C-myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells.
C-myc is implicated in the initiation, progression and estrogen response of breast cancer. To further investigate the role of c-myc in breast cancer, we have developed clonal MCF-7 human breast cancer cell lines harboring a stably-transfected human c-myc gene, whose expression was stringently controlled by the bacterial reverse tetracycline transcription activator protein. The expression of the endogenous genomic c-myc gene in MCF-7 cells was abolished by the potent pure estrogen antagonist, ICI 182,780. Functional c-Myc protein was identified by both Western immunoblotting and by its ability to transactivate a chimeric plasmid consisting of E-box sequences upstream of the luciferase reporter gene. One MCF-7 clone, 35im, was chosen for further characterization. C-myc induction by doxycycline was rapid and dose dependent; c-myc mRNA appeared as early as 30 min after doxycycline addition and stimulation of c-myc expression required as little as 50 ng/ml doxycycline, with c-myc mRNA levels reaching a plateau at 2.5 microg/ml doxycycline. ICI 182,780 or doxycycline (a tetracycline analog) treatment did not alter the mRNA levels of Max, the c-myc binding partner. As in wildtype MCF-7 cells, the growth of clone 35im was inhibited by 1 microM or less of ICI 182,780 and stimulated by 10 nM to 1 microM 17beta-estradiol. When maintained in a complete medium containing 5% normal fetal bovine serum (FBS) and ICI 182,780, doxycycline induced cell growth by 400% in an 8-day assay. A similar level of growth was achieved with doxycycline treatment in cells that were arrested by the use of charcoal-stripped FBS. Doxycycline had no effect on the growth of a control MCF-7 clone (18c). Apoptosis, assessed by caspase-dependent cleavage of poly(ADP-ribose) polymerase, was unchanged in clone 35im cells after treatments with doxycycline or ICI 182,780. The present study demonstrates that c-myc alone is sufficient to confer antiestrogen resistance in human breast cancer. Our novel c-myc-inducible MCF-7 cell model offers a unique opportunity to study the diverse actions of the c-myc proto-oncogene in human breast cancer.


Towards global Guinea worm eradication in 2015: the experience of South Sudan.
For centuries, the Guinea worm parasite (Dracunculus medinensis) has caused disabling misery, infecting people who drink stagnant water contaminated with the worm's larvae. In 2012, there were 542 cases of Guinea worm reported globally, of which 521 (96.1%) were reported in South Sudan. Protracted civil wars, an inadequate workforce, neglect of potable water provision programs, suboptimal Guinea worm surveillance and case containment, and fragmented health systems account for many of the structural and operational factors encumbering South Sudan's Guinea worm eradication efforts. This article reviews the impacts of six established Guinea worm control strategies in South Sudan: (1) surveillance to determine actual caseload distribution and trends in response to control measures; (2) educating community members from whom worms are emerging to avoid immersing affected parts in sources of drinking water; (3) filtering potentially contaminated drinking water using cloth filters or filtered drinking straws; (4) treating potentially contaminated surface water with the copepod larvicide temephos (Abate); (5) providing safe drinking water from boreholes or hand-dug wells; and (6) containment of transmission through voluntary isolation of each patient to prevent contamination of drinking water sources, provision of first aid, and manual extraction of the worm. Surveillance, community education, potable water provision, and case containment remain weak facets of the program. Abate pesticide is not a viable option for Guinea worm control in South Sudan. In light of current case detection and containment trends, as well as capacity building efforts for Guinea worm eradication, South Sudan is more likely to eradicate Guinea worm by 2020, rather than by 2015. The author highlights areas in which substantial improvements are required in South Sudan's Guinea worm eradication program, and suggests improvement strategies.


Survival and metabolism of hydroxycinnamic acids by Dekkera bruxellensis in monovarietal wines.
Volatile phenols in wines are responsible for unpleasant aromas, which negatively affect the quality of the wine. These compounds are produced from the metabolism of hydroxycinnamic acids, mainly by the yeasts Brettanomyces/Dekkera. Relevant data, potentially useful to support decisions on how to manage the risk of contamination of wines by Brettanomyces/Dekkera, according to the grape varieties used in the vinification, is important to the wine industry. Therefore, the aim of this work was to evaluate the survival and the metabolism of hydroxycinnamic acids by Dekkera bruxellensis in monovarietal wines. Yeast growth and survival were monitored in fifteen wines, five from each of the grape varieties Touriga Nacional, Cabernet Sauvignon and Syrah, inoculated with a strain of D. bruxellensis. Yeast culturable populations of 107 CFU mL-1 were reduced to undetectable numbers in 24 h in all wines. Plate counts of 104-106 CFU mL-1 were, however, detected after 48 h in most of Touriga Nacional and Cabernet Sauvignon wines and later in Syrah. Viability measurement by flow cytometry showed that a significant part of the populations was in a viable but non-culturable state (VBNC). The time required for the recovery of the culturable state was dependent on the wine, being longer on Syrah wines. Besides the production of ethylphenols, the metabolism of hydroxycinnamic acids by VBNC cells led to the accumulation of vinylphenols at relatively high levels, independently of the grape variety. The flow cytometry methodology showed a higher survival capacity of D. bruxellensis in Touriga Nacional wines, which corroborates with the higher amounts of volatile phenols found on this variety.


A shortened postpartum magnesium sulfate prophylaxis regime in pre-eclamptic women at low risk of eclampsia.
To determine whether magnesium sulfate (MgSO(4)) prophylaxis is needed for up to 24 hours postpartum in all patients with pre-eclampsia. In a randomized open clinical trial conducted in a tertiary health center in India between September 2008 and April 2010, 150 women with severe pre-eclampsia who received intrapartum MgSO(4) and delivered at more than 2 weeks gestation were enrolled. After 6hours postpartum, the participants were randomized to continue receiving (control group) or to discontinue (intervention group) MgSO(4), and outcomes were compared. Administration of MgSO(4) had to be reinstituted for 1 woman in the intervention group. Under the current protocol in the institution, all 75 women in the intervention group would have received MgSO(4) for 24 hours postpartum. A significant reduction in time spent by the doctors (P<0.001) and nurses (P<0.001) was seen in the intervention group. The pain score in the intervention group was significantly less (P<0.001), and women in the intervention group were able to look after themselves better (P<0.001). For women at low risk for postpartum eclampsia, a shortened (6-hour) MgSO(4) regime was as effective for seizure prophylaxis as the conventional 24-hour regime, with significant benefits in terms of cost and morbidity.


Convergence of signals in the zona incerta for angiotensin-mediated and osmotic thirst.
Extracellular single-unit activity was recorded from 109 neurons in the diencephalon of urethane-anesthetized rats. Injections of angiotensin II (ANG II) into the subfornical organ (SFO) increased the activity of 15 zona incerta (ZI) neurons and decreased the activity of 9. Injections of ANG II into the SFO increased the activity of 8 lateral hypothalamic neurons and decreased the activity of 7. Of the units which responded to the injection of ANG II into the SFO, 9 neurons in the ZI and 5 in the lateral hypothalamus (LH) also responded to injections of hyperosmotic saline into the medial preoptic area. The SFO and preoptic area are possible sites of receptors for ANG II-mediated and osmotic thirst, respectively, and the present results suggest that signals important for the initiation of these thirst mechanisms converge on neurons in the ZI and LH. These findings are discussed in relation to other neural structures that have been implicated in the regulation of water intake.


Ablation profiles for wavefront-guided correction of myopia and primary spherical aberration.
To calculate ablation profiles for wavefront-guided correction of ametropia and primary spherical aberration. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA. The primary spherical aberrations of the ocular surfaces of an aspheric eye model were calculated before and after simulated ablations for correction of myopia ranging from 0 to 10 diopters. The corneal asphericity to correct primary spherical aberration and the corresponding ablation profiles were also calculated. The corneal asphericity factor that produces zero primary spherical aberration ranges from -0.45 to -0.47. The calculated ablation profiles are parabolic in first approximation, and the ablation depth varies linearly with the amount of correction. To control residual primary spherical aberration with a tolerance of one-quarter wavelength, the precision of the ablation must range from 0.2 to 0.3 microm. Ocular aberrometry and corneal topography can be used to calculate ablations for the correction of ametropia and primary spherical aberration. Precise control of postoperative spherical aberration appears to be feasible in theory.


Utero-placental cellular and nuclear expression of bradykinin B2 receptors in normal and preeclamptic pregnancies.
The bradykinin type 2 receptor (B2R), main effector of the pleiotropic kallikrein-kinin system (KKS), has been localized in the key sites related to placentation in human, rat and guinea pig utero-placental units. The present study was directed to characterize the content, the cellular and subcellular localization of B2R in the villi and basal plate of placentas from normal and preeclamptic pregnancies by means of western blotting, immunohistochemistry and immunoelectron microscopy. The protein content of B2R was demonstrated in both placental zones. The villous placenta of normal and preeclamptic pregnancies expressed B2R in syncytiotrophoblast and fetal endothelium; the basal plate displayed B2R in extravillous trophoblasts and decidual cells. Lastly, immunogold electron microscopy revealed B2R in fetal endothelium, syncytiotrophoblast, extravillous cytotrophoblasts and decidual cells; in all cell types the receptor was mainly located in the cytosol and nucleus. The protein content of placental homogenates and the immunoreactivity in the different cells types did not differ between both study groups; however the abundance of nuclear immunogold B2R positive beads in extravillous trophoblasts was greater in the normal than in the preeclamptic placentas. The purpose of describing nuclear B2R in the utero-placental unit, and its increment in normal extravillous trophoblasts, is to stimulate the study of the functional pathways that may be relevant to understand the local role of the B2R in normal and preeclamptic gestation.


Comparison of the embryo survival rate in heifers following artificial insemination, non-surgical blastocyst transfer or both.
In Exp. 1, embryo survival rates of 45 and 47% were recorded after artificial insemination and ipsilateral transfer respectively. In Exp. 2, pregnancy rates of 62 and 60% were recorded after artificial insemination and contralateral transfer to inseminated recipients respectively. In this experiment the contralateral transferred embryo survival rate was 44%. Transferred embryo survival was lower overall when donors and recipients were out of phase by 1 day than when exactly synchronous.


