Characteristics, outcomes, and risk factors of surgery for acute lower gastrointestinal bleeding: nationwide cohort study of 10,342 hematochezia cases.
Current evidence on the surgical rate, indication, procedure, risk factors, mortality, and postoperative rebleeding for acute lower gastrointestinal bleeding (ALGIB) is limited. We constructed a retrospective cohort of 10,342 patients admitted for acute hematochezia at 49 hospitals (CODE BLUE J-Study) and evaluated clinical data on the surgeries performed. Surgery was performed in 1.3% (136/10342) of the cohort with high rates of colonoscopy (87.7%) and endoscopic hemostasis (26.7%). Indications for surgery included colonic diverticular bleeding (24%), colorectal cancer (22%), and small bowel bleeding (16%). Sixty-four percent of surgeries were for hemostasis for severe refractory bleeding. Postoperative rebleeding rates were 22% in patients with presumptive or obscure preoperative identification of the bleeding source and 12% in those with definitive identification. Thirty-day mortality rates were 1.5% and 0.8% in patients with and without surgery, respectively. Multivariate analysis showed that surgery-related risk factors were transfusion need ≥ 6 units (P < 0.001), in-hospital rebleeding (P < 0.001), small bowel bleeding (P < 0.001), colorectal cancer (P < 0.001), and hemorrhoids (P < 0.001). Endoscopic hemostasis was negatively associated with surgery (P = 0.003). For small bowel bleeding, the surgery rate was significantly lower in patients with endoscopic hemostasis as 2% compared to 12% without endoscopic hemostasis. Our cohort study elucidated the outcomes and risks of the surgery. Extensive exploration including the small bowel to identify the source of bleeding and endoscopic hemostasis may reduce unnecessary surgery and improve the management of ALGIB.


A study of motoneuron groups and motor columns of the human spinal cord.
Eight normal human spinal cords were studied for motoneuron (Mn) groups and columns. Spinal segments (C1 to Coc.) were identified and embedded in paraffin wax. Serial cross sections were cut at 25 microm and stained by cresyl violet. Cross-sectional profiles of the spinal cord were traced for each segmental level and the outlines of the various Mn groups superimposed. These charts (maps) were used to examine intra and intersegmental changes in the relative positions of the columns. An attempt was made to provide topographical picture of Mn groups of individual segments. In the cervical region neuronal groups were more numerous but smaller and less distinct, while in the lumbosacral region they were fewer, larger and at many levels better circumscribed. The average number of Mn groups at any segmental level was 3-4 and never exceeded 5. C4, C5, C6, C7, L4, L5 and S1 contained numerous Mn groups. Maximum intrasegmental changes were noted at C3, C4, C7, T1, and S2, while at C5, C6, all thoracic, L1 L2 and L3, the pattern was constant throughout the segment. Eleven motor columns were traced in the human spinal cord. Column 1 belonged to the medial division and columns 2-11 to the lateral division of the ventral grey horn. Columns 1 and 2 were the most extensive as they were traceable from the lower medulla to S3 segment. Columns 3-8 were confined to cervical segments (including T1), while columns 9-11 were traced in lumbosacral segments. In general, motor columns followed a definite mode for their appearance and disappearance. Many of them showed rotation from a dorsal to a ventromedial direction.


Left ventricle: fully automated segmentation based on spatiotemporal continuity and myocardium information in cine cardiac magnetic resonance imaging (LV-FAST).
CMR quantification of LV chamber volumes typically and manually defines the basal-most LV, which adds processing time and user-dependence. This study developed an LV segmentation method that is fully automated based on the spatiotemporal continuity of the LV (LV-FAST). An iteratively decreasing threshold region growing approach was used first from the midventricle to the apex, until the LV area and shape discontinued, and then from midventricle to the base, until less than 50% of the myocardium circumference was observable. Region growth was constrained by LV spatiotemporal continuity to improve robustness of apical and basal segmentations. The LV-FAST method was compared with manual tracing on cardiac cine MRI data of 45 consecutive patients. Of the 45 patients, LV-FAST and manual selection identified the same apical slices at both ED and ES and the same basal slices at both ED and ES in 38, 38, 38, and 41 cases, respectively, and their measurements agreed within -1.6 ± 8.7 mL, -1.4 ± 7.8 mL, and 1.0 ± 5.8% for EDV, ESV, and EF, respectively. LV-FAST allowed LV volume-time course quantitatively measured within 3 seconds on a standard desktop computer, which is fast and accurate for processing the cine volumetric cardiac MRI data, and enables LV filling course quantification over the cardiac cycle.


Successful treatment of Chromobacterium violaceum sepsis in South Africa.
Chromobacterium violaceum sepsis is extremely rare and usually fatal. A very few cases of C. violaceum infection have been reported from Africa, but never from South Africa. As far as could be ascertained, this infection has never been reported in a patient with leukaemia. We describe what we believe to be the first such case of C. violaceum sepsis, in a 16-year-old female patient with acute biphenotypic leukaemia, which developed during the neutropenic phase after intensive chemotherapy. The infection was due to a non-pigmented strain of C. violaceum and was associated with a co-infection with Candida parapsilosis; both were successfully treated using broad-spectrum antibiotics, antifungals and removal of a Hickman line.


Accumulation and turnover of the classical Folch-Lees proteolipid proteins in developing and adult rat brain.
The turnover of classical Folch-Lees proteolipid proteins was studied after administration of [2,3-3H]tryptophan to both developing and adult rat brain. The animals were killed from 2h to 250 days after subcutaneous injections of [3H]tryptophan. The measured specific radioactivity in developing brain attained maximum value 24h after the administration of label, whereas the total radioactivity per brain reached a maximum 21 days after injection. The half-life of proteolipid protein from the measured specific radioactivity was 7-20 days, depending on the time-points used for the calculation, whereas calculation from total radioactivity between 28-77 and 91-257 days gave half-lives of 35-40 and 188 days respectively. In contrast, in animals injected at 40 days of age, the half-life from the whole-brain-radioactivity data was 188 days. The problem of the recycling of radioactivity for the synthesis of myelin proteins from either a general or a discrete amino acid pool is discussed.


Internet-based virtual classroom and educational management software enhance students' didactic and clinical experiences in perfusion education programs.
A challenge faced by many university-based perfusion education (PE) programs is the need for student clinical rotations at hospital locations that are geographically disparate from the main educational campus. The problem has been addressed through the employment of distance-learning environments. The purpose of this educational study is to evaluate the effectiveness of this teaching model as it is applied to PE. Web-based virtual classroom (VC) environments and educational management system (EMS) software were implemented independently and as adjuncts to live, interactive Internet-based audio/video transmission from classroom to classroom in multiple university-based PE programs. These Internet environments have been used in a variety of ways including: 1) forum for communication between the university faculty, students, and preceptors at clinical sites, 2) didactic lectures from expert clinicians to students assigned to distant clinical sites, 3) small group problem-based-learning modules designed to enhance students analytical skills, and 4) conversion of traditional face-to-face lectures to asynchronous learning modules. Hypotheses and measures of student and faculty satisfaction, clinical experience, and learning outcomes are proposed, and some early student feedback was collected. For curricula that emphasize both didactic and clinical education, the use of Internet-based VC and EMS software provides significant advancements over traditional models. Recognized advantages include: 1) improved communications between the college faculty and the students and clinical preceptors, 2) enhanced access to a national network of clinical experts in specialized techniques, 3) expanded opportunity for student distant clinical rotations with continued didactic course work, and 4) improved continuity and consistency of clinical experiences between students through implementation of asynchronous learning modules. Students recognize the learning efficiency of on-line information presentation but still prefer the traditional face-to-face classroom environment. Traditional paradigms impose limitations that are rooted in dependence upon the students and instructors being physically located in the same place at the same time. These represents significant impediments for PE programs that use geographically separate clinical sites to provide clinical experience. Historically this has led to a disintegration of the presentation of theory, and a reduction in the quantity or quality of clinical experience opportunities. New PE models help to eliminate limitations and improve the quality of education especially in the face of economic challenges. Perfusion education students and faculty will have to work together to find computer-based offerings that are equivalent to traditional classroom methods.


Use of Aspirin and Statins in Relation to Inflammation in Benign Prostate Tissue in the Placebo Arm of the Prostate Cancer Prevention Trial.
Aspirin and statin use may lower the risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the 7-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, and c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker [OR, 5.60; 95% confidence interval (CI), 1.16-27.07], and statin users were more likely to have low CD68, a macrophage marker (OR, 1.63; 95% CI, 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.


Feature Completion for Occluded Person Re-Identification.
Person re-identification (reID) plays an important role in computer vision. However, existing methods suffer from performance degradation in occluded scenes. In this work, we propose an occlusion-robust block, Region Feature Completion (RFC), for occluded reID. Different from most previous works that discard the occluded regions, RFC block can recover the semantics of occluded regions in feature space. First, a Spatial RFC (SRFC) module is developed. SRFC exploits the long-range spatial contexts from non-occluded regions to predict the features of occluded regions. The unit-wise prediction task leads to an encoder/decoder architecture, where the region-encoder models the correlation between non-occluded and occluded region, and the region-decoder utilizes the spatial correlation to recover occluded region features. Second, we introduce Temporal RFC (TRFC) module which captures the long-term temporal contexts to refine the prediction of SRFC. RFC block is lightweight, end-to-end trainable and can be easily plugged into existing CNNs to form RFCnet. Extensive experiments are conducted on occluded and commonly holistic reID benchmarks. Our method significantly outperforms existing methods on the occlusion datasets, while remains top even superior performance on holistic datasets. The source code is available at https://github.com/blue-blue272/OccludedReID-RFCnet.


A Prospective Comparison of 18F-Sodium Fluoride PET/CT and PSMA-Targeted 18F-DCFBC PET/CT in Metastatic Prostate Cancer.
The purpose of this study was to compare the diagnostic performance of 18F-DCFBC PET/CT, a first-generation 18F-labeled prostate-specific membrane antigen (PSMA)-targeted agent, and 18F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18F-DCFBC PET/CT and 18F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2-12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18F-NaF or 18F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue-only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18F-DCFBC only and 185 bone lesions detected on 18F-NaF or 18F-DCFBC. 18F-NaF detected significantly more bone lesions than 18F-DCFBC (P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18F-DCFBC (ρ > 0.5, P < 0.01) and poor in 18F-NaF (ρ < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy (n = 11) demonstrated more lesions on 18F-NaF than 18F-DCFBC (P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy (n = 8) showed equal to or more lesions on 18F-DCFBC than on 18F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18F-NaF PET/CT, 18F-DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18F-DCFBC PET/CT shows good concordance with NaF PET/CT.


A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia.
Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.


IFNL3 (IL28B) and IFNL4 polymorphisms are associated with treatment response in Thai patients infected with HCV genotype 1, but not with genotypes 3 and 6.
Recent studies have shown an association between single nucleotide polymorphisms (SNPs) in the interferon lambda-3 (IFNL3 or IL-28B) and IFNL4 genes and treatment response to hepatitis C virus genotype 1 (HCV-1) infection. The importance of these SNPs for HCV genotype 3 (HCV-3), and particularly HCV genotype 6 (HCV-6), remains to be elucidated. We analyzed a cohort of 225 Thai individuals with chronic HCV infection treated with pegylated-interferon and ribavirin, of whom 69 (30.7%), 114 (50.7%) and 42 (18.6%) patients were infected with HCV-1, HCV-3, and HCV-6, respectively. DNA extracted from blood samples was analyzed for the SNPs rs12979860 and ss469415590. The distribution of CC, CT, and TT genotypes of rs12979860 was 189 (84%), 28 (12.4%) and 8 (3.6%), respectively, while the distribution of TT/TT, ΔG/TT, and ΔG/ΔG genotypes of ss469415590 was 192(85.3%), 28(12.5%), and 5(2.2%), respectively. Significantly lower frequencies of the favorable genotypes CC (for rs12979860) and TT/TT (for ss469415590) were found in the HCV-1 group in comparison with the other groups. The favorable genotypes were associated significantly with rapid and sustained virological response in the HCV-1 group. However, they were only associated with rapid virological response in the HCV-3 and HCV-6 groups. Furthermore, both SNPs were associated equally with the treatment outcome in the HCV-1 group. In contrast, the role of these SNPs in predicting treatment response was attenuated in the HCV-3 and HCV-6 groups. Thus, identification of these SNPs may be useful only in patients with refractory HCV-1 infection.


Epithelial expression of profibrotic mediators in a model of allergen-induced airway remodeling.
Airway remodeling, including subepithelial fibrosis, is a characteristic feature of asthma and likely contributes to the pathogenesis of airway hyperresponsiveness. We examined expression of genes related to airway wall fibrosis in a model of chronic allergen-induced airway dysfunction using laser capture microdissection and quantitative real-time PCR. BALB/c mice were sensitized and subjected to chronic ovalbumin exposure over a 12-wk period, after which they were rested and then harvested 2 and 8 wk after the last exposure. Chronic allergen-exposed mice had significantly increased indices of airway remodeling and airway hyperreactivity at all time points, although no difference in expression of fibrosis-related genes was found when mRNA extracted from whole lung was examined. In contrast, fibrosis-related gene expression was significantly upregulated in mRNA obtained from microdissected bronchial wall at 2 wk after chronic allergen exposure. In addition, when bronchial wall epithelium and smooth muscle were separately microdissected, gene expression of transforming growth factor-beta1 and plasminogen activating inhibitor-1 were significantly upregulated only in the airway epithelium. These data suggest that transforming growth factor-beta1 and other profibrotic mediators produced by airway wall, and specifically, airway epithelium, play an important role in the pathophysiology of airway remodeling.


Cerebral cavernous malformations: congruency of histopathological features with the current clinical definition.
Cerebral cavernous malformations (CCMs) are defined as a mulberry-like assembly of thin walled vascular sinusoids lined by a thin endothelium lacking smooth muscle and elastin, displaying no intervening brain parenchyma. In this study, we analyse the congruency of histopathological features with the current clinical definition on a large series of neuroradiologically verified CCMs. 87 patients who received no primary treatment prior to surgery were included. Preoperative MRIs of all patients were reviewed. 12 histopathological parameters were assessed systematically, using haematoxylin-eosin, Prussian blue, elastica van Gieson and congo red for amyloid detection. 71/87 (81.6%) of the cases fulfilled the basic histological criteria of CCMs. However, the thickness of the vessel walls and the calibre of the malformed vessels were highly variable. 16/87 cases (18.4%) were histologically non-diagnostic. Non-diagnostic specimens were significantly associated with radiological signs of haemorrhage (p = 0.001). A few cases (4.6%) regionally contained capillary-like malformed vessels. Intervening brain parenchyma between malformed vessels throughout the lesion was seen in 50/71 (70.4%) diagnosable lesions. Haemosiderin deposits, gliosis, thrombosis, fibrotic changes, hyalinised vessel walls, calcification and cholesterol crystals were present in a considerable range. In addition, we found amyloid deposits in 14/87 (16.1%) specimens. Contrary to the current clinical definition, the absence of intervening brain parenchyma does not represent an essential histopathological criterion of CCMs in our series. Furthermore, the diameter of the vessel lumina and the thickness of vessel walls varied considerably. Based on these findings, adaptation of the current definition on the basis of interdisciplinary interaction needs to be considered.


Differential binding cell-SELEX method to identify cell-specific aptamers using high-throughput sequencing.
Aptamers have in recent years emerged as a viable alternative to antibodies. High-throughput sequencing (HTS) has revolutionized aptamer research by increasing the number of reads from a few (using Sanger sequencing) to millions (using an HTS approach). Despite the availability and advantages of HTS compared to Sanger sequencing, there are only 50 aptamer HTS sequencing samples available on public databases. HTS data in aptamer research are primarily used to compare sequence enrichment between subsequent selection cycles. This approach does not take full advantage of HTS because the enrichment of sequences during selection can be due to inefficient negative selection when using live cells. Here, we present a differential binding cell-SELEX (systematic evolution of ligands by exponential enrichment) workflow that adapts the FASTAptamer toolbox and bioinformatics tool edgeR, which are primarily used for functional genomics, to achieve more informative metrics about the selection process. We propose a fast and practical high-throughput aptamer identification method to be used with the cell-SELEX technique to increase the aptamer selection rate against live cells. The feasibility of our approach is demonstrated by performing aptamer selection against a clear cell renal cell carcinoma (ccRCC) RCC-MF cell line using the RC-124 cell line from healthy kidney tissue for negative selection.


The effect of different implant-abutment connections on screw joint stability.
Dental implants with an internal connection have been designed to establish a better stress distribution when lateral external forces act on the prosthesis and minimize the forces transmitted to the fastening screw. In the present study, 10 externally and 10 internally hexed implants were tested with a compressive force applied with an Instron Universal machine. Four cycles of loading-unloading were applied to each specimen to achieve displacements of 0.5, 1, 2, and 2.5 mm. The mean loads for the first cycle were 256.70 N for the external connection and 256 N for the internal connection implants. The independent t test did not reveal any significant differences among the 2 tested groups (P = .780). For the second cycle, the mean loads needed for a displacement of 1 mm were 818.19 N and 780.20 N for the external connection and the internal connection implants, respectively. The independent t test revealed significant differences among the 2 tested groups (P < .001). In the third cycle, the mean load values for a 2-mm displacement were 1394.10 N and 1225.00 N. The independent t test revealed significant differences among the 2 tested groups (P < .001). The mean loads for the fourth cycle were 1488.00 N for the external connection and 1029.00 N for the internal connection implants. These loads were required for a displacement of 2.5 mm. The independent t test revealed significant differences among the 2 tested groups (P < .001). The results of this in vitro study suggest that the internal connection design of the examined implant system could not prevent screw loosening during overloading. No implant or prosthesis failure was noticed in either group.


The slippery slope: critical perspectives on in vitro research methodologies.
This paper attempts to provide critical perspectives on common in vitro research methodologies, including shear bond testing, wear testing, and load-to-failure tests. Origins of interest in high-quality laboratory data is reviewed, in vitro data is categorized into property and simulation protocols, and two approaches are suggested for establishing clinical validity. It is hoped that these insights will encourage further progress toward development of in vitro tests that are validated against clinical performance and/or by producing clinically validated failure or damage mechanisms. Published shear and tensile bond data (macro and micro) is examined in light of published finite element analyses (FEA). This data is subjected to a Weibull scaling analysis to ascertain whether scaling is consistent with failure from the bonded interface or not. Wear tests results are presented in light of the damage mechanism(s) operating. Quantitative wear data is re-examined as being dependent upon contact pressure. Load-to-failure test results are re-analyzed by calculating contact stresses at failure for 119 tests from 54 publications over more than 25 years. FEA analyses and reported failure modes (adhesive, mixed, cohesive) are consistent with failure not involving interfacial "shear stresses" as calculated in published work. Weibull scaling clearly suggests failure involving external surfaces of specimens, not interfacial origins. Contact stresses (pressures) are clearly an important variable in wear testing and are not well-controlled in published work. Load-to-failure tests create damage not seen clinically due to excessively high contact stresses. Most contact stresses in the 119 tests examined were calculated to be between 1000MPa and 5000MPa, whereas clinical contact stresses at wear facets have been measured not to exceed 40MPa. Our community can do a much better job of designing in vitro tests that more closely simulate clinical conditions, especially when contact is involved. Journals are encouraged to thoughtfully consider a ban on publishing papers using bond tests and load-to-failure methods that are seriously flawed and have no clinical relevance.


Identification and kinetic studies of an inducible mannokinase from a Streptomyces strain.
Crude extracts from cells of a Streptomyces strain isolated from a palm-grove soil and grown on different carbon sources showed a constitutive glucokinase. Specifically inducible kinase activity for mannose was found in cells grown on mannose or beta-D-mannan. The activity on mannose was due to a highly specific mannokinase (ATP:D-mannose 6-phosphotransferase, EC 220.127.116.11) which has been separated from the glucokinase by Ultrogel AcA 54 gel filtration chromatography. Initial velocity and inhibition product studies were carried out to investigate the reaction pathway. In the absence of products, reciprocal plots intersecting on the abscissas were observed when either mannose or ATP concentration was varied in the presence of several fixed concentrations of the non-varied substrate. Km values for mannose and Mg-ATP complex are 0.33 and 1.1 mM, respectively. In the product inhibition studies, mannose-6-P was observed to be competitive with mannose and non-competitive with Mg-ATP. The reverse was observed when ADP was used as inhibitor. These data are consistent with a random sequential Bi-Bi mechanism with two dead-end ternary complexes.


Insights into Circular Horticulture: Knowledge Diffusion, Resource Circulation, One Health Approach, and Greenhouse Technologies.
The integration of the circular economy in agriculture has promoted sustainable innovation in food production systems such as horticulture. The present paper illustrates how horticulture is transitioning to the circular economy. This research field's performance approaches and trends were assessed through a bibliometric and text-mining analysis of the literature. Our findings revealed that circular horticulture is a recent research field that is constantly growing. Its approach has been neither systemic nor integrative but fragmented. Bioeconomy, urban agriculture, recycled nutrients, biochar, fertigation, and desalination have been positioned as research hotspots. Vegetables and fruits are the most studied crops. Resource circulation has focused primarily on biowaste recovery to provide benefits such as biofertilizers and linear-substrate substitutes, and on water reuse for the establishment of hydroponic systems. The One Health approach is scarcely explored and, therefore, weakly articulated, wherein the absence of assessment methodologies encompassing the health of ecosystems, animals, and people is a notable limitation. Science-policy interfaces between One Health and food systems need to be improved. Lastly, greenhouse technologies are aligned with bioenergy, sustainable materials, and sensing technologies. Challenges and directions for future research have been raised to promote the redesign of horticultural production systems, integrating long-term circularity.


Teriflunomide for multiple sclerosis.
Disease-modifying therapies (DMTs) for multiple sclerosis aim to specifically reduce inflammation in relapsing multiple sclerosis and promote neuroprotection and neurorepair in progressive multiple sclerosis (MS). Most of the currently available disease-modifying drugs (DMDs) require regular and frequent parenteral administration, which imposes a burden on patients and leads to reduced adherence. Not all MS patients respond adequately to current DMDs and, therefore, alternative MS treatments with less invasive routes of administration and new modes of action are required to expand the current treatment repertoire, increase adherence, and thereby improve efficacy. As one of the oral DMDs, teriflunomide is a potentially promising new oral agent in the treatment of relapsing MS. It inhibits dihydro-orotate dehydrogenase (DHODH) and the synthesis of pyrimidine and has selective immunosuppressive and immunomodulatory properties. To explore the potential benefits of teriflunomide and so expand the available DMT options, the effectiveness and safety of teriflunomide, as monotherapy or combination therapy, were assessed versus placebo or approved DMDs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS. The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 June 2012). We checked references in identified trials and manually searched the reports (2004 to June 2012) from neurological associations and MS societies. We also communicated with researchers participating in trials on teriflunomide and contacted Sanofi-Aventis. All randomised, double-blind, controlled, parallel clinical trials (RCTs) with a length of follow-up of at least one year evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other treatments (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for patients with MS. Titles and abstracts of the citations retrieved by the literature search were screened independently for inclusion or exclusion by two review authors. Any disagreement regarding inclusion was resolved by discussion or by referral to a third assessor if necessary. Two review authors independently extracted data and assessed trial quality. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation of information. Two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFN-β, versus placebo for adult patients with relapsing forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)) and an entry Expanded Disability Status Scale (EDSS) score of ≤ 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add-on IFN-β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified. We found low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS, due to the limited quality of the available RCTs. We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Short-term teriflunomide, 7 or 14 mg alone or with add-on IFN-β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing trials. RCTs with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life.


[Specific features of lymphogenic metastazing in gastric cancer].
The authors made an analysis of specific skip-metastazing in gastric cancer (GC). Their own material was used: an experience with operative treatment of 55 patients was analyzed using the method of intraoperative mapping of lymphatic ducts. Nine cases of probable skip-metastazing were detected. The data of an analysis of this group of patients are given with special reference to the distribution in gender, age, TNM stage, localization of the primary tumor and its type by Borman classification, bed, histological structure of the tumor.


The differential diagnosis of generalized pain.
Patients whose symptoms include widespread, diffuse musculoskeletal pain are commonly referred for rheumatological evaluation, even when the underlying cause may lie out with the remit of rheumatology. A diagnosis of fibromyalgia may seem highly probable even from the referral letter, or after a few leading questions during the consultation. However, the lack of specificity of the many symptoms associated with widespread pain means that other diagnoses have to be considered. The history and examination must bear in mind alternative and concomitant musculoskeletal disorders, such as mild systemic lupus erythematosus, polyarticular osteoarthritis, rheumatoid arthritis, polymyalgia rheumatica, hypermobility syndromes and even osteomalacia. Non-rheumatological diseases may also have symptomatic similarities to fibromyalgia, including neoplastic and neurological diseases, hypothyroidism and other endocrine disorders, chronic infections, as well as a variety of psychiatric conditions. A rational approach to investigation will usually allow other diagnostic possibilities to be excluded without reinforcing the abnormal illness behaviour so common in chronic pain states.


Structure solution of the new titanate Li4Ti8Ni3O21 using precession electron diffraction.
A sample having stoichiometry Li[Ti(1.5)Ni(0.5)]O(4) has been synthesized to obtain a spinel structure. The resulting crystalline powder revealed a multiphase nature with spinel as the minor phase. The main phase is a new trigonal phase having a = 5.05910 (1), c = 32.5371 (1) A. The structure has been solved by direct methods working on a three-dimensional set of intensities obtained from a precession electron-diffraction experiment, and refined on synchrotron powder diffraction data in the space group P3c1. The model consists of hexagonal layers of edge-sharing octahedra occupied either by the heavy cations Ti and Ni, or preferentially by Li. On the basis of cation-site occupancies the stoichiometry becomes Li(4)Ti(8)Ni(3)O(21), which is compatible with the microanalysis results.


Investigation of L - Carnitine Concentrations in Treated Patients with Maple Syrup Urine Disease.
Maple syrup urine disease (MSUD), also known as branched-chain α ketoaciduria, is a metabolic disorder caused by an inborn deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex. Severe neurological damage occurs in most patients with MSUD although the exact mechanism of neurotoxicity still remains unknown. Studies have suggested that neuropathology in patients with MSUD may be related to oxidative stress. L - carnitine mediates the transport of fatty acids into the mitochondria that are required for β-oxidation and ATP production. Along with the important roles it plays in lipid metabolism, L-carnitine also protects tissues from oxidative damage through its antioxidant properties. The study included a total of 15 patients with MSUD who attended regular follow-up visits, and 15 age-matched healthy control subjects, and aimed to investigate L - carnitine levels in treated patients with MSUD and healthy control subjects. L - carnitine levels were found to be significantly lower in the patient group than in the healthy controls. No significant correlation was identified between the plasma branched-chain amino acids leucine, isoleucine, valine, and L - carnitine levels. Patients with MSUD can be treated with adjuvant therapy with L - carnitine supplementation.


Hyperlipidemia and its significance in the aged population.
Starting in childhood, blood lipid levels rise progressively with each ten-year period until age 70, when cholesterol and triglyceride levels begin to stabilize and then decline. By age 80 there is a precipitous drop to approximately the values noted in persons of the 20-30 age group. Data on 195 residents of a geriatric center are included. Despite the lower average lipid levels, 30 per cent of the elderly show some lipid abnormality. There is a definite increase in the risk of death from coronary artery disease in hyperlipidemic persons as compared to those who are normolipidemic, even during the eighth and ninth age decades. Hyperlipidemia appears to be a significant risk in the elderly, as in persons of any age, and should be treated accordingly.


General mental ability and goal type as antecedents of recurrent adaptive task performance.
Even though considerable work has demonstrated a robust positive relationship between general mental ability (GMA) and task performance, recent work indicates that the expected relationship may not hold in the context of adaptive performance. By integrating the concept of choking, or performing worse than expected, with goal theory, the present work advances a theoretical framework aimed at furthering our understanding of how and when GMA is most likely to meaningfully impact performance. Drawing on this perspective, we propose that the relationship between GMA and adaptive performance is uniquely dependent on the type of goal individuals are striving to achieve. Additionally, we note that the nature of this relationship may evolve as people gain experience dealing with unexpected changes. Results of a discontinuous growth model fit to data obtained from a stock market exercise generally indicate that compared with performance goals, do-your-best and learning goals strengthen the relationship between GMA and adaptive performance. Further, we find that performance goals seem to effectively neutralize the GMA-adaptive performance relationship by benefiting those lower on GMA while simultaneously hindering those with higher levels. In contrast, the relationship is largely positive when either a do-your-best or a learning goal is being pursued, particularly after individuals are exposed to a second change. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Evidence-Based Review of Antibiofilm Agents for Wound Care.
Significance: Biofilms in vivo are small densely packed aggregations of microbes that are highly resistant to host immune responses and treatment. They attach to each other and to nearby surfaces. Biofilms are difficult to study and identify in a clinical setting as their quantification necessitates the use of advanced microscopy techniques such as confocal laser scanning microscopy. Nonetheless, it is likely that biofilms contribute to the pathophysiology of chronic skin wounds. Reducing, removing, or preventing biofilms is thus a logical approach to help clinicians heal chronic wounds. Recent Advances: Wound care products have demonstrated varying degrees of efficacy in destroying biofilms in in vitro and preclinical models, as well as in some clinical studies. Critical Issues: Controlled studies exploring the beneficial role of biofilm eradication and its relationship to healing in patients with chronic wounds are limited. This review aims to discuss the mode of action and clinical significance of currently available antibiofilm products, including surfactants, dressings, and others, with a focus on levels of evidence for efficacy in disrupting biofilms and ability to improve wound healing outcomes. Future Directions: Few available products have good evidence to support antibiofilm activity and wound healing benefits. Novel therapeutic strategies are on the horizon. More high-quality clinical studies are needed. The development of noninvasive techniques to quantify biofilms will facilitate increased ease of research about biofilms in wounds and how to combat them.


Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice.
Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on α-synuclein (αS) homeostasis and related PD neuropathology remain unknown. Here, we used an αS tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on αS tetramerization and solubility, formation of vesicle-rich αS+ aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ∼10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher αS tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for αS tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology in vivo Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.SIGNIFICANCE STATEMENT The mechanisms responsible for the male-to-female preponderance in Parkinson's disease (PD) are not well understood yet important for treatment efficacy. We previously showed that abrogating native α-synuclein (αS) tetramers produces a close PD model, including dopaminergic and cortical fiber loss and a progressive motor disorder responsive to l-DOPA. Here, we analyzed sex and use 10b-17β-dihydroxyestra-1,4-dien-3-one treatment of symptomatic 3K males, and demonstrate that the beneficial effects of female sex on PD-like neuropathology can be reinstated by elevating estrogen in the male brain. The study provides evidence that 17β-estradiol restores the tetramer-to-monomer ratio by autophagy turnover of excess αS monomers, vesicle and fiber integrity in brain regions critically involved in motor behavior. These data provide the basis for understanding sex differences in αS homeostasis and the development of therapeutic approaches to treating men and postmenopausal women with PD.


Chronic femoral arteriovenous fistula masquerading as the postphlebitic syndrome.
A patient with a traumatic femoral arteriovenous fistula was misdiagnosed for 11 years as having "postphlebitic syndrome." Angiography revealed diffuse dilatation of the veins and arteries of the right lower extremity with the iliac vein measuring 16.0 cm in diameter and the cava 6.0 cm in diameter. Operative repair of the fistula has resulted in marked clinical improvement and return of the patient to fulltime employment. A history of trauma should be sought when a patient presents with unilateral chronic venous insufficiency.


Donepezil treatment of older adults with cognitive impairment and depression (DOTCODE study): clinical rationale and design.
Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.


A small-molecule/cytokine combination enhances hematopoietic stem cell proliferation via inhibition of cell differentiation.
Accumulated evidence supports the potent stimulating effects of multiple small molecules on the expansion of hematopoietic stem cells (HSCs) which are important for the therapy of various hematological disorders. Here, we report a novel, optimized formula, named the SC cocktail, which contains a combination of three such small molecules and four cytokines. Small-molecule candidates were individually screened and then combined at their optimal concentration with the presence of cytokines to achieve maximum capacity for stimulating the human CD34+ cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. The functional preservation of HSC stemness was confirmed by additional cell and molecular assays in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment of human cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through quantitative polymerase chain reaction (qPCR) during the process of CD34+ cell expansion. The SC cocktail supported the retention of the immunophenotype of hematopoietic stem/progenitor cells remarkably well, by yielding purities of 86.6 ± 11.2% for CD34+ cells and 76.2 ± 10.5% for CD34+CD38- cells, respectively, for a 7-day culture. On day 7, the enhancement of expansion of CD34+ cells and CD34+CD38- cells reached a maxima of 28.0 ± 5.5-fold and 27.9 ± 4.3-fold, respectively. The SC cocktail-expanded CD34+ cells preserved the characteristics of HSCs by effectively inhibiting their differentiation in vitro and retained the multilineage differentiation potential in primary and secondary in vivo murine xenotransplantation trials. Further gene expression analysis suggested that the small-molecule combination strengthened the ability of the cytokines to enhance the Notch pathway for the preservation of HSC stemness, and inhibited the ability of the cytokines to activate the Wnt pathway for HSC differentiation. We developed an optimal small-molecule/cytokine combination for the enhancement of HSC expansion via inhibition of differentiation. This approach indicates promising application for preparation of both the HSCs and the mature, functional hematopoietic cells for clinical transplantation.


Radical external beam radiotherapy for prostate cancer in Japan: differences in the patterns of care among Japan, Germany, and the United States.
Optimal management of radiotherapy for prostate cancer patients has become a major concern for physicians in Japan. We reviewed published reports identifying the differences in the patterns of care for prostate cancer patients treated with radical external beam radiotherapy in Japan, Germany, and the United States. The reports indicate that Japanese patients have more advanced primary disease than patients in Germany or the United States. These patient characteristics for Japan and the United States have been almost unchanged for several years. Regarding radiotherapy, conformal radiotherapy was less frequently administered to patients in Japan than patients in Germany or the United States, and the total radiation dose was higher in Germany and the United States than in Japan. Concerning changes in trends in the patterns of radiotherapy, the percentage of patients treated with higher dose levels in the United States has rapidly increased, whereas the percentage of patients receiving these dose levels in Japan has remained extremely low. On the other hand, hormonal therapy has been used more frequently in Japan than in Germany or the United States. These findings indicate that patient characteristics and patterns of care for prostate cancer in Japan are considerably different from those in Germany or the United States.


Bidirectional substrate fluxes through the system N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver.
System N (SNAT3 and SNAT5) amino acid transporters are key mediators of glutamine transport across the plasma membrane of mammalian cell types, including hepatocytes and astrocytes. We demonstrate that SNAT5 shows simultaneous bidirectional glutamine fluxes when overexpressed in Xenopus oocytes. Influx and efflux are both apparently Na+ dependent but, since they are not directly coupled, the carrier is capable of mediating net amino acid movement across the cell membrane. The apparent Km values for glutamine influx and efflux are similar (approximately 1 mm) and the transporter behaviour is consistent with a kinetic model in which re-orientation of the carrier from outside- to inside-facing conformations (either empty or substrate loaded) is the limiting step in the transport cycle. In perfused rat liver, the observed relationship between influent (portal) glutamine concentration and net hepatic glutamine flux may be described by a simple kinetic model, assuming the balance between influx and efflux through System N determines net flux, where under physiological conditions efflux is generally saturated owing to high intracellular glutamine concentration. SNAT5 shows a more periportal mRNA distribution than SNAT3 in rat liver, indicating that SNAT5 may have particular importance for modulation of net hepatic glutamine flux.


ASAP-CORPS: A Semi-Autonomous Platform for COntact-Rich Precision Surgery.
Remote military operations require rapid response times for effective relief and critical care. Yet, the military theater is under austere conditions, so communication links are unreliable and subject to physical and virtual attacks and degradation at unpredictable times. Immediate medical care at these austere locations requires semi-autonomous teleoperated systems, which enable the completion of medical procedures even under interrupted networks while isolating the medics from the dangers of the battlefield. However, to achieve autonomy for complex surgical and critical care procedures, robots require extensive programming or massive libraries of surgical skill demonstrations to learn effective policies using machine learning algorithms. Although such datasets are achievable for simple tasks, providing a large number of demonstrations for surgical maneuvers is not practical. This article presents a method for learning from demonstration, combining knowledge from demonstrