limited to translation. By comparing the genetic capacity and physiological responses to starvation of RB2256 to those of the copiotrophic marine bacterium Vibrio angustum S14 (J. Ostling, L. Holmquist, and S. Kjelleberg, J. Bacteriol. 178:4901-4908, 1996), the characteristics of a distinct starvation response were defined for Sphingomonas strain RB2256. The capacity of this ultramicrobacterium to respond to starvation is discussed in terms of the ecological relevance of complete nutrient deprivation in an oligotrophic marine environment. These studies provide the first evidence that marine oligotrophic ultramicrobacteria may be expected to include a starvation response and the capacity for a high degree of gene regulation.


Selection of DNA aptamers for capture and detection of Salmonella Typhimurium using a whole-cell SELEX approach in conjunction with cell sorting.
Alternative ligands such as nucleic acid aptamers can be used for pathogen capture and detection and offer advantages over antibodies, including reduced cost, ease of production and modification, and improved stability. DNA aptamers demonstrating binding specificity to Salmonella enterica serovar Typhimurium were identified by whole-cell-systematic evolution of ligands by exponential enrichment (SELEX) beginning with a combinatorial library of biotin-labeled single stranded DNA molecules. Aptamer specificity was achieved using whole-cell counter-SELEX against select non-Salmonella genera. Aptamers binding to Salmonella were sorted, cloned, sequenced, and characterized for binding efficiency. Out of 18 candidate aptamers screened, aptamer S8-7 showed relatively high binding affinity with an apparent dissociation constant (K d value) of 1.73 ± 0.54 μM and was selected for further characterization. Binding exclusivity analysis of S8-7 showed low apparent cross-reactivity with other foodborne bacteria including Escherichia coli O157: H7 and Citrobacter braakii and moderate cross-reactivity with Bacillus cereus. Aptamer S8-7 was successfully used as a ligand for magnetic capture of serially diluted Salmonella Typhimurium cells, followed by downstream detection using qPCR. The lower limit of detection of the aptamer magnetic capture-qPCR assay was 10(2)-10(3) CFU equivalents of Salmonella Typhimurium in a 290-μl sample volume. Mean capture efficiency ranged from 3.6 to 12.6 %. Unique aspects of the study included (a) the use of SELEX targeting whole cells; (b) the application of flow cytometry for aptamer pool selection, thereby favoring purification of ligands with both high binding affinity and targeting abundant cell surface moieties; and (c) the use of pre-labeled primers that circumvented the need for post-selection ligand labeling. Taken together, this study provides proof-of-concept that biotinylated aptamers selected by whole-cell SELEX can be used in a qPCR-based capture-detection platform for Salmonella Typhimurium.


Age differences in the perception of goal structure in everyday activity.
Human activity is structured by goals and subgoals. To understand an everyday activity, a viewer must perceive its goal structure, and viewers may segment activity into units that correspond to perceived goals. In this study, we examined age differences in the ability to perceive hierarchical goal structure in ongoing activity. A group of younger and older adults viewed short movies of an actor doing everyday activities, segmented them into events, and described the events as they segmented. We investigated how participants' event descriptions were related to the hierarchical goal structure, and whether participants' event segmentation was related to moment-by-moment changes in actor goals. We found that both coarse and fine event segmentation behavior was related to changes in the goal hierarchy. Descriptions of coarse-grained events were more likely to contain information about higher level goals, and descriptions of fine-grained events were more likely to mention lower level goals. Critically, in both segmentation behavior and event descriptions, younger adults showed these effects more strongly than older adults. These results show that event segmentation recovers the hierarchical goal structure of events, and that older adults may have difficulty perceiving that structure. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The association between thromboelastographic parameters and total estimated blood loss in patients undergoing elective cesarean delivery.
In this study, we assessed the relationship between coagulation parameters using kaolin-activated thromboelastography (TEG®) and total estimated blood loss (EBL) in patients undergoing elective cesarean delivery (CD). TEG® parameters were recorded in 52 patients before and after elective CD. Laboratory markers of coagulation (prothrombin time, activated partial thromboplastin time, fibrinogen) were also assessed in a smaller subset (21 patients). Correlation and linear regression analysis was used to assess the relationship among TEG® parameters, relevant clinical variables, and total EBL. Secondary analysis included comparisons of TEG® and coagulation profiles pre-CD versus post-CD. EBL weakly correlated with percentage change in maximum amplitude (r=0.3; P=0.04) and post-CD maximum rate of thrombus generation (r=0.31; P=0.02). Post-CD values for split point, reaction time, time to maximum rate of thrombin generation, prothrombin time, and activated partial thromboplastin time were significantly increased compared with baseline values (P<0.05). Post-CD α angle, maximum amplitude, total thrombus generation, fibrinogen, and platelet counts were significantly decreased compared with baseline values (P<0.05). There is a weak association between clot strength (as assessed by kaolin-activated TEG®) and EBL in patients undergoing elective CD under neuraxial anesthesia, and a modest reduction in the degree of maternal hypercoagulability occurs in the early postpartum period after elective CD.


The Use of SP/Neurokinin-1 as a Therapeutic Target in Colon and Rectal Cancer.
Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation, proliferation, and migration as well as angiogenesis and metastasis of a wide range of solid tumors including colorectal cancer. Until now, the selective high-affinity antagonist of human SP/NK1-R aprepitant (Emend) has been authorized by the Food and Drug Administration as a low dosage medication to manage and treat chemotherapy-induced nausea. However, increasing evidence in recent years support the potential utility of high doses of aprepitant as an antitumor agent and thus, opening the possibility to the pharmacological repositioning of SP/NK1-R antagonists as an adjuvant therapy to conventional cancer treatments. In this review, we summarize current knowledge on the molecular basis of colorectal cancer as well as the pathophysiological importance of SP/NK1-R and the potential utility of SP/NK-1R axis as a therapeutic target in this malignancy.


Sequential assembly of myosin II, an IQGAP-like protein, and filamentous actin to a ring structure involved in budding yeast cytokinesis.
We have identified a Saccharomyces cerevisiae protein, Cyk1p, that exhibits sequence similarity to the mammalian IQGAPs. Gene disruption of Cyk1p results in a failure in cytokinesis without affecting other events in the cell cycle. Cyk1p is diffused throughout most of the cell cycle but localizes to a ring structure at the mother-bud junction after the initiation of anaphase. This ring contains filamentous actin and Myo1p, a myosin II homologue. In vivo observation with green fluorescent protein-tagged Myo1p showed that the ring decreases drastically in size during cell division and therefore may be contractile. These results indicate that cytokinesis in budding yeast is likely to involve an actomyosin-based contractile ring. The assembly of this ring occurs in temporally distinct steps: Myo1p localizes to a ring that overlaps the septins at the G1-S transition slightly before bud emergence; Cyk1p and actin then accumulate in this ring after the activation of the Cdc15 pathway late in mitosis. The localization of myosin is abolished by a mutation in Cdc12p, implicating a role for the septin filaments in the assembly of the actomyosin ring. The accumulation of actin in the cytokinetic ring was not observed in cells depleted of Cyk1p, suggesting that Cyk1p plays a role in the recruitment of actin filaments, perhaps through a filament-binding activity similar to that demonstrated for mammalian IQGAPs.


Access to Mammography Facilities and Detection of Breast Cancer by Screening Mammography: A GIS Approach.
OBJECTIVES: The objective of the study was to examine the association between access to mammography facilities and utilization of screening mammography in an urban population. METHODS: Data on female breast cancer cases were obtained from an extensive mammography surveillance project. Distance to mammography facilities was measured by using GIS, which was followed by measuring geographical access to mammography facilities using Floating Catchment Area (FCA) method (considering all available facilities within an arbitrary radius from the woman's residence by using Arc GIS 9.0 software). RESULTS: Of 2,024 women, 91.4% were Caucasian; age ranged from 25 to 98 years; most (95%) were non-Hispanic in origin. Logistic regression found age, family history, hormone replacement therapy, physician recommendation, and breast cancer stage at diagnosis to be significant predictors of having had a previous mammogram. Women having higher access to mammography facilities were less likely to have had a previous mammogram compared to women who had low access, considering all the facilities within 10 miles (OR=0.41, CI=0.22-0.76), 30 miles (OR=0.52, CI=0.29-0.91) and 40 miles (OR=0.51, CI=0.28-0.92) radiuses. CONCLUSIONS: Physical distance to mammography facilities does not necessarily predict utilization of mammogram and greater access does not assure greater utilizations, due to constraints imposed by socio economic and cultural barriers. Future studies should focus on measuring access to mammography facilities capturing a broader dimension of access considering qualitative aspect of facilities, as well as other travel impedances.


Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.
Weight regain after weight loss is a major problem in the treatment of persons with obesity. In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).


Analytical modeling of glucose biosensors based on carbon nanotubes.
In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.


Alveolar bone resorption after primary tooth loss has a negative impact on straightforward implant installation in patients with agenesis of the lower second premolar.
To compare the alveolar bone dimensions in patients with lower second premolar (P2) agenesis prior to and after primary molar loss on CT scans, and assess the possibility for straightforward implant placement. Alveolar bone dimensions were evaluated on 150 mandibular CT scans in three groups: (i) agenesis of P2, with the primary tooth in situ, and regularly erupted first premolar (P1) and molar (M1) (AW); (ii) agenesis of P2, without the primary tooth in situ for ≥3 m, but regularly erupted P1 and M1 (AWO); and (iii) P1, P2, and M1 regularly erupted (CTR). The possibility of straightforward placement of an implant 3.5 or 4.3 mm in Ø × 10 mm long was digitally simulated and compared to the actually performed treatment. Buccolingual width (7.3 ± 2.0 mm) at the coronal aspect of the ridge in the AWO group was statistically significantly smaller comparing with both the AW (9.2 ± 1.4 mm) and the CTR (9.5 ± 1.1 mm) group; width reduction appeared to be mainly due to "collapse" of the buccal aspect of the ridge. Simulated straightforward placement of implants with a diameter of 3.5 or 4.3 mm was possible in 62% and 56% of the cases in the AWO vs. 86% and 84% in the AW group (p = .006 and .002, respectively). Straightforward implant placement was actually possible in all patients (22) in the AW group, while 28% (11 of 39) of the patients in the AWO group needed additional hard tissue augmentation. Significant dimensional differences exist in the alveolar ridge, especially in the coronal part, at lower P2 agenesis sites missing the primary tooth for ≥3 m, when compared to P2 agenesis sites with the primary tooth in situ. It seems thus reasonable to advise that the primary second molar should be kept as long as possible, in order to facilitate straightforward implant installation and reduce the probability of additional bone augmentation procedures.


Treatment of late-stage Sézary syndrome with 2-Chlorodeoxyadenosine.
2-Chlorodeoxyadenosine (2-CdA), a purine adenosine analog, is safe and effective chemotherapy for patients with hairy cell leukemia and low-grade lymphomas. Adverse effects include neutropenia, lymphocytopenia, and infectious complications. Our objective was to evaluate the efficacy of 2-CdA (2-6 seven-day cycles) in the treatment of late-stage, recalcitrant Sézary syndrome. Retrospective review of medical records of six patients with Sézary syndrome who had received 2-CdA cycles at Mayo Clinic, Rochester between March 1995 and March 2000. Variables assessed from the records included improvement in global appearance, extent of erythroderma, size of lymph nodes, pruritus, and leukocyte, lymphocyte, and absolute Sézary cell counts. Two patients, both with stage III Sézary syndrome, whose previous treatment consisted of only two modalities, responded well to the treatment, with moderate to total clearing of erythroderma and pruritus associated with a significant decrease in Sézary cell counts. The other four patients had only a partial response (one patient) or no response (three patients) to 2-CdA. The mortality rate was 50%. All three patients died of Staphylococcus aureus sepsis. However, only one patient was receiving 2-CdA treatment when he died. The other two patients died 8 and 9 weeks after the last 2-CdA cycle. This high mortality rate is attributed to infectious complications after 2-CdA treatment in patients with recalcitrant disease. 2-Chlorodeoxyadenosine shows efficacy in stage III Sézary syndrome, but it also carries a substantial risk of septic complications and mortality. It can be used if no other suitable alternatives are available. Caution should be exercised in all these patients regarding skin care and avoidance of infections or sepsis.


Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-beta receptors.
TGF-beta is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-beta to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-beta superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-beta1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-beta1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-beta receptors (TGF-beta RI). Moreover, BMP-2 significantly shortened the half-life of TGF-beta RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-beta RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-beta RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-beta. We demonstrated that BMP-2 significantly reversed the TGF-beta1-induced increase in pSmad2/3 and reversed the TGF-beta1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-beta RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson's trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-beta RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-beta RI and Smads.


Risk factors influencing survival in acute renal failure treated by hemodialysis.
A retrospective analysis of 58 patients with acute renal failure treated by hemodialysis between 1980 and 1984 was carried out to study mortality and the risk factors that might adversely influence survival. Twenty-six factors, suggested by published data to be relevant to the short-term prognosis of such patients, were evaluated by univariate analysis. Survivors were found to be significantly younger, they were less frequently malnourished or jaundiced, and fewer required inotropic drugs (due to hypotension) or ventilator support after the first week of their illness. Sepsis, heart failure, central nervous system depression, and a greater number of the above complications were characteristic in the nonsurvivors. Multivariate analysis suggests that the probability of survival could be estimated by taking into account three of these factors: age, central nervous system depression, and hypotension. Further studies would be appropriate to test the predictive value of such a probability equation.


Normal values in ambulatory oesophageal pH monitoring at two levels in Spain.
Upper oesophageal pH monitoring may play a significant role in the study of extra-oesophageal GERD, but limited normal data are available to date. Our aim was to develop a large series of normal values of proximal oesophageal acidification. 155 healthy volunteers (74 male) participated in a multi-centre national study including oesophageal manometry and 24 hours oesophageal pH monitoring using two electrodes individually located 5 cm above the LOS and 3 cm below the UOS. 130 participants with normal manometry completed all the study. Twelve of them were excluded for inadequate pH tests. Twenty-seven subjects had abnormal conventional pH. The remaining 91 subjects (37 M; 18-72 yrs age range) formed the reference group for normality. At the level of the upper oesophagus, the 95th percentile of the total number of reflux events was 30, after eliminating the meal periods 22, and after eliminating also the pseudo-reflux events 18. Duration of the longest episodes was 5, 4 and 4 min, respectively (3.5 min in upright and 0.5 min in supine). The upper limit for the percentage of acid exposure time was 1.35, 1.05 and 0.95%, respectively. No reflux events were recorded in the upper oesophagus in 8 cases. This is the largest series of normal values of proximal oesophageal reflux that confirm the existence of acid reflux at that level in healthy subjects, in small quantity and unrelated to age or gender. Our data support the convenience of excluding pseudo-reflux events and meal periods from analysis.


Excision of the Tol2 transposable element of the medaka fish Oryzias latipes in Xenopus laevis and Xenopus tropicalis.
The Tol2 transposable element from the medaka fish belong to the hAT family of transposons. In the previous studies, we have identified an autonomous member of this element, which encodes a fully functional transposase, and have shown that it can catalyze transposition in the zebrafish germ lineage. To date, the Tol2 element is the only natural transposon in vertebrates from which an autonomous member has been identified. We report here transposase-dependent excision of the Tol2 element in Xenopus laevis and Xenopus (Silurana) tropicalis embryos. We coinjected a plasmid DNA containing a nonautonomous Tol2 element and the transposase mRNA synthesized in vitro into two-cell-stage embryos, and analyzed DNA extracted from the injected embryos by polymerase chain reaction (PCR). We demonstrated that the Tol2 element could be excised from the plasmid DNA in both X. laevis and X. tropicalis only when it was coinjected with the transposase mRNA. In most cases, a complete loss of the Tol2 sequence was accompanied by addition of a short DNA sequence to the target sequence, indicating that transposase-dependent excision occurred. While these footprints were characteristic to those created upon excision of transposons of the hAT family, the additional bases found in Xenopus were longer and their structures were more complicated than those detected upon excision in zebrafish. This may reflect differences in the activities of host factors involved in either transposition, repair, or both between fish and frog. Our present study suggests that the Tol2 transposon system should be used as a novel genetic tool to develop transgenesis and mutagenesis methods in Xenopus.


Treatment of Patients With Atrial Fibrillation and Heart Failure With Reduced Ejection Fraction.
Atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) frequently coexist, and each complicates the course and treatment of the other. Recent population-based studies have demonstrated that the 2 conditions together increase the risk of stroke, heart failure hospitalization, and all-cause mortality, especially soon after the clinical onset of AF. Guideline-directed pharmacological therapy for HFrEF is important; however, although there are various treatment modalities for AF, there is no clear consensus on how best to treat AF with concomitant HFrEF. This in-depth review discusses the available data for the treatment of AF in the setting of HFrEF, focuses on areas where more investigation is necessary, examines the clinical implications of randomized and observational clinical trials, and presents suggestions for individualized treatment strategies for specific patient groups.


Bedside diagnosis of influenzavirus infections in hospitalized children.
For preventing nosocomial influenza infections and to facilitate prompt antiviral therapy, an accessible, rapid diagnostic method for influenzavirus is needed. We evaluated the performance of a lateral-flow immunoassay (QuickVue Influenza Test) completed at the bedside of hospitalized children during the influenza season. All children who were evaluated at a large teaching hospital during the 1999 to 2000 influenza season were eligible if they were 1) younger than 19 years and hospitalized with respiratory symptoms or 2) younger than 3 years and hospitalized with fever. Each study child had 2 nasal swabs obtained--1 for influenzavirus culture and polymerase chain reaction (PCR) and the other for the QuickVue Influenza Test. The performance of the rapid diagnostic test was compared with the results of culture or PCR for influenza A or B. Of 303 eligible children, 233 (77%) were enrolled. In this population, 19 children had culture- and/or PCR-confirmed influenza A infection, prevalence of 8%. The QuickVue Influenza Test had a sensitivity of 74%, specificity of 98%, positive predictive value of 74%, and negative predictive value of 98%. Among children hospitalized with fever/respiratory symptoms during the influenza season, negative bedside QuickVue Influenza Tests indicated very low likelihood of influenza infection, whereas positive tests greatly increased the probability of influenza-associated illness.


Cloning and characterization of the Drosophila U7 small nuclear RNA.
Base pairing between the 5' end of U7 small nuclear RNA (snRNA) and the histone downstream element (HDE) in replication-dependent histone pre-mRNAs is the key event in 3'-end processing that leads to generation of mature histone mRNAs. We have cloned the Drosophila U7 snRNA and demonstrated that it is required for histone pre-mRNA 3'-end processing in a Drosophila nuclear extract. The 71-nt Drosophila U7 snRNA is encoded by a single gene that is embedded in the direct orientation in an intron of the Eip63E gene. The U7 snRNA gene contains conserved promoter elements typical of other Drosophila snRNA genes, and the coding sequence is followed by a 3' box indicating that the Drosophila U7 snRNA gene is an independent transcription unit. Drosophila U7 snRNA contains a trimethyl-guanosine cap at the 5' end and a putative Sm-binding site similar to the unique Sm-binding site found in other U7 snRNAs. Drosophila U7 snRNA is approximately 10 nt longer than mammalian U7 snRNAs because of an extended 5' sequence and has only a limited potential to form a stem-loop structure near the 3' end. The extended 5' end of Drosophila U7 snRNA can base pair with the HDE in all five Drosophila histone pre-mRNAs. Blocking the 5' end of the U7 snRNA with a complementary oligonucleotide specifically blocks processing of a Drosophila histone pre-mRNA. Changes in the HDE that abolish or decrease processing efficiency result in a reduced ability to recruit U7 snRNA to the pre-mRNA.


[Population-genetic structure of Dolly varden (Salvelinus malma Walbaum) from Southeastern Sakhalin and Southern Kuril islands].
The genetic structure of Dolly Varden (Salvelinus malma Walbaum) populations from six rivers of southeastern Sakhalin and six rivers of the Kuril Islands was examined using electrophoretic, analysis of 22 enzyme systems encoded by 45 loci. In all populations, mean heterozygosities (0.044-0.105), mean numbers of alleles per locus (1.15-1.52), and proportions of polymorphic loci (18.2-39.4%) were estimated for all loci that had clear resolution. Highly significant heterogeneity of allele frequencies was detected among populations of both Sakhalin and the Kuril islands. By means of cluster analysis and multidimentional scaling, all populations were divided into the Sakhalin and Kuril groups. Within the groups, no association of genetic similarity with geographic distance between populations was observed. Although the average genetic diversity was similar in these regions, the relative interpopulation diversity was almost three times higher in the Kuril (17.6%) than in the Sakhalin (6.5%) groups. In all, the proportion of genetic diversity between regions (8.4%) was somewhat lower than the proportion of mean interpopulation diversity (11.3%). In small populations isolated from the sea, genetic variation was lower than in nonisolated populations. Allozyme differences between the northern and the southern forms of Dolly Varden are discussed.


Combined modality therapy for unresectable stage III non-small cell lung cancer: new chemotherapy combinations.
Over the last decade, we have witnessed improved outcome among patients with non-small cell lung cancer (NSCLC), principally through the use of new and novel treatment programs. A meta-analysis of randomized clinical trials comparing combined chemotherapy and radiation to radiation therapy alone clearly has shown a survival benefit with platinum-based combination chemotherapy administered sequentially or concurrently with thoracic radiation therapy over radiation therapy alone. In addition, combining thoracic radiation therapy with novel drugs or new drug combinations has yielded improvements in median survival duration and long-term survival rates in locally advanced unresectable NSCLC. Paclitaxel and carboplatin are two novel agents that have undergone extensive clinical evaluation at various doses and schedules in combination with thoracic radiation therapy in patients with locally advanced disease. There remains a need, however, for further improvement in metastatic control and prevention of locoregional recurrences. This will likely be achieved through the optimization of chemotherapy regimens to be used in combined modality therapy with thoracic radiation therapy.


Structural and nanomechanical properties of BiFeO3 thin films deposited by radio frequency magnetron sputtering.
The nanomechanical properties of BiFeO3 (BFO) thin films are subjected to nanoindentation evaluation. BFO thin films are grown on the Pt/Ti/SiO2/Si substrates by using radio frequency magnetron sputtering with various deposition temperatures. The structure was analyzed by X-ray diffraction, and the results confirmed the presence of BFO phases. Atomic force microscopy revealed that the average film surface roughness increased with increasing of the deposition temperature. A Berkovich nanoindenter operated with the continuous contact stiffness measurement option indicated that the hardness decreases from 10.6 to 6.8 GPa for films deposited at 350°C and 450°C, respectively. In contrast, Young's modulus for the former is 170.8 GPa as compared to a value of 131.4 GPa for the latter. The relationship between the hardness and film grain size appears to follow closely with the Hall-Petch equation.


[Lipodystrophy and 'buffalo hump' during treatment with HIV protease inhibitors].
In three patients, a 36-year-old HIV seropositive homosexual man and two women aged 35 and 59 years who had acquired HIV infection through heterosexual contact, signs of lipodystrophy developed after prolonged anti-HIV triple therapy. The observed syndrome is seen after prolonged use of HIV protease inhibitors: it is characterized by peripheral fat wasting, central fat accumulation, hyperlipidaemia and insulin resistance. Typically the subcutaneous fatty tissue disappears resulting in prominent zygomata, veins and muscles and thinning of extremities and buttocks. In addition to abdominal fat accumulation, there have been reports on the occurrence of a dorsocervical fat pad, the so-called buffalo hump. Lipodystrophy caused by protease inhibitors is a risk factor for cardiovascular disease. Recognition of the syndrome is essential for adequate follow-up and possible treatment.


Vascular Resection and Reconstruction in Pancreatic Tumours.
Option for borderline resectable pancreatic cancer is pancreaticoduodenectomy (PD) with vascular resection and reconstruction. We would like to share our experience of vascular reconstruction. First patient was a 51-year male with pancreatic head carcinoma, involving posterior wall of portal vein (PV) and replacing right hepatic artery (RHA). Along with PD, he underwent PV and RHA resection and reconstruction. Second case was a 33-year female who had distal pancreatic cyst and PV-splenic vein junction involved by tumor. Distal pancreatectomy+splenectomy and PV primary resection-reconstruction was done. Third case was a 72-year male with pancreatic neck adenocarcinoma involving PV-SMV junction. Subtotal pancreatecomy+splenectomy was done along with PV-reconstruction via splenic vein patch graft. Fourth case was a 77-year male with cystic pancreatic head mass involving PV. PD with resection and reconstruction of portal vein was done. Fifth case was a 35-year female with peri-ampullary tumor replacing RHA, coursing through the pancreatic parenchyma. So RHA was resected and reconstructed in an end-to-end fashion. Vascular resection-reconstruction can be done in borderline pancreatic cancer patients, and a considerable survival benefit can be achieved.


Radial k-t SPIRiT: autocalibrated parallel imaging for generalized phase-contrast MRI.
To extend SPIRiT to additionally exploit temporal correlations for highly accelerated generalized phase-contrast MRI and to compare the performance of the proposed radial k-t SPIRiT method relative to frame-by-frame SPIRiT and radial k-t GRAPPA reconstruction for velocity and turbulence mapping in the aortic arch. Free-breathing navigator-gated two-dimensional radial cine imaging with three-directional multi-point velocity encoding was implemented and fully sampled data were obtained in the aortic arch of healthy volunteers. Velocities were encoded with three different first gradient moments per axis to permit quantification of mean velocity and turbulent kinetic energy. Velocity and turbulent kinetic energy maps from up to 14-fold undersampled data were compared for k-t SPIRiT, frame-by-frame SPIRiT, and k-t GRAPPA relative to the fully sampled reference. Using k-t SPIRiT, improvements in magnitude and velocity reconstruction accuracy were found. Temporally resolved magnitude profiles revealed a reduction in spatial blurring with k-t SPIRiT compared with frame-by-frame SPIRiT and k-t GRAPPA for all velocity encodings, leading to improved estimates of turbulent kinetic energy. k-t SPIRiT offers improved reconstruction accuracy at high radial undersampling factors and hence facilitates the use of generalized phase-contrast MRI for routine use.


The clinical pattern of chronic pyogenic osteomyelitis in a Nigerian community.
Fifty-six cases of chronic pyogenic osteomyelitis encountered over a period of 1 year (1976-1977) were analysed. Males were more often affected than females. The sex ratio was 1.4:1. However, within the specific age group of 5-15 years, the sex ratio was reversed, more females were affected and the bones of the lower extremity were more often affected. Of these, the proximal end of the tibia was more involved than the distal end. The lower end of the femur was the second more commonly affected bone. Infections of the skull and spine were not encountered. Haematogenous spread of infection was common. The onset of infection was either acute or subacute. Penicillin-resistant Staphylococcus aureus was the major organism implicated (50%). Mixed infection was common (23%). A striking feature found in this study was the absence of Salmonella infection in sickle-cell disease patients with chronic osteomyelitis. Gross forms of the disease with massive sequestra and involucra, and widespread destruction of bone were common. Trauma in the form of insect bites, minor cuts, thorn-pricks, open fractures, and surgical operations constituted the aetiological factors.


A robust ex vivo experimental platform for molecular-genetic dissection of adult human neocortical cell types and circuits.
The powerful suite of available genetic tools is driving tremendous progress in understanding mouse brain cell types and circuits. However, the degree of conservation in human remains largely unknown in large part due to the lack of such tools and healthy tissue preparations. To close this gap, we describe a robust and stable adult human neurosurgically-derived ex vivo acute and cultured neocortical brain slice system optimized for rapid molecular-genetic manipulation. Surprisingly, acute human brain slices exhibited exceptional viability, and neuronal intrinsic membrane properties could be assayed for at least three days. Maintaining adult human slices in culture under sterile conditions further enabled the application of viral tools to drive rapid expression of exogenous transgenes. Widespread neuron-specific labeling was achieved as early as two days post infection with HSV-1 vectors, with virally-transduced neurons exhibiting membrane properties largely comparable to uninfected neurons over this short timeframe. Finally, we demonstrate the suitability of this culture paradigm for optical manipulation and monitoring of neuronal activity using genetically encoded probes, opening a path for applying modern molecular-genetic tools to study human brain circuit function.


Biodegradable polymers boost reproduction in the earthworm Eisenia fetida.
Microplastic contamination in soil has become a global environmental threat as it adversely affects terrestrial organisms like earthworms as well as soil properties. Especially biodegradable polymers have recently been used as an alternative to conventional polymer types, although their impact remains poorly understood. Thus, we studied the effect of conventional (polystyrene: PS, polyethylene terephthalate: PET, polypropylene: PP) versus aliphatic polyesters classified as biodegradable polymers (poly-(l-lactide): PLLA, polycaprolactone: PCL) on the earthworm Eisenia fetida and soil properties (pH and cation exchange capacity). We addressed direct effects on the weight gain and reproductive success of E. fetida, and indirect effects, like changes in the gut microbial composition as well as the production of short-chain fatty acids by the gut microbiota. Earthworms were exposed for eight weeks in an artificial soil amended with two environmentally relevant concentrations (1 % and 2.5 % (w/w)) of the different microplastic types. PLLA and PCL boosted the number of cocoons produced by 135 % and 54 %, respectively. Additionally, exposure to these two polymers increased number of hatched juveniles, changed gut microbial beta-diversity, and increased the production of the short chain fatty acid lactate compared to the control treatments. Interestingly, we also found a positive effect of PP on the earthworm's bodyweight and reproductive success. The interaction of microplastic and earthworms decreased soil pH by about 1.5 units in the presence of PLLA and PCL. No polymer effect on the cation exchange capacity of soil was found. In general, neither the presence of conventional nor biodegradable polymers had any adverse effects on any of the studied endpoints. Our results suggest that the effects of microplastic highly depend on the polymer type, and that the degradation of biodegradable polymers might be enhanced in the gut of earthworms, which implies that they may use biodegradable polymers as a potential carbon source.


A nondestructive method to estimate the chlorophyll content of Arabidopsis seedlings.
Chlorophyll content decreases in plants under stress conditions, therefore it is used commonly as an indicator of plant health. Arabidopsis thaliana offers a convenient and fast way to test physiological phenotypes of mutations and treatments. However, chlorophyll measurements with conventional solvent extraction are not applicable to Arabidopsis leaves due to their small size, especially when grown on culture dishes. We provide a nondestructive method for chlorophyll measurement whereby the red, green and blue (RGB) values of a color leaf image is used to estimate the chlorophyll content from Arabidopsis leaves. The method accommodates different profiles of digital cameras by incorporating the ColorChecker chart to make the digital negative profiles, to adjust the white balance, and to calibrate the exposure rate differences caused by the environment so that this method is applicable in any environment. We chose an exponential function model to estimate chlorophyll content from the RGB values, and fitted the model parameters with physical measurements of chlorophyll contents. As proof of utility, this method was used to estimate chlorophyll content of G protein mutants grown on different sugar to nitrogen ratios. This method is a simple, fast, inexpensive, and nondestructive estimation of chlorophyll content of Arabidopsis seedlings. This method lead to the discovery that G proteins are important in sensing the C/N balance to control chlorophyll content in Arabidopsis.


Analyzing generic and branded substitution patterns in the Netherlands using prescription data.
As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics. We utilized a linked prescription dataset originating from a general practitioner (GP) and a pharmacy database, both from the northern Netherlands. We selected specific drugs of interest, containing about 55,000 prescriptions from 15 different classes. We used a crossed generalized linear mixed model to estimate the effects that certain patient and pharmacy characteristics as well as timing have on the likelihood that a prescription will eventually be substituted by the pharmacist. Generic substitution occurred at 25% of the branded prescriptions. Generic substitution was more likely to occur earlier in time after patent expiry and to patients that were older and more experienced in their drug use. Individually owned pharmacies had a lower probability of generic substitution compared to chain pharmacies. Oppositely, branded substitution occurred in 10% of generic prescriptions and was positively related to the patients' experience in branded use. Individually owned pharmacies were more likely to substitute a generic drug to a branded compared to other pharmacies. Antidepressant and PPI prescriptions were less prone to generic and more prone to branded substitution. Analysis of prescription substitution by the pharmacist revealed strong relations between substitution and patient experience on drug use, pharmacy status and timing. These findings can be utilised to design further strategies to enhance generic substitution.


A unified mixed effects model for gene set analysis of time course microarray experiments.
Methods for gene set analysis test for coordinated changes of a group of genes involved in the same biological process or molecular pathway. Higher statistical power is gained for gene set analysis by combining weak signals from a number of individual genes in each group. Although many gene set analysis methods have been proposed for microarray experiments with two groups, few can be applied to time course experiments. We propose a unified statistical model for analyzing time course experiments at the gene set level using random coefficient models, which fall into the more general class of mixed effects models. These models include a systematic component that models the mean trajectory for the group of genes, and a random component (the random coefficients) that models how each gene's trajectory varies about the mean trajectory. We show that the proposed model (1) outperforms currently available methods at discriminating gene sets differentially changed over time from null gene sets; (2) provides more stable results that are less affected by sampling variations; (3) models dependency among genes adequately and preserves type I error rate; and (4) allows for gene ranking based on predicted values of the random effects. We describe simulation studies using gene expression data with "real life" correlations and we demonstrate the proposed random coefficient model using a mouse colon development time course dataset. The agreement between results of the proposed random coefficient model and the previous reports for this proof-of-concept trial further validates this methodology, which provides a unified statistical model for systems analysis of microarray experiments with complex experimental designs when re-sampling based methods are difficult to apply.


Outcomes of endoscopic submucosal dissection in esophageal adenocarcinoma staged T1bN0 by endoscopic ultrasound in non-surgical patients.
Patients with esophageal adenocarcinoma (EAC) invading submucosa (T1b) are traditionally treated with esophagectomy and with chemoradiotherapy in poor surgical patients. Endoscopic submucosal dissection (ESD) has emerged as an alternative treatment in these patients. In this case series, we analyzed the outcomes of ESD in EAC staged T1bN0 by endoscopic ultrasound (EUS). Patients with EAC staged T1bN0M0 by EUS and PET scan who underwent ESD by a single operator (MS) between 2014 and 2017 at our institution were included. They were deemed as poor surgical candidates and ESD was considered as the most appropriate treatment option after a multi-disciplinary evaluation. There were 8 patients (male =5; female =3) with average age of 70.5 years old (range, 53-84 years old). ESD was completed in 7 and aborted in 1 patient due to tumor invasion into muscularis propria. En bloc, R0 and curative resection rates were 86% (6/7), 86% (6/7) and 71% (5/7) respectively. Final histology was intramucosal (T1a) in 4 and submucosal (T1b) in 3. One patient (14%) developed stricture requiring balloon dilation. Mean follow-up duration was 10 months (range, 3-15 months) and 71% (5/7) remain in clinical remission. Two patients required CRT, one with T1a who developed recurrence and another with T1b with lymphovascular invasion. In poor surgical candidates, ESD was associated with accurate staging and favorable outcomes in EAC staged T1bN0 by EUS. We suggest considering ESD in EAC staged T1bN0 for accurate histological staging, curative potential and also to help determine further course of treatment.


Extension of the organ pool in kidney transplantation: first year experience of the Israel Transplant Center.
Over a 12 month period, the Israel Transplant Center doubled the number of donors by assigning a nurse coordinator to each of 22 hospitals around the country and by using kidneys from elderly donors. To evaluate the impact of our "marginal donors" policy on the results immediately following transplantation. Between October 1997 and September 1998, 140 cadaveric kidney transplantations from 72 donors were performed in Israel. We defined two groups of recipients: patients with immediate graft function and patients with either delayed graft function requiring > 1 week of dialysis post-transplant or with primary graft non-function. We compared the following parameters between groups: donor and recipient age and gender, cause of donor's death, length of stay in the intensive care unit, vasopressor dosage and creatinine levels before harvesting, cold ischemic time, and the number of recipient grafts. There were 102 recipients (72.8%) with immediate graft function and 38 with either PNF (n = 13, 9.3%) or DGF (n = 25, 17.9%). On regression analysis, donor age > 50 year and retransplantation were significant risk factors for PNF or DGF (odds ratio 4.4 and 2.8, respectively). Of the 56 kidneys from donors > 50 years old, 21 (37.5%) developed either PNF (n = 9) or DGF (n = 12). We conclude that kidneys from donors over age 50 are at increased risk for graft non-function or delayed function. Better assessment of functional capacity of kidneys from "aged" donors may help to choose appropriate donors from that pool.


Clinical and Echocardiographic Outcomes of Patients Undergoing Transcatheter Edge-to-Edge Repair for Functional vs Degenerative Mitral Valve Regurgitation.
To analyze clinical and echocardiographic outcomes after transcatheter edge-to-edge repair (TEER) with mitral valve clip device (MitraClip-TM) for functional vs degenerative mitral valve regurgitation (MR). All consecutive 185 patients undergoing TEER between January 2019 and March 2023 were included in the study. A propensity-adjusted analysis investigated differences among functional vs degenerative MR mechanism groups. Preoperatively, functional vs degenerative MR included 43 vs 142 patients, respectively. Mean ejection fraction (EF) values were 37% vs 57.8%, mean STS-PROM risk score was 7% vs 4% while patients with severe MR included 29 (67.4%) vs 129 (90.9%) patients, respectively. Postoperatively, functional MR patients experienced a higher incidence of prolonged postoperative length of stay (LOS), reduced creatinine clearance, and EF<50% compared to the degenerative MR group. Mean EF was 35.9% vs 56.2% (P < 0.0001) and 1 (2.3%) vs 16 (11.3%) patients had residual severe MR (P = 0.01) in functional vs degenerative MR groups, respectively. At 30-days follow-up, all-cause death incidence was 1 (2.3%) vs 3 (2.1%) patients in functional vs degenerative MR, respectively (P = 0.9). At a mean of 1.6-years follow-up, all-cause death (P = 0.01), major adverse cardiovascular and cerebrovascular events (MACCE) (P = 0.02), cardiac death (P = 0.01) and hazard ratio for all-cause death higher in functional vs degenerative MR group. Mean EF was 39.7% vs 56% (P < 0.001) while residual severe MR was 4 (9.3%) vs 34 (24.5%) (P = 0.1) in functional vs degenerative MR groups, respectively. TEER with MitraClip device showed a higher incidence of all-cause death, cardiac death, and MACCE at follow-up for functional compared to degenerative MR after TEER.


Integrated Mapping of Yaws and Trachoma in the Five Northern-Most Provinces of Vanuatu.
Yaws and trachoma are targeted for eradication and elimination as public health problems. In trachoma-endemic populations mass administration of azithromycin can simultaneously treat yaws. We conducted a population-based prevalence survey in the five northernmost provinces of Vanuatu, where trachoma and yaws are suspected to be co-endemic. Clinical signs of trachoma were evaluated using the WHO simplified grading system, and skin examination with a serological rapid diagnostic test used to identify yaws. We enrolled 1004 households in 59 villages over 16 islands, and examined 3650 individuals of all ages for trachoma. The overall adjusted prevalence of trachomatous inflammation-follicular (TF) in 1-9 year-olds was 12.0% (95% Confidence Interval: 8.1-16.7%), and the overall adjusted prevalence of TT in those aged 15 years and greater was 0.04% (95% CI 0-0.14%). In multivariate analysis, the odds of children having TF was 2.6 (95% CI = 1.5-4.4) times higher in households with unimproved latrines, and independently associated with the number of children in the household (OR 1.3, 95% CI = 1.0-1.6 for each additional child). We examined the skin of 821 children aged 5-14 years. Two children had yaws, giving an estimated prevalence of active yaws in those aged 5-14 years of 0.2% (95% CI = 0.03-0.9%). Mass treatment with azithromycin is recommended in these provinces. Given the apparent low burden of yaws, integration of yaws and trachoma control programmes is likely to be useful and cost-effective to national programmes.


Dietary flavonoids activate the constitutive androstane receptor (CAR).
The constitutive androstane receptor (CAR) is known as a xeno-sensor that regulates genes involved in xenobiotic excretion and energy metabolism. This study tested a variety of polyphenols for their ability to modulate CAR activity. HepG2 cells were transfected with a CAR expression plasmid and a reporter plasmid containing the human CYP2B6 regulatory region and then treated with flavonoids, catechins, and other bioactive polyphenols. Luciferase assays revealed that baicalein (5,6,7-OH flavone) was a potent activator of both human and mouse CAR. Catechin gallates also activated human and mouse CAR. Wild-type and CAR knockout mice were treated with baicalein and chrysin (5,7-OH flavone), and their liver mRNA was analyzed by real-time polymerase chain reaction (PCR). A significant increase in cyp2b10 mRNA content was observed only in wild-type mice fed chrysin. These results suggest that dietary flavonoids regulate CAR activity and thereby accelerate both detoxification and energy metabolism.


Development of a minimally invasive laser needle system: effects on cortical bone of osteoporotic mice.
Many studies have shown the positive effects of low-level laser therapy in the treatment of bone disease. However, laser radiation is scattered in the skin surface which reduces the initial photon density for tissue penetration and consequently the therapeutic efficacy. We developed a minimally invasive laser needle system (MILNS) to avoid laser scattering in tissue and investigated its stimulatory effects in the cortical bone of osteoporotic mice. The MILNS was designed to stimulate cortical bone directly by employing fine hollow needles to guide 100 μm optical fibers. The study animals comprised 12 mice which were subjected to sciatic denervation of the right hind limb and were randomly divided into two groups, a sham group and a laser group which were treated using the MILNS for 2 weeks without and with laser irradiation, respectively. In vivo micro-CT images were taken to analyze the structural parameters and bone mineral density. After 2 weeks of treatment with the MILNS, the relative changes in mean polar moment inertia, cross-section thickness, and periosteal perimeter were significantly higher in the laser group than in the sham group. Moreover, the distribution of bone mineral density index was higher in the laser group. The MILNS was developed as a minimally invasive treatment modality for bone disease and resulted in positive therapeutic efficacy in the cortical bone of osteoporotic mice.


Sex Differences in the Prevalence and Incidence of Cognitive Impairment: Does Immigration Matter?
We aimed to examine the associations between immigration-related factors and prevalent and incident cognitive impairment (CI) and whether the associations varied by sex among US Chinese older adults. Two-wave prospective study. The greater Chicago area. Community-dwelling adults aged 60 and older who self-identified as Chinese, who were interviewed at two time points during 2011-2013 (N = 3157) and 2013-2015 (N = 2713). CI was assessed by the 30-item Chinese Mini-Mental State Examination (C-MMSE). CI prevalence was determined by the percentage of respondents whose C-MMSE score was below 18 at baseline (N = 3033), and CI incidence was determined by the percentage of the respondents whose score was 18 or above at baseline (N = 2443) but dropped below 18 at wave 2. Immigration-related factors included age at migration, immigration reasons, and acculturation. The CI prevalence rate was 7.62% at baseline, and the incidence rate was 5.12% at wave 2. Women were more likely than men to have CI, consisting of 77.06% and 75.20% among persons with CI at the time points. None of the immigration-related factors were related to CI prevalence and incidence. Older age, fewer years of education, and more instrumental activities of daily living limitations were risk factors of CI in the whole, male, and female samples. Older Chinese women were generally disadvantaged in cognition and overall health as compared with older Chinese men. Yet immigration experience does not link to CI for both men and women after equalizing the well-established effects of age and education on cognition. Future research needs to investigate whether the risk of CI in late life is related to the biological and contextual factors earlier in the life course. Decreasing sex disparities in the risk of dementia may focus on reducing educational and health disparities in the early life stage. J Am Geriatr Soc 67:S513-S518, 2019.