Validation of the society of thoracic surgeons predicted risk of mortality score for long-term survival after cardiac surgery in Israel.
Long-term survival is an important metric in assessing procedural value. We previously confirmed that the Society of Thoracic Surgeons predicted risk of mortality score (PROM) accurately predicts 30-day mortality in Israeli patients. The present study investigated the ability of the PROM to reliably predict long-term survival. Data on 1279 patients undergoing cardiac surgery were prospectively entered into our database and used to calculate PROM. Long-term mortality was obtained from the Israeli Social Security Database. Patients were stratified into five cohorts according to PROM (A: 0-0.99%, B: 1.0-1.99%, C: 2.0-2.99%, D: 3.0-4.99% and E: ≥ 5.0%). Kaplan-Meier estimates of survival were calculated for each cohort and compared by Wilcoxon signed-rank test. We used C-statistics to assess model discrimination. Cox regression analysis was performed to identify predictors of long-term survival. Follow-up was achieved for 1256 (98%) patients over a mean period of 62 ± 28 months (median 64, range 0-107). Mean survival of the entire cohort was 95 ± 1 (95% CI 93-96) months. Higher PROM was associated with reduced survival: A-104 ± 1 (103-105) months, B-96 ± 2 (93-99) months, C-93 ± 3 (88-98) months, D-89 ± 3 (84-94) months, E-74 ± 3 (68-80) months (p < 0.0001). The Area Under the Curve was 0.76 ± 0.02 indicating excellent model discrimination. Independent predictors of long-term mortality included advanced age, lower ejection fraction, reoperation, diabetes mellitus, dialysis and PROM. The PROM was a reliable predictor of long-term survival in Israeli patients undergoing cardiac surgery. The PROM might be a useful metric for assessing procedural value and surgical decision-making.


Detection of an aortoenteric fistula in a patient with intermittent bleeding.
A 57-year-old male with an aortobifemoral bypass graft presented to a gastroenterology clinic with a 3-month history of intermittent hematemesis, melena and fever. The patient had received antibiotic therapy 2 months before for the same symptoms; however, following brief regression ( approximately 3 weeks) the symptoms had returned. Physical examination; analysis of full blood count; measurement of erythrocyte sedimentation rate, C-reactive protein levels, liver enzymes, electrolytes, renal function, serum cholesterol and serum triglyceride; HIV serology; blood, sputum, urine and stool culture analysis; performance of esophagogastroduodenoscopy, colonoscopy, abdominal ultrasonography and multidetector CT scanning. Aortoenteric fistula with an inflammatory mass surrounding the aortobifemoral bypass graft. Laparotomy with removal of the aortobifemoral bypass graft, performance of an extra-anatomic right axillofemoral bypass graft and an extra-anatomic right-left femorofemoral bypass graft.


An Uncommon Presentation of the Common Sinusitis.
A nine-year-old child was brought to the emergency room by her mother because of an upper respiratory infection symptoms and forehead swelling. The patient was seen by the emergency department physician and diagnosed with an upper respiratory infection; the forehead swelling was felt to be related to forceful coughing. The patient and patient's mother returned on a second visit because the forehead swelling had not improved. A CT scan of the head was subsequently done which demonstrated pansinusitis.


Different forms of brain acetylcholinesterase and muscarinic binding in Parkinson's disease.
Choline acetyltransferase (ChAT) activity, the sedimentation and solubility forms of acetylcholinesterase (AChE) as well as total (3H-quinuclidinyl benzilate, QNB) and M1 (3H-pirenzepine, PZ) muscarinic binding were investigated in the temporal cortex (TC) and nucleus caudatus (NC) of both non-demented and demented parkinsonian patients and controls. ChAT activity and low-salt-soluble and detergent-soluble AChE were lower in the TC of demented patients with Parkinson's disease than in controls. ChAT activity and the solubility forms of AChE in the NC did not differ between controls and parkinsonian patients. In the TC, the activity of the intermediate form of AChE was lower in parkinsonian patients, but the activity of the light form of AChE did not differ between controls and parkinsonian patients. In the TC of patients with Parkinson's disease the Bmax of 3H-QNB binding was slightly higher than in controls, but the Bmax of 3H-PZ binding did not differ between controls and parkinsonian patients. In the NC the Bmax of 3H-QNB binding was unchanged compared to that of the controls. The concomitant decrease of ChAT with soluble as well as membrane-bound tetrameric AChE suggests a close relationship between ChAT and tetrameric form of AChE. M1 receptors (3H-PZ binding sites) are not affected in the TC, but are decreased in the NC of demented parkinsonian patients. This decrease may be secondary to the loss of dopaminergic neurons projecting from the substantia nigra to the striatum.


Normalizing considerations for time to stabilization assessment.
Because of the growing use of time to stabilization (TTS) and similar measures with single-limb landings in lower extremity research, it is important to determine if the task performance needs to be normalized further. The purpose of this study was to compare TTS of healthy participants using a standardized versus a normalized horizontal jumping distance. Crossover study. Twenty-one healthy participants performed single landings using two horizontal jumping distances: standardized (70 cm) and normalized (leg length). Resultant vector TTS (RVTTS) was calculated to represent the dynamic stability performance. For RVTTS, the participants took significantly longer to stabilize when using the normalized jumping distance (1.997±0.181 s) compared with the standardized jumping distance (1.921±0.126 s) (t=5.134; p<0.001; power=0.65). RVTTS during the normalized jumping distance was more strongly correlated with leg length (r=0.628; p=0.002) than during the standardized jumping distance (r=0.563; p=0.008). Normalizing the horizontal jumping distance during the single-limb jumping task creates a performance decrement in RVTTS among healthy participants. Because dynamic stability measured with RVTTS when jumping a normalized distance is more strongly correlated with leg length than when jumping a standardized jumping distance, researchers using this task and analysis may want to consider using this additional normalizing step in future investigations.


Aspiration of equine oocytes from immature follicles after treatment with equine pituitary extract (EPE) alone or in combination with hCG.
This study examined the effect of treating mares with equine pituitary extract (EPE) alone or in combination with hCG on the recovery rate of immature follicles by transvaginal follicular aspiration (ovum pick-up; OPU). Ten normally cycling crossbred mares aged 3-15 years and weighing 350-400 kg were subjected to each of three treatments in a random sequence with each exposure to a new treatment separated by a rest cycle during which a spontaneous ovulation occurred. The treatments were (1) superovulated with 25mg EPE and treated with 2500 IU hCG, (2) superovulation with 25mg EPE, and (3) control (no exogenous treatment). Treatments 7 days after spontaneous ovulation; and all the follicles >10mm were aspirated 24h after the largest follicle achieved a diameter of 27-30 mm for control group, and most follicles reached 22-27 mm for the EPE alone treatment. To the group EPE+hCG, when the follicles reached 22-27 mm, hCG was administered, 24h before OPU. Superovulation increased the number of follicles available for aspiration. The total number of follicles available for aspiration was 61 in the EPE/hCG group, 63 in the EPE group and 42 in the control. The proportion of follicles aspirated varied from 63.5% to 73.8%. Oocyte recovery rate ranged from 15.0% to 16.7% and the proportion of mares that yielded at least one oocyte was 70% (7/10) in the EPE/hCG, 60% (6/10) in the EPE alone and 50% (5/10) in control group. The EPE/hCG treatment had a higher proportion of follicles with expanded granulose cells (64.4%) than the control (3.3%; p<0.05) and the EPE treatment (25.0%). The intervals from spontaneous ovulation to aspiration were similar for all treatments (11-12 days). However, superovulatory treatment significantly increased the aspiration to ovulation interval from 15+/-4 days for control to 27+/-15 days for EPE (p<0.05) and to 23+/-13 days for EPE/hCG treatment with commensurate increases in the time between spontaneous ovulations.


[The quantitative changes of defeacation during the larval development ofCerura vinula L. (Lepidoptera)].
During the larval development ofCerura vinula L. consecutive instars are of increasing length. The time requirement for each instar is temperature dependent. They are shorter at higher and longer at lower temperatures.The data of the first larval instars suggest that the leaves were digested at a much higher rate at 18° C than at 25°C and 30° C. The data of the 5. instar do not show this difference as clearly. During the 5. instar maximum of defeacation was reached by an s-shaped curve. This curve may be divided into two different phases: During the first phase there is a steady increase. During the second phase the rise decreases steadily until the maximum of defeacation is reached. The first phase may be shortened by higher temperatures, while the second phase may not be altered. Short cyclic variations with irregular periodic length of 8-16 hours seeme to be superimposed on this s-shaped curve. There is evidence that the position of their maxima and minima are correlated with the day-night cycle. This effect is described quantitatively by the tendency-curve.


Periostin as a key molecule defining desmoplastic environment in colorectal cancer.
Categorizing desmoplastic reaction (DR) based on the histological findings of cancer-associated fibroblasts is shown to be a promising novel method to predict prognosis of patients with colorectal cancer (CRC). Periostin (POSTN) in cancer-associated stroma is reportedly associated with poor clinical outcomes. Immunohistochemical staining with an anti-POSTN antibody was performed in 73 patients with pStage III CRC (cohort 1). In addition, to evaluate mRNA and protein expression levels of POSTN, we analyzed paired normal and invasive cancer frozen specimens by quantitative real-time polymerase chain reaction and western blot analysis in 41 patients (cohort 2). In cohort 1, according to the DR categorization, 18, 22, and 33 patients were classified as immature, intermediate, and mature, respectively. High immunoreactivity of POSTN was observed 100%, 68.2%, and 27.3%, respectively (p < 0.0001). The 5-year relapse-free survival rates were 56.8% and 82.7% in high and low POSTN expression subgroups, respectively (p = 0.015). In cohort 2, the POSTN mRNA and protein levels were significantly higher in the immature stroma as compared to the stroma characterized as other DR patterns. POSTN expression was closely associated with DR categorization. POSTN may be a key molecule that contributes to the malignant potential of CRC.


Dosimetric analysis of postoperative radiotherapy for thymoma.
To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50Gy and fractional dose of 2.0Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.


Phenotypic and genotypic characterization of non-typhoidal Salmonella isolated from a Brazilian pork production chain.
Pork products are important sources of foodborne non-typhoidal Salmonella in Brazil where antibiotics are commonly used throughout the pork production process and this has the potential to selectively favor antibiotic-resistant strains. We characterized the genotypic and phenotypic diversity of S. enterica isolates (n = 41) that were isolated in Brazil. Isolates were collected from ten swine farms and one slaughterhouse. Whole-genome sequencing and in silico serotyping demonstrated that the S. enterica serovar Typhimurium was the most common serotype (n = 17), but eight additional servoars were identified. Isolates presented high similarity based on comparison of DNA sequences (minimum of 89.6%), and sequence variation grouped according to serotype. Eight multilocus sequence types were identified with ST19 being most common (n = 21). Several plasmids replicons were detected, with Col (RNAI) the most abundant (n = 30), followed by IncR (n = 22), IncI1 (n = 10) and IncA/C2 (n = 10). Minimum inhibitory concentration assays showed that the principle resistance phenotypes were for streptomycin (90.2%), tetracycline (87.8%), ampicillin (80.5%), chloramphenicol (70.7%) and ciprofloxacin (51.2%). Only two isolates were resistant to third-generation cephalosporins and no isolates were resistant to two tested carbapenems. Twenty-six unique antimicrobial-resistance genes were identified with blaTEM-1A and blaTEM-1B likely responsible for most beta-lactam resistance and floR responsible for most chloramphenicol resistance. Six strains were positive for mcr-1. At the time of collection, the sampled farms were adding ciprofloxacin to feed and this may have contributed to the high prevalence of resistance to this antibiotic. The high number of multidrug resistant Salmonella and the presence of multiple resistant genes and plasmids emphasize the diversity of Salmonella in the studied pork chain, specially from serotype Typhimurium.


Spectrometric evaluation of post-mortem optical skin changes.
As to their optical properties, the components of human skin can be divided into two different categories: the light-scattering components shown as peaks and those absorbing light appearing as dips in the reflectance spectrum. As the post-mortem interval progresses, the concentration of scatterers and absorbers and thus the reflectance spectra change due to post-mortem tissue breakdown and degradation. Based on a total number of 532 reflectance spectrometric measurements in 195 deceased, a characteristic change in the reflectance spectra could be documented in the post-mortem course. Subsequently, an algorithm to calculate the post-mortem interval was developed by analysing the reflectance spectrometric extrema.


The Ups and Downs of the Striatum: Dopamine Biases Upstate Balance of Striosomes and Matrix.
Prager et al. demonstrate an opposite regulation of activity in striosomes and matrix of the striatum. By a D1-receptor-linked L-VGCC-dependent mechanism, dopamine release can extend upstates in matrix D1-expressing direct pathway projection neurons (dSPNs) but shorten them in striosomal dSPNs.


Ependymomas: results of radiation treatment.
Between 1958 and 1980, 102 patients with the diagnosis of ependymoma were seen at the Princess Margaret Hospital. Eleven patients had recurrent disease or were treated elsewhere and 91 patients received radiation therapy following their primary surgical procedure. Fifty patients had cranial tumors and 41 had spinal tumors. The overall survival at five years was 60% and at 10 years was 54%. Those patients with spinal tumours did significantly better with a five year survival of 83% versus 43% for the group with cranial tumors. The other prognostic factors included tumor grade, functional status, age of the patient and interval from surgery to radiation. The most common site of relapse was at the original tumor location, but five patients did show spread through the craniospinal axis. An analysis of dose and the volume treated is made and recommendations for therapy given.


Seven immune-related genes prognostic power and correlation with tumor-infiltrating immune cells in hepatocellular carcinoma.
Given poor prognosis and the lack of efficient therapy for advanced hepatocellular carcinoma, immunotherapy has emerged as an increasingly important role. However, there were few reports on the correlation between immune-related genes and HCC. The purpose of this study is to construct a novel immune-related gene-based prognostic signature for HCC and to explore the potential mechanisms. We organized expression data of 374 HCC samples and 50 nontumor samples from TCGA database. A robust signature was constructed by Cox regression analysis based on the immune-related genes, which were filtered by differential genes analysis and Cox regression analysis. Then, the correlation analysis between the signature and clinical characteristics was conducted. And the signature was validated in ICGC database. Furthermore, the relationships between immune cell infiltration and the signature were explored by bioinformatics analysis. Seven genes-based model (Risk score = BIRC5 * 0.0238 + FOS * 0.0055 + DKK1 * 0.0085 + FGF13 * 0.3432 + IL11 * 0.0135 + IL17D * 0.0878 + SPP1 * 0.0003) was constructed eventually and it was proved to be an independent prognostic factor for HCC patients. The signature-calculated risk scores were shown to be positively correlated with the infiltration of these five immune cells, including macrophages, neutrophils, CD8+T, dendritic, and B cells. And the results suggested that high amplication of BIRC5, FGF13, IL11, IL17D, and SPP1 were more likely correlated with immune cell infiltration. Finally, PPI network, TFs-based regulatory network and gene enrichment plots were performed to show potential molecular mechanisms. We construct a robust immune-related gene-based prognostic signature with seven genes and explore potential mechanisms about it, which may contribute to the immunotherapy research for HCC.


Associations between quality of life, fatigue, and cytokine levels in patients aged 50+ with acute myeloid leukemia.
Quality of life (QOL) is significantly impaired in patients with acute myeloid leukemia (AML), and fatigue is the most common and disabling symptom; effective treatment measures have yet to be found. Cytokines, biomarkers of inflammation, may moderate both health outcomes, but published data are limited. We looked at the role of cytokines in modulating QOL and fatigue in an older AML population. We recruited 34 English-speaking patients (23 men, 11 women) aged 50 or older with AML within 1 year of diagnosis. QOL and fatigue were assessed with validated questionnaires. Blood was simultaneously drawn for quantitative measurement of a 13-cytokine panel. Repeat measurements were done 4-6 weeks later (n = 28 patients). Spearman correlations between health measures and cytokine levels were examined at baseline, as were changes in variables between time points. A potentially clinically important correlation was defined as an r > or = 0.30. At baseline, potentially clinically important correlations were noted between global QOL and interferon (IFN)-gamma (r = -0.376, p = 0.031), interleukin (IL)-2 (r = -0.340, p = 0.053), IL-5 (r = -0.368, p = 0.035), IL-8 (r = -0.312, p = 0.077), and TNF-alpha (r = -0.326, p = 0.064). A similar correlation was observed between IL-6 and fatigue (r = 0.332, p = 0.059). Between time points, there were no potentially important correlations between changes in global QOL and any cytokine. However, potentially important correlations with fatigue were seen with both IL-5 (r = 0.344, p = 0.073) and IL-10 (r = 0.326, p = 0.091) between time points. These preliminary data provide support for a larger controlled study of cytokines, fatigue, and QOL in patients with AML.


Effects of therapeutic paracentesis on systemic and hepatic hemodynamics and on renal and hormonal function.
Thirteen patients with cirrhosis and tense ascites (six with and seven without peripheral edema) underwent 4- to 15-liter paracentesis without intravenous "colloid" replacement. Cardiac output increased from 6.6 +/- 0.7 liters per min at baseline to 8.2 +/- 0.7 liters per min (p less than 0.003) 1 hr after large-volume paracentesis completion and fell to 7.5 +/- 0.69 liters per min (p less than 0.05 vs. baseline, p less than 0.02 vs. 1 hr) 24 hr after large-volume paracentesis completion. There was no change in mean arterial pressure or mean pulmonary artery pressure. Central venous pressure fell from 9.1 +/- 0.8 mm Hg at baseline to 8.6 +/- 1.4 mm Hg 1 hr post-large-volume paracentesis to 6.8 +/- 1.0 mm Hg (p less than 0.005 vs. baseline, p less than 0.02 vs. 1 hr value) at 24 hr, and pulmonary capillary wedge pressure fell from 13.1 +/- 0.9 to 11.1 +/- 1.3 mm Hg 1 hr after large-volume paracentesis and to 9.89 +/- 1.2 (p less than 0.01 vs. baseline, p less than 0.03 vs. 1 hr after large-volume paracentesis) at 24 hr. Heart rate fell from 90 +/- 3.0 to 85 +/- 2.9 beats per min (p less than 0.01) 1 hr after large-volume paracentesis completion, but increased to 89 +/- 2.5 beats per min (p less than 0.02 vs. 1 hr after large-volume paracentesis) at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)


Substance P stimulates proliferation of spinal neural stem cells in spinal cord injury via the mitogen-activated protein kinase signaling pathway.
Substance P (SP) is a neuropeptide that can influence neural stem/progenitor cell (NSPC) proliferation and neurogenesis in the brain. However, we could not find any experimental study that investigates SP action in the spinal cord. The aims of our study were to investigate the potential of the neuropeptide SP in promoting the proliferation of spinal cord-derived NSPCs (SC-NSPCs) after spinal cord injury (SCI) and to clarify the roles of the mitogen-activated protein (MAP) kinase signaling pathway in the process. This is a randomized animal study. The SC-NSPCs were suspended in 100 μL of a neurobasal medium containing SP (binds neurokinin-1 receptor [NK1R]) or L-703,606 (NK1R antagonist) and cultured in a 96-well plate for 5 days. A cell proliferation assay was performed using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. A cord clipping method was used for the SCI model. Substance P and the NK1R antagonist (L-703,606) were infused intrathecally in SCI and sham models. Neural stem/progenitor cell proliferation was evaluated with immunostaining for bromodeoxyuridine (BrdU) and the immature neural marker nestin. An immunoblotting method was used for evaluating the MAP kinase signaling protein that contains extracellular signal-regulated kinases (ERKs and p38) and β-actin as the control group. In vitro, SP (0.01-10 μmol/L) increased the proliferation of cultured SC-NSPCs, with a peak increase of 35±2% at the 0.1 μmol/L concentration. Substance P of 0.1 μmol/L continuously increased SC-NSPC proliferation from 6 hours to 5 days, whereas the proliferation decreased from 18% to 98% with L-703,606 (1-10 μM). Intrathecal infusion of SP (1 μmol/L) for 7 days significantly increased the number of proliferating NPSCs (cells positive for both BrdU and nestin) in the spinal cord (by 120±17%, p<.05) in adult rats, but infusion of L-703,606 (10 μmol/L) significantly decreased the post-SCI induction of NPSC proliferation in the spinal cord (by 87±4%). Also, SP stimulates proliferation of SC-NSPCs via the MAP kinase signaling pathway, especially the phosphorylated ERK and phosphorylated p38 proteins. The phosphorylated ERK and phosphorylated p38 protein levels increased with SP (0.1 μmol/L, p<.05). These data indicate that SP can promote proliferation of SC-NSPCs in SCI and normal conditions and have important roles in neuronal regeneration after SCI. Also, ERKs and p38 MAP kinases are important signaling proteins in this process.


Identification of genes associated with black rot resistance in cabbage through suppression subtractive hybridization.
The suppression subtractive hybridization was employed to elucidate the resistance mechanism in Brassica oleracea var. capitata upon infection with Xanthomonas campestris pv. campestris. A cDNA library was constructed enriched in differentially expressed transcripts in the resistant cultivar Pusa mukta. A total of 150 unigenes were classified into five functional categories. The present study indicates that the defense-related unigenes accounted for the 35 % of the total unigenes studied. Confirmation of defense-specific representation genes through semiquantitative RT-PCR revealed their increased expression in the resistant cultivar which was validated by qPCR. The resistant cultivar elicited a strong hypersensitive response upon attack by black rot pathogen. The study is first of its kind where the resistant cultivar Pusa mukta in India has been assessed for its resistance to the bacterial pathogen.


Genetic predisposition to acute kidney injury--a systematic review.
The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design.


Using multi-step proposal distribution for improved MCMC convergence in Bayesian network structure learning.
Bayesian networks have become popular for modeling probabilistic relationships between entities. As their structure can also be given a causal interpretation about the studied system, they can be used to learn, for example, regulatory relationships of genes or proteins in biological networks and pathways. Inference of the Bayesian network structure is complicated by the size of the model structure space, necessitating the use of optimization methods or sampling techniques, such Markov Chain Monte Carlo (MCMC) methods. However, convergence of MCMC chains is in many cases slow and can become even a harder issue as the dataset size grows. We show here how to improve convergence in the Bayesian network structure space by using an adjustable proposal distribution with the possibility to propose a wide range of steps in the structure space, and demonstrate improved network structure inference by analyzing phosphoprotein data from the human primary T cell signaling network.


Development of an LC-MS method for ultra trace-level determination of 2,2,6,6-tetramethylpiperidine-1-oxl (TEMPO), a potential genotoxic impurity within active pharmaceutical ingredients.
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable free radical which has been widely used for various research and industrial applications, including the manufacture of many active pharmaceutical ingredients. TEMPO has been identified as a potential genotoxic impurity resulting in the need for analytical methodology to accurately determine its level at several orders of magnitude less than typical impurity quantitation limits. TEMPO can undergo disproportionation to form both oxidized and reduced TEMPO, making individual determination unreliable. To overcome this challenge, all TEMPO related species were converted to the reduced form through reduction with sodium ascorbate. Given the ultra-trace (0.5 ppm) level requirements and the lack of UV response in the reduced form, a single quadrupole mass spectrometer (MS) was utilized. In order to implement a highly sensitive MS method in a GMP environment, several approaches were employed to optimize accuracy and robustness including: internal standard correction for drift elimination, six-level standard addition to reduce matrix effects, and weighted linear regression to cover a broad analytical range. The method was fully validated according to ICH guidelines. The method is specific, linear, accurate, precise, and robust within a range of 0.5-100 ppm.


Male-mediated developmental toxicity.
In recent years, the public has become more aware that exposure of males to certain agents can adversely affect their offspring and cause infertility and cancer. The hazards associated with exposure to ionising radiation have been recognised for nearly a century, but interest was aroused when a cluster of leukaemia cases was identified in young children living in Seascale, close to the nuclear processing plant at Sellafield in West Cumbria. There was a civil court case on behalf of two of the alleged victims of paternal irradiation at Seascale against British Nuclear Fuels. The case foundered on "the balance of probabilities". Nevertheless, there was support for paternal exposure from Japanese experimental X-ray studies in mice. The tumours were clearly heritable as shown by F2 transmission. Also, effects of a relatively non-toxic dose of radiation (1Gy) on cell proliferation transmitted to the embryo were manifested in the germ line of adult male mice even after two generations. In addition in humans, smoking fathers appear to give rise to tumours in the F(1) generation. Using rodent models, developmental abnormalities/congenital malformations and tumours can be studied after exposure of males in an extended dominant lethal assay and congenital malformations can be determined which have similar manifestations in humans. The foetuses can also be investigated for skeletal malformations and litters can be allowed to develop to adulthood when tumours, if present, can be observed. Karyotype analysis can be performed on foetuses and adult offspring to determine if induced genetic damage can be transmitted. Using this study design, cyclophosphamide, 1,3-butadiene and urethane have been examined and each compound produced positive responses: cyclophosphamide in all endpoints examined, 1,3-butadiene in some and urethane only produced liver tumours in F(1) male offspring. This suggests the endpoints are determined by independent genetic events. The results from heritable studies with 1,3-butadiene have been used in the parallelogram approach to determine a risk assessment for the germ cells in man.


Struggles for Equal Rights and Social Justice as Unrepresented and Represented in Psychological Research.
Issues of equality and social justice remain important concerns for contemporary societies. Struggles for equal rights and fair treatment continue in both organized movements and in acts of everyday life. We first consider trends in psychological research that fail to address such struggles and may even impede theoretical understanding of the complex processes of thought and action involved when individuals confront situations of welfare, justice, and rights. Then, we consider research, which attempts to address these issues. We review studies on the development of moral judgments and on understandings of equality and distributive justice. We also discuss research that accounts for the varying social contexts of individual lives and conceives of human behavior as engaged in moral judgments, which often produce resistance and opposition to injustice. In conclusion, we call for more attention in psychological research to issues of equity and social justice.


Mechanism of Ds1 excision from the genome of maize streak virus.
We have previously shown that the maize transposable element Ds1 introduced into maize plants by agroinfection can be excised from the genome of geminivirus maize streak virus (MSV). Excision depended strictly on the presence of an active Ac element in the plants. In this study, the excision products or "footprints" left in the MSV genome after Ds1 excision were extensively characterized and the effects of flanking sequences on Ds1 excision were analysed. Most types of footprints obtained were comparable to those described for Ds1 excision in the maize genome, and could be explained by the models proposed for excision of plant transposable elements. In two revertants, however, some terminal sequences of the Ds1 element were found to have been left behind at the excision site. The finding of this novel type of Ds1 footprint indicated that gene conversion events occurred during and/or after Ds1 excision from the MSV genome. A partial deletion of one copy of the 8 bp duplications flanking the Ds1 element had no effect on the frequency or on the types of footprints of Ds1 excision from the MSV genome. Thus, the duplicated 8 bp sequences flanking the transposable element are not involved in Ds1 excision. These results, as well as a statistical analysis of the modifications of the bases flanking the Ds1 element after excision, are discussed in terms of excision models.


Enhancing 18F-FDG-PET/CT analysis in lung cancer patients. Is CT-CT image fusion helpful in predicting pleural involvement? A pilot study.
To retrospectively evaluate the feasibility and value of CT-CT image fusion to assess the shift of peripheral lung cancers with/-out chest wall infiltration, comparing computed tomography acquisitions in shallow-breathing (SB-CT) and deep-inspiration breath-hold (DIBH-CT) in patients undergoing FDG-PET/CT for lung cancer staging. Image fusion of SB-CT and DIBH-CT was performed with a multimodal workstation used for nuclear medicine fusion imaging. The distance of intrathoracic landmarks and the positional shift of tumours were measured using semi-transparent overlay of both CT series. Statistical analyses were adjusted for confounders of tumour infiltration. Cutoff levels were calculated for prediction of no-/infiltration. Lateral pleural recessus and diaphragm showed the largest respiratory excursions. Infiltrating lung cancers showed more limited respiratory shifts than non-infiltrating tumours. A large respiratory tumour-motility accurately predicted non-infiltration. However, the tumour shifts were limited and variable, limiting the accuracy of prediction. This pilot fusion study proved feasible and allowed a simple analysis of the respiratory shifts of peripheral lung tumours using CT-CT image fusion in a PET/CT setting. The calculated cutoffs were useful in predicting the exclusion of chest wall infiltration but did not accurately predict tumour infiltration. This method can provide additional qualitative information in patients with lung cancers with contact to the chest wall but unclear CT evidence of infiltration undergoing PET/CT without the need of additional investigations. Considering the small sample size investigated, further studies are necessary to verify the obtained results.


Measuring motivational relationship processes in experience sampling: A reliability model for moments, days, and persons nested in couples.
The investigation of within-person process models, often done in experience sampling designs, requires a reliable assessment of within-person change. In this paper, we focus on dyadic intensive longitudinal designs where both partners of a couple are assessed multiple times each day across several days. We introduce a statistical model for variance decomposition based on generalizability theory (extending P. E. Shrout & S. P. Lane, 2012), which can estimate the relative proportion of variability on four hierarchical levels: moments within a day, days, persons, and couples. Based on these variance estimates, four reliability coefficients are derived: between-couples, between-persons, within-persons/between-days, and within-persons/between-moments. We apply the model to two dyadic intensive experience sampling studies (n1 = 130 persons, 5 surveys each day for 14 days, ≥ 7508 unique surveys; n2 = 508 persons, 5 surveys each day for 28 days, ≥ 47764 unique surveys). Five different scales in the domain of motivational processes and relationship quality were assessed with 2 to 5 items: State relationship satisfaction, communal motivation, and agentic motivation; the latter consists of two subscales, namely power and independence motivation. Largest variance components were on the level of persons, moments, couples, and days, where within-day variance was generally larger than between-day variance. Reliabilities ranged from .32 to .76 (couple level), .93 to .98 (person level), .61 to .88 (day level), and .28 to .72 (moment level). Scale intercorrelations reveal differential structures between and within persons, which has consequences for theory building and statistical modeling.


The fatigue of voluntary contraction and the peripheral electrical propagation of single motor units in man.
1. Single human motor units from the short extensors of the toes were classified by their voluntary threshold and axonal conduction velocity. The voluntary discharge intervals, and the shortest discharge intervals at which action potentials were conducted to the muscle fibres, were studied during maximal voluntary effort maintained for 1 min, and were compared with the intervals calculated to be necessary for full fusion.2. Electromyographic techniques were used. High selectivity of the recordings was obtained after blocking of the main motor nerve with lidocaine in subjects with an accessory innervation of just a few motor units or 6 months after lesions to intramuscular nerve twigs, when the muscle-fibre density within the motor units was increased.3. For a whole minute of maximal voluntary effort, motor units with low threshold and low conduction velocity fired tonically at a rate that should have been sufficient for maximal tension. These intervals were longer than the intervals at which blocking occurred.4. In ordinarily motivated and untrained subjects, motor units with high threshold and high conduction velocity fired tonically at intervals sufficient for full tension for some seconds. Under these circumstances the voluntary intervals were longer than the critical ones.5. Through extraordinary motivation and training, motor units with high threshold and high conduction velocity could also be driven tonically for 20-60 s at the high rates required for full tension. The critical intervals then approached the voluntary ones. Blockings occurred and increased in frequency as the contraction continued.6. When motor units with high threshold and high conduction velocity were tetanized electrically at 20 Hz, which was the lowest discharge rate of these units in tonic voluntary contraction, blockings occurred within 60 s.7. The role of the peripheral block is discussed in relation to loss of tension in prolonged voluntary contraction.


Glucose requirement for induction by sodium butyrate of the glycoprotein hormone alpha subunit in HeLa cells.
Butyric acid produces multiple effects on mammalian cells in culture, including alterations in morphology, depression of growth rate, increased histone acetylation, and modified production of various proteins and enzymes. The latter effect is exemplified by the induction in HeLa cells of the glycoprotein hormone alpha subunit by millimolar concentrations of the fatty acid. This report demonstrates that increased subunit accumulation in response to sodium butyrate is strikingly dependent on the presence of glucose (or mannose) in the growth medium. In contrast, basal levels of subunit synthesis are only marginally affected when the culture medium is supplemented with one of a variety of hexoses. An increase in the accumulation of HeLa alpha does not occur in medium containing pyruvate as the energy source, and sustained induction requires the simultaneous and continued presence of both glucose and butyrate. The effects of butyrate on HeLa cell morphology and subunit induction can be separated, since the latter is glucose-dependent while the former is not. Failure of butyrate to induce alpha in medium containing pyruvate does not result from restricted subunit secretion, since the levels of intracellular alpha are not increased disproportionately relative to those in the medium. The hexoses which support induction of HeLa alpha (glucose greater than or equal to mannose greater than galactose greater than fructose) are identical to those which have been shown previously to stimulate the glucosylation of lipid-linked oligosaccharides and enhance the synthesis of certain glycoproteins. Labeling of various glycosylation intermediates with [3H]mannose indicates that in glucose medium there is a decrease in the level of radioactivity associated with both dolicholpyrophosphoryl oligosaccharide and cellular glycoproteins and a concomitant increase in the fraction of label recovered in secreted glycoproteins. Butyrate also causes a decrease in [3H]mannose-labeled cellular glycoproteins and an increase in tritiated extracellular glycoproteins, particularly in glucose medium. Likewise, glucose stimulates the incorporation of [3H]glucosamine into immunoprecipitable alpha subunit relative to the bulk of HeLa-secreted glycoproteins, and this is further enhanced by butyrate. However, as demonstrated by lectin chromatography of conditioned media, a nonglycosylated subunit does not accumulate in pyruvate medium, either in the absence or presence of butyrate.(ABSTRACT TRUNCATED AT 400 WORDS)


Biological characterization of microwave based synthesized ZnO and Ce doped ZnO nanoflowers impeded chitosan matrix with enhanced antioxidant and anti-diabetic properties.
The chitosan matrix was used as a substrate for ZnO nanoflowers (ZnO/CH) and Ce-doped ZnO nanoflowers (Ce-ZnO/CH) by microwave-induced hydrothermal synthesis processes. The obtained hybrid structures were assessed as enhanced antioxidant and antidiabetic agents considering the synergetic effect of the different components. The integration of chitosan and cerium induced significantly the biological activity of ZnO flower-like particles. Ce-doped ZnO nano-flowers show higher activities than both ZnO nanoflowers and ZnO/CH composite reflecting the strong effect of surface electrons that were formed by the doping process as compared to the high interactive interface of the chitosan substrate. As an antioxidant the synthetic Ce-ZnO/CH composite achieved remarkable scavenging efficiencies for DPPH (92.4 ± 1.33 %), nitric oxide (95.2 ± 1.81 %), ABTS (90.4 ± 1.64 %), and superoxide (52.8 ± 1.22 %) radicals which are significantly higher values than Ascorbic acid as standard and the commercially used ZnO nanoparticles. Also, its antidiabetic efficiency enhanced greatly achieving strong inhibition effects on porcine α-amylase (93.6 ± 1.66 %), crude α-amylase (88.7 ± 1.82 %), pancreatic α-glucosidase (98.7 ± 1.26 %), crude intestinal α-glucosidase (96.8 ± 1.16 %), and amyloglucosidase (97.2 ± 1.72 %) enzymes. The recognized inhibition percentages are notably higher than the determined percentages using miglitol drug and slightly higher than acarbose. This recommends the Ce-ZnO/CH composite as a potential antidiabetic and antioxidant agent compared with the high cost and the reported side effects of the commonly used chemical drug.


Age-related changes in the neural dynamics of bottom-up and top-down processing during visual object recognition: an electrophysiological investigation.
When recognizing objects in our environments, we rely on both what we see and what we know. While older adults often display increased sensitivity to top-down influences of contextual information during object recognition, the locus of this increased sensitivity remains unresolved. To examine the effects of aging on the neural dynamics of bottom-up and top-down visual processing during rapid object recognition, we probed the differential effects of object perceptual ambiguity and scene context congruity on specific EEG event-related potential components indexing dissociable processes along the visual processing stream. Older adults displayed larger behavioral scene congruity effects than young adults. Older adults' larger visual P2 amplitudes to object perceptual ambiguity (as opposed to the scene congruity P2 effects in young adults) suggest continued resolution of perceptual ambiguity that interfered with scene congruity processing, while post-perceptual semantic integration (as indexed by N400) remained largely intact. These findings suggest that compromised bottom-up perceptual processing in healthy aging leads to an increased involvement of top-down processes to resolve greater perceptual ambiguity during object recognition.


Relationship and prognostic significance of phospho-(serine 166)-murine double minute 2 and Akt activation in node-negative breast cancer with regard to p53 expression.
The Akt signalling pathway plays a central role in tumourigenesis. Activation of Akt is related to a more aggressive phenotype in various human cancers, including breast cancer. Its activation contributes to cancer progression via pleiotropic effects, including suppression of apoptosis and modulation of cell cycle regulation. Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumour suppressor protein. Cell culture studies show that Akt-related phosphorylation of MDM2 at serine 166 allows MDM2 to gain nuclear entry and fulfil its p53 regulating function. This study was designed to analyse the relationship of phospho-MDM2 (pMDM2) expression with Akt activation to determine a possible prognostic relevance of pMDM2 in node-negative breast cancer with respect to Akt activation and p53 status. pMDM2, phospho-Akt (pAkt) and p53 protein expression status were analysed immunohistochemically in 121 paraffin-embedded breast cancer cases. Expression of pMDM2 correlated with Akt activation (P<0.001). Univariate analysis identified pMDM2 as a prognostic factor (P=0.0458) in node-negative breast cancers. The unfavourable prognostic significance was even more pronounced in tumours with a pMDM2(+)/pAkt(+) immunophenotype (P=0.0205). Stratification into a p53-negative subgroup further strengthened the adverse prognostic influence. These data confirm that MDM2 phosphorylation at serine 166 is mediated by Akt kinase. Besides the prognostic impact of pMDM2, our findings suggest that Akt-mediated modulation of the MDM2/p53 complex contributes to increased tumour aggressiveness especially in p53-negative breast cancers. However, due to the relatively small number of patients in this cohort, the results obtained need to be confirmed by larger cohorts.


Activation network mapping for integration of heterogeneous fMRI findings.
Functional neuroimaging techniques have been widely used to probe the neural substrates of facial emotion processing in healthy people. However, findings are largely inconsistent across studies. Here, we introduce a new technique termed activation network mapping to examine whether heterogeneous functional magnetic resonance imaging findings localize to a common network for emotion processing. First, using the existing method of activation likelihood estimation meta-analysis, we showed that individual-brain-based reproducibility was low across studies. Second, using activation network mapping, we found that network-based reproducibility across these same studies was higher. Validation analysis indicated that the activation network mapping-localized network aligned with stimulation sites, structural abnormalities and brain lesions that disrupt facial emotion processing. Finally, we verified the generality of the activation network mapping technique by applying it to another cognitive process, that is, rumination. Activation network mapping may potentially be broadly applicable to localize brain networks of cognitive functions.


The impacts of political hierarchy on corporate pollution emissions: Evidence from a spatial discontinuity in China.
Exploiting Chongqing's promotion to a province-level municipality, this paper investigates the causal effect of political hierarchy on corporate SO2 emissions using a spatial regression discontinuity (RD) design. In 1997, the prefecture-level Chongqing was promoted to a province-level municipality, obtaining a substantial increase in decision-making power over fiscal, personnel and administrative affairs. Given the fact that the areas around the Chongqing-Sichuan border shared the same social, economic, and geographical conditions prior to the treatment, the novel findings show that political hierarchy negatively affects corporate SO2 emissions and Chongqing's enterprises adjacent to the border have a 26% (1-e-0.301) reduction of SO2 emissions comparatively. The effects are robust enough using alternative model specifications and bandwidths. Besides, this paper provides empirical evidence that enterprises of Chongqing have resource-receiving and external-financing advantages owing to its higher political status. These interwoven advantages help enterprises in Chongqing exhibit better financial performance and enable them to conduct energy substitution, improve energy efficiency and adopt more end-of-pipe treatment, thereby mitigating SO2 emissions. Based on these findings, this study provides policy implications by shedding light on the effects of political hierarchy on corporate pollution emissions.


Electrokinetic remediation of organochlorines in soil: enhancement techniques and integration with other remediation technologies.
Electrokinetic remediation has been increasingly used in soils and other matrices for numerous contaminants such as inorganic, organic, radionuclides, explosives and their mixtures. Several strategies were tested to improve this technology effectiveness, namely techniques to solubilize contaminants, control soil pH and also couple electrokinetics with other remediation technologies. This review focus in the experimental work carried out in organochlorines soil electroremediation, aiming to systemize useful information to researchers in this field. It is not possible to clearly state what technique is the best, since experimental approaches and targeted contaminants are different. Further research is needed in the application of some of the reviewed techniques. Also a number of technical and environmental issues will require evaluation for full-scale application. Removal efficiencies reported in real contaminated soils are much lower than the ones obtained with spiked kaolinite, showing the influence of other factors like aging of the contamination and adsorption to soil particles, resulting in important challenges when transferring technologies into the field.


Prevalence of unruptured intracranial aneurysms in healthy asymptomatic Japanese adults: differences in gender and age.
We aimed to assess the prevalence of unruptured intracranial aneurysms (UIAs) in healthy asymptomatic adults, and investigate the differences in incidence due to gender and age in Japan. Magnetic resonance angiography (MRA) results of healthy asymptomatic adults who underwent the procedure for examination of the brain, from April 2010 to March 2012, were retrospectively examined. Patients with a history of ruptured aneurysm and UIAs were excluded. UIAs greater than 2.0 mm in size were counted. In accordance with these criteria, 8,696 people with a mean age of 52.2±9.5 years were examined, and 37.4 % of these individuals were women. The overall prevalence of UIAs was 3.2 %. The prevalence in women was higher than that in men (4.4 % versus 2.5 %, OR, 1.81; 95% CI, 1.4 to 2.31). The prevalence increased with age in both genders. In under 49 years, the prevalence in women and men were 2.7 % and 1.9 %, respectively, with no significant differences (OR, 1.47; CI, 0.91 to 2.37). In over 50 years, the prevalence in women was higher than that in men (5.4 % versus 2.8 %, OR, 2.01; CI, 1.52–2.67). There were significant differences in the locations of UIAs by gender (P <0.001); Internal carotid artery was more frequent in women, whereas anterior cerebral artery and middle cerebral artery were more common inmen. This study provides etiological data on the prevalence of UIAs in healthy asymptomatic Japanese adults, and may be useful in determining therapeutic managements for UIAs.


[Epidemiology of Menière's disease in Cantabria].
To know the main epidemiologic characteristics of Meniere's disease in Cantabria. All the patients diagnosed of "definitive" Meniere's disease between 1992 and 2002 in Sierrallana Hospital of Torrelavega (Cantabria, Spain) were reviewed. Incidence, prevalence, presence of bilateral disease, age at diagnosis and gender were recorded. A total of 75 patients were diagnosed of "definitive" Meniere's" disease" during this time. The incidence was 3/100,000 people/year, the prevalence 75/100,000, male/female ratio was 0.38. Most frequent age at onset was between 40 and 60 years and bilateral cases were 5.3%. Meniere's Disease is not uncommon in Cantabria. It is more prevalent among middle aged women. Bilateral cases are rare.


The effect of growth hormone adjuvant therapy on assisted reproductive technologies outcomes in patients with diminished ovarian reserve or poor ovarian response.
Low response of patients with diminished ovarian reserve to exogenous gonadotropins in controlled ovarian stimulation (COS) protocols is one of the important problems of reproductive endocrinology. Various treatment protocols have been developed in patients with diminished ovarian reserve (DOR) or poor ovarian response (POR). Recently, the addition of growth hormone (GH) to treatment protocols has been brought to the agenda in these patients. In this study, we aimed to investigate the effect of GH adjuvant treatment on intracytoplasmic sperm injection (ICSI) cycle results in patients with DOR or POR. This retrospective cohort study was carried out with patients who diagnosed as DOR or POR and underwent ICSI. The patients were divided into the groups according to whether GH was used. In this study, ongoing pregnancy rates and live birth rates were observed to be significantly higher in the group receiving GH compared to the control group. In addition, there was a significant increase in embryo quality in the group receiving GH. As a result, the addition of GH to COS protocols in DOR and POR patients may increase the ongoing pregnancy rate, live birth rate, embryo quality.


Interlaboratory comparison studies for the improvement of the analysis of zearalenone in Europe.
The employed analytical methods and results of a current large-scale study in the field of the analysis of zearalenone have been compared to several previous interlaboratory comparison studies. Generally, a change in the clean-up techniques could be observed. The more frequent use of immunoaffinity clean-up techniques and the employment of a common reference calibrant resulted in a considerable improvement of the agreement of results between the participating laboratories and an enhanced performance of the employed methods.


Synthesis of tetrahydro-β-carbolines via isomerization of N-allyltryptamines: a metal-catalyzed variation on the Pictet-Spengler theme.
An efficient and broadly applicable alternative to the classical Pictet-Spengler synthesis of tetrahydro-β-carbolines is presented. The method relies on metal-catalyzed isomerization of allylic amines to form reactive iminium intermediates which can be trapped by a tethered indole nucleophile.


A semi-defined medium without serum for small ruminant mycoplasmas.
The composition of the medium used to cultivate Mycoplasma species is very important. Serum is one of the most important additives as it contains lipids (cholesterol) and serum proteins, which are essential for the growth of the organisms. This work reports the development of a semi-defined medium, called MWS (Medium Without Serum) produced without animal serum and bovine serum albumin. MWS seems to be suitable for cultivating several species of caprine mycoplasma, especially M. mycoides subsp. mycoides (LC) and M. mycoides subsp. capri.


The impact of medical interpretation method on time and errors.
Twenty-two million Americans have limited English proficiency. Interpreting for limited English proficient patients is intended to enhance communication and delivery of quality medical care. Little is known about the impact of various interpreting methods on interpreting speed and errors. This investigation addresses this important gap. Four scripted clinical encounters were used to enable the comparison of equivalent clinical content. These scripts were run across four interpreting methods, including remote simultaneous, remote consecutive, proximate consecutive, and proximate ad hoc interpreting. The first 3 methods utilized professional, trained interpreters, whereas the ad hoc method utilized untrained staff. Audiotaped transcripts of the encounters were coded, using a prespecified algorithm to determine medical error and linguistic error, by coders blinded to the interpreting method. Encounters were also timed. Remote simultaneous medical interpreting (RSMI) encounters averaged 12.72 vs 18.24 minutes for the next fastest mode (proximate ad hoc) (p = 0.002). There were 12 times more medical errors of moderate or greater clinical significance among utterances in non-RSMI encounters compared to RSMI encounters (p = 0.0002). Whereas limited by the small number of interpreters involved, our study found that RSMI resulted in fewer medical errors and was faster than non-RSMI methods of interpreting.


Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes.
Several familial syndromes are associated with an increased incidence of nervous system tumors. Recognition of these syndromes is critical to provide optimal clinical care and genetic counseling to affected patients and their families. Identification of the genetic defects responsible for these relatively uncommon disorders has led to the improved understanding of critical molecular pathways involved in tumorigenesis and has contributed to the emergence of molecularly targeted therapeutics against cancer. The hereditary syndromes and diseases included in this review are limited to those associated with brain tumors: neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis complex, von Hippel-Lindau disease, and the less frequently encountered Cowden disease and Li-Fraumeni, Turcot's, and Gorlin's syndromes.


Genetic code: an alternative model of translation.
Our earlier studies of translation have led us to a specific numeric coding of nucleotides (A = 0, C = 1, G = 2, and U = 3)--that is, a quaternary numeric system; to ordering of digrams and codons (read right to left: .yx and Z.yx) as ordinal numbers from 000 to 111; and to seek hypothetic transformation of mRNA to 20 canonic amino acids. In this work, we show that amino acids match the ordinal number--that is, follow as transforms of their respective digrams and/or mRNA-codons. Sixteen digrams and their respective amino acids appear as a parallel (discrete) array. A first approximation of translation in this view is demonstrated by a "twisted" spiral on the side of "phantom" codons and by ordering amino acids in the form of a cross on the other side, whereby the transformation of digrams and/or phantom codons to amino acids appears to be one-to-one! Classification of canonical amino acids derived from our dynamic model clarifies physicochemical criteria, such as purinity, pyrimidinity, and particularly codon rules. The system implies both the rules of Siemion and Siemion and of Davidov, as well as balances of atomic and nucleon numbers within groups of amino acids. Formalization in this system offers the possibility of extrapolating backward to the initial organization of heredity.


What can we do to optimize mitochondrial transplantation therapy for myocardial ischemia-reperfusion injury?
Mitochondrial transplantation is a promising solution for the heart following ischemia-reperfusion injury due to its capacity to replace damaged mitochondria and restore cardiac function. However, many barriers (such as inadequate mitochondrial internalization, poor survival of transplanted mitochondria, few mitochondria colocalized with cardiac cells) compromise the replacement of injured mitochondria with transplanted mitochondria. Therefore, it is necessary to optimize mitochondrial transplantation therapy to improve clinical effectiveness. By analogy, myocardial ischemia-reperfusion injury is like a withered flower, it needs to absorb enough nutrients to recover and bloom. In this review, we present a comprehensive overview of "nutrients" (source of exogenous mitochondria and different techniques for mitochondrial isolation), "absorption" (mitochondrial transplantation approaches, mitochondrial transplantation dose and internalization mechanism), and "flowering" (the mechanism of mitochondrial transplantation in cardioprotection) for myocardial ischemia-reperfusion injury.


Adenosine A1 and A2A receptor cross-talk during ageing in the rat myocardium.
Adenosine (Ado), a naturally occurring autacoid, exerts cardioprotective effects against myocardial ischemia and reperfusion injury, through activation of its receptors type 1 (A1) and 2A (A2A). Since ageing involves a complex change in these effects, we evaluated A1 and A2A gene expression in left (LV) and right ventricle (RV) from 2-, 5-, 12-, and 21-month-old Sprague-Dawley rats. LV end-diastolic (EDD) and end-systolic (ESD) internal dimensions (mm) and LV fractional shortening (FS, %) were measured by M-mode echocardiography. Senescence was associated with a reduction in FS (42+/-1, 38+/-2, 39+/-2 and 35+/-2, in 2-, 5-, 12- and 21-month-old rats; p<0.02) and increases in EDD (7.5+/-0.2, 8.1+/-0.2, 8.5+/-0.2 and 8.8+/-0.2; p<0.001) and ESD (4.2+/-0.1, 4.4+/-0.2, 4.7+/-0.2 and 5.1+/-0.2; p=0.002). Ado A1 mRNA levels were highest in 12 and 21-month-old animals in both ventricles (LV: p<0.001; RV: p=0.001). By contrast, Ado A2A gene expression was lower in the aged LV (p<0.001), but higher in the aged RV (p<0.001). These modifications of Ado receptor gene expression and especially the increase in A1 receptor mRNA may partially explain the stronger antiadrenergic effects of Ado in the senescent heart.


Ancient gene duplications have shaped developmental stage-specific expression in Pristionchus pacificus.
The development of multicellular organisms is accompanied by gene expression changes in differentiating cells. Profiling stage-specific expression during development may reveal important insights into gene sets that contributed to the morphological diversity across the animal kingdom. We sequenced RNA-seq libraries throughout a developmental timecourse of the nematode Pristionchus pacificus. The transcriptomes reflect early larval stages, adult worms including late larvae, and growth-arrested dauer larvae and allowed the identification of developmentally regulated gene clusters. Our data reveals similar trends as previous transcriptome profiling of dauer worms and represents the first expression data for early larvae in P. pacificus. Gene expression clusters characterizing early larval stages show most significant enrichments of chaperones, while collagens are most significantly enriched in transcriptomes of late larvae and adult worms. By combining expression data with phylogenetic analysis, we found that developmentally regulated genes are found in paralogous clusters that have arisen through lineage-specific duplications after the split from the Caenorhabditis elegans branch. We propose that gene duplications of developmentally regulated genes represent a plausible evolutionary mechanism to increase the dosage of stage-specific expression. Consequently, this may contribute to the substantial divergence in expression profiles that has been observed across larger evolutionary time scales.


Quantifying plant phenotypes with isotopic labeling & metabolic flux analysis.
Analyses of metabolic flux using stable isotopes in plants have traditionally been restricted to tissues with presumed homogeneous cell populations and long metabolic steady states such as developing seeds, cell suspensions, or cultured roots and root tips. It is now possible to describe these and other metabolically more dynamic tissues such as leaves in greater detail using novel methods in mass spectrometry, isotope labeling strategies, and transient labeling-based flux analyses. Such studies are necessary for a systems level description of plant function that more closely represents biological reality, and provides insights into the genes that will need to be modified as natural resources become ever more limited and environments change.


Ameliorating the drought stress tolerance of a susceptible soybean cultivar, MAUS 2 through dual inoculation with selected rhizobia and AM fungus.
Drought stress is currently the primary abiotic stress factor for crop loss worldwide. Although drought stress reduces the crop yield significantly, species and genotypes differ in their stress response; some tolerate the stress effect while others not. In several systems, it has been shown that, some of the beneficial soil microbes ameliorate the stress effect and thereby, minimizing yield losses under stress conditions. Realizing the importance of beneficial soil microbes, a field experiment was conducted to study the effect of selected microbial inoculants namely, N-fixing bacteria, Bradyrhizobium liaoningense and P-supplying arbuscular mycorrhizal fungus, Ambispora leptoticha on growth and performance of a drought susceptible and high yielding soybean cultivar, MAUS 2 under drought condition. Drought stress imposed during flowering and pod filling stages showed that, dual inoculation consisting of B. liaoningense and A. leptoticha improved the physiological and biometric characteristics including nutrient uptake and yield under drought conditions. Inoculated plants showed an increased number of pods and pod weight per plant by 19% and 34% respectively, while the number of seeds and seed weight per plant increased by 17% and 32% respectively over un-inoculated plants under drought stress condition. Further, the inoculated plants showed higher chlorophyll and osmolyte content, higher detoxifying enzyme activity, and higher cell viability because of less membrane damage compared to un-inoculated plants under stress condition. In addition, they also showed higher water use efficiency coupled with more nutrients accumulation besides exhibiting higher load of beneficial microbes. Dual inoculation of soybean plants with beneficial microbes would alleviate the drought stress effects, thereby allowing normal plants' growth under stress condition. The study therefore, infers that AM fungal and rhizobia inoculation seems to be necessary when soybean is to be cultivated under drought or water limiting conditions.


Prognosis and related risk factors analysis of total anomalous pulmonary venous connection correction.
This study was performed to analyze the surgical outcomes of our center biventricular correction with total anomalous pulmonary venous connection (TAPVC) and to explore the risk factors associated with postoperative mortality and postoperative pulmonary venous obstruction (PVO). In total, 104 patients diagnosed with TAPVC and underwent biventricular correction from January 1, 2009 to December 31, 2021, in Beijing Children's Hospital Affiliated with Capital Medical University were included. The primary endpoints were early and late postoperative mortality and postoperative pulmonary vein obstruction. Multivariable analysis indicated that prolonged cardiopulmonary bypass (CPB) time was the only independent risk factor for early postoperative mortality. Emergency surgery, preoperative moderate, and severe pulmonary hypertension (PH), and prolonged CPB time were independent risk factors for postoperative PVO. According to ROC curve analysis, the cut-off value of CPB time for predicting early mortality was 148 min (AUC = 0.916, 95% CI 0.811-1.000). In the past 12 years, with surgical technique and perioperative management advancement, the prognosis of children treated with TAPVC biventricular correction in our center has generally improved. However, surgical repair remains challenging, and early mortality remains high in children with prolonged CPB time during surgery. Postoperative PVO often occurs in children who underwent emergency surgery, combined with moderate and severe PH and prolonged CPB time.


Can pre-eclampsia explain higher cesarean rates in the different groups of Robson's classification?
To evaluate the impact of pre-eclampsia on cesarean delivery by using the Robson classification. A retrospective cross-sectional study including all women who delivered in a referral maternity hospital in southeast Brazil from January 2017 to February 2018. Women were classified into 1 of 10 Robson groups and then further subdivided into pre-eclampsia (PE) and non-PE (NPE) groups. Frequency of cesarean was determined for each group and compared by using χ2 and prevalence ratio. Overall, 3102 women were included, of whom 1578 (50.9%) delivered by cesarean. Classification in Robson group 5 was the most frequent among all women (n=727, 23.4%). In the PE group (n=258, 8.3%), group 10 was the most frequent classification (n=120, 46.5%); in NPE, Robson group 5 was the most frequency (n=682, 24.0%). Pre-eclampsia was associated with a higher occurrence of cesarean (77.5% vs 48.4%; prevalence ratio, 2.29; 95% confidence interval, 1.82-2.82), owing to higher rates in Robson groups 1, 5, and 10. Pre-eclampsia was associated with a higher occurrence of cesarean delivery in some Robson groups. Robson classification may be used to evaluate the impact of specific conditions at a facility level to help plan future interventions to optimize the use of cesarean.


Benefit-risk appraisal of lip-split mandibular "swing" vs. transoral approaches to posterior oral/oropharyngeal carcinomas using number needed to treat, to harm, and likelihood to be helped or harmed.
s: To evaluate benefit-risk profiles of lip-split mandibular "swing" vs. transoral approaches (LS-MSA; TOA) to the American Joint Committee on Cancer (AJCC) stage I-III posterior oral/oropharyngeal carcinomas (PO/OPC). Using a retrospective double-cohort study design, we enrolled stage I-III PO/OPC patients treated in two German medical centers during a 4-year interval. The predictor variable was surgical technique (LS-MSA/TOA), and main outcomes were complete resection with R0 margins (CR-R0), 5-year overall survival and recurrence (OS5; R5), and adverse events (AEs). Descriptive and bivariate statistics were computed with α = 95%. Benefit-risk profiles were investigated using number needed to treat (NNT), to harm (NNH), and likelihood to be helped or harmed (LLH). At 5-year follow-ups of 202 subjects, LS-MSA caused significantly better CR-R0 (P = 0.001; NNT: 4) and fewer R5 (P = 0.003; NNT: 5), but more risks of wound dehiscence ([WD]; P = 0.01; NNH = 8), and orocutaneous fistula ([OCF]; P = 0.01; NNH: 10). LLH calculations demonstrated that LS-MSA was 2 and 1.6 times more likely to result in CR-R0 and fewer R5 than an incident of WD. There was no significant difference in OS5, postoperative infections (within 30 postoperative days) and AE domains according to the University of Washington Quality of Life questionnaire version 4 (UW-QoLv4) between the surgical approach groups. Compared to TOA, LS-MSA is an efficacious and tolerable intervention for inspecting and eradicating stage I-III PO/OPCs, and reducing recurrences at 5-year follow-ups. Post-LS-MSA WD and OCF require meticulous concerns and more investigations.


Development and adult organization of the lateral part of the bed nucleus of the stria terminalis in the chicken.
The lateral part of the bed nucleus of the stria terminalis (BSTL) is a component of the subpallial amygdala located near the ventral sulcus of the lateral ventricle, but its limits have not been well defined in birds. In this study, we analyzed the expression patterns of a number of neurochemical markers: GABA, calbindin (CB), calretinin (CR), or neuronal nitric oxide synthase (nNOS), in the embryonic and adult chicken brain, to further characterize the organization of the avian BSTL. From embryonic day 16, it was possible to distinguish three different regions within BSTL on the basis of cytoarchitectonic and immunohistochemical features. A central region, referred to as lateral bed nucleus of the stria terminalis pars densocellularis (BSTLdc), is characterized by numerous tightly packed cell bodies, most of which are GABA-immunoreactive (ir), and two peripheral regions with lower cellular density displaying a moderate GABA expression, referred to as lateral bed nucleus of the stria terminalis, plexiform part 1 (BSTLp1) and plexiform part 2 (BSTLp2), respectively. In contrast to BSTLdc, both plexiform parts are characterized by the presence of many fibers and terminals immunoreactive for nNOS and CR, as well as some CR-ir scattered cells. A distinctive feature of BSTLp2 is a population of CB-ir cells embedded in a slightly CB-ir neuropil. Comparison of our immunohistochemical data with gene expression data suggests that BSTLdc and BSTLp1 are pallidal in nature, whereas BSTLp2 receives important contributions from the entopeduncular/preoptic area.


Morphological and biomechanical changes of the feeding apparatus in developing southern flounder, Paralichthys lethostigma.
The feeding biomechanics of premetamorphic, metamorphic, and postmetamorphic southern flounder, Paralichthys lethostigma, were investigated to better understand the origin and design of adult pleuronectiform feeding mechanisms. Larval P. lethostigma were sampled from culture tanks every day from first feeding through metamorphosis. Fish were then fixed, cleared, and double stained for cartilage and bone. Postmetamorphic juvenile and adult fish were obtained from aquaculture facilities, fixed, and the muscles and bones of the head dissected. All fish were digitally photographed from both sides of the head. Measurements from digital images included head depth, head length, and quadratal angle (a measure of articular-quadrate position). Measurements were also made of closing in-lever, opening in-lever, and out-lever moment arm lengths for the determination of lower jaw opening and closing mechanical advantage. In premetamorphic larvae, quadratal angle increased from 40 degrees to 80 degrees , opening lever ratio increased from 0.10 to 0.37, and closing lever ratio increased from 0.06 to 0.40. From these measurements and observations of cleared and double-stained specimens, it was determined that lower jaw depression and elevation changed from a hyoid-based to an opercular-based mechanism prior to the onset of metamorphosis. With migration of the right eye to the left side of the head, quadratal angle remained relatively unchanged at 72 degrees to 84 degrees , opening lever ratio decreased from a high of 0.32 to a low of 0.14, and closing lever ratio decreased to as low as 0.17. Postmetamorphic fish exhibited little change with a quadratal angle of 83 degrees to 84 degrees , an opening lever ratio of 0.19, and a closing lever ratio of 0.17 to 0.19. Paired measurements made on the left (ocular) and right (blind) sides of the head indicated that quadratal angle was asymmetrical during metamorphosis (P = 0.003, alpha = 0.017). Mechanical advantage for lower jaw elevation was also bilaterally asymmetrical following metamorphosis (P = 0.002, alpha = 0.013). Because mechanical advantage for lower jaw depression was not directionally asymmetrical in metamorphic or postmetamorphic P. lethostigma, functional asymmetry (lateral jaw flexion) is not predicted for jaw opening. These results suggest differences in the design and function of feeding mechanisms for premetamorphic, metamorphic, and postmetamorphic P. lethostigma.


Sufficient Cartilage for Most Talar Articular Defects Can Be Harvested From the Non-Loadbearing Talus: A Cadaveric Analysis.
To assess the quantity of morselized cartilage that can be harvested from the non-load-bearing portion of the talus for immediate reimplantation. Non-load-bearing talar cartilage was harvested from 5 cadaveric specimens using a standard arthroscopic approach. Cartilage was separated from the talus in maximum dorsiflexion at the junction of the talar head and neck, grasped, and morselized into a graft using a cartilage particulator. The volume of reclaimed cartilage was measured, and the extrapolated area of coverage was compared to average osteochondral lesions of the talus previously reported. The total yield of cartilage graft following processing that was obtained from 5 ankle joints ranged from 0.3 mL to 2.1 mL with a mean volume of 1.3 ± 0.7 mL, yielding a theoretical 13.2 ± 7.1 cm2 coverage with a 1-mm monolayer. While the average size of osteochondral lesions of the talus is difficult to estimate, they may range from 0.5 cm2 to 3.7 cm2 according to the literature. This study validated that it is possible to harvest sufficient amount of cartilage for an autologous morselized cartilage graft via a single-stage, single-site surgical and processing technique to address most talar articular cartilage defects. Particulated cartilage autografts have shown promise in surgical management of cartilage defects. A single-site, single-staged procedure that uses a patient's autologous talar cartilage from the same joint has the potential to reduce morbidity associated with multiple surgical sites, multistaged procedure, or nonautologous tissue in ankle surgery.


Hypoxic tumor cell radiosensitization through nitric oxide.
Hypoxia is a principal signature of the tumor microenvironment and is considered to be the most important cause of clinical radioresistance and local failure. Oxygen is so far the best radiosensitizer, but tumor oxygenation protocols are compromised by its metabolic consumption and therefore limited diffusion inside tumors. Many chemical radiosensitizers can selectively target hypoxic tumor cells, but their systemic toxicity compromises their adequate clinical use. NO is an efficient hypoxic radiosensitizer, as it may mimic the effects of oxygen on fixation of radiation-induced DNA damage, but the required levels cannot be obtained in vivo because of vasoactive complications. Our laboratory explored whether this problem may be overcome by endogenous production of NO inside tumors. We demonstrated that iNOS, activated by pro-inflammatory cytokines, is capable of radiosensitizing tumor cells through endogenous production of NO, at non-toxic extracellular concentrations. We observed that this radiosensitizing effect is transcriptionally controlled by hypoxia and by NF-kappaB. Tumor-associated immune cells may contribute to the iNOS-mediated radiosensitization by the generation of pro-inflammatory cytokines and NO, which may diffuse towards bystander tumor cells. Our findings indicate a rationale for combining immunostimulatory and radiosensitizing strategies in the future.


Antimicrobial and Antioxidant Activities of Natural Compounds: Enhance the Safety and Quality of Food.
Nature has offered us a tremendous diversity of natural compounds, for which antimicrobial and antioxidant properties have been intensively explored and nowadays are plenty recognized [...].


Anomalous vessel in the middle ear: the role of CT and MR angiography.
An 8-year-old child was examined because of conductive hearing loss with a retrotympanic mass on otoscopy. CT and MR angiography showed a large inferior tympanic artery traversing the hypotympanum and joining a thin, irregular internal carotid artery with a normal middle meningeal artery. These investigations, coupled with knowledge of the embryological development allowed a diagnosis of a complex vascular anomaly in the middle ear and avoided potential surgical complications.


Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer.
Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5'-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors. Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo.


A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy.
Mutations in CAPN3 cause limb girdle muscular dystrophy R1 (LGMDR1, formerly LGMD2A) and lead to progressive and debilitating muscle wasting. Calpain 3 deficiency is associated with impaired CaMKIIβ signaling and blunted transcriptional programs that encode the slow-oxidative muscle phenotype. We conducted a high-throughput screen on a target of CaMKII (Myl2) to identify compounds to override this signaling defect; 4 were tested in vivo in the Capn3 knockout (C3KO) model of LGMDR1. The leading compound, AMBMP, showed good exposure and was able to reverse the LGMDR1 phenotype in vivo, including improved oxidative properties, increased slow fiber size, and enhanced exercise performance. AMBMP also activated CaMKIIβ signaling, but it did not alter other pathways known to be associated with muscle growth. Thus, AMBMP treatment activates CaMKII and metabolically reprograms skeletal muscle toward a slow muscle phenotype. These proof-of-concept studies lend support for an approach to the development of therapeutics for LGMDR1.


Trichophyton rubrum in the external auditory meatus.
We report the case of a 28-year-old immunocompetent male suffering from otitis externa. The right external auditory meatus was filled with cerumen and detritus, the tympanic membrane covered wallpaper-like with layers of fungi. Mycological analysis revealed Trichophyton rubrum. With further examination tinea pedis of plantar and interdigital type and concomitant onychomycosis of the toenails due to T. rubrum could be detected. The auditory meatus was cleaned and treated topically with clotrimazole. Two weeks later the auditory meatus and the tympanic membrane were bare of fungi and the inflammation was resolved. Treatment of tinea pedis and onychomycosis with terbinafine (systemically and topically) is still lasting.


Temporal trend in the natural history of ulcerative colitis in a country with a low incidence of ulcerative colitis from 2000 through 2018.
The incidence of ulcerative colitis (UC) in Thailand (crude incidence rate of 0.28 per 100,000 persons) is much lower than in the West. The burden of UC varies in different populations. The aim of this study was to evaluate the natural history of UC over the two decades in Bangkok, Thailand. This retrospective study included patients who were diagnosed with UC between 2000 and 2018 in 2 university hospitals. To evaluate changes in the disease course, we stratified patients into 2000-2009 cohort and 2010-2018 cohort. The cumulative probability of endoscopic healing, UC-related hospitalization and colectomy was estimated using the Kaplan-Meier method. A total of 291 UC patients were followed for total of 2,228 person-years. Comparison between 2 cohorts, there were no differences in disease pattern and severity whereas an increase in the combination use of oral and topical mesalamine and the early use of thiopurine was observed. Only 1% of patients for each cohort required biologic agent at 5 years. The rate of achieving mucosal healing increased from 15% to 46% at 3 years (P< 0.01). The rate of UC-related hospitalization decreased from 30% to 21% at 5 years (P< 0.05). The rate of colectomy decreased from 6% to 2% at 5 years (P< 0.05). The natural history of UC in a low incidence country was less aggressive than the West. Over the past two decades, the rates of UC-related hospitalization and colectomy have been decreasing which were similar to the West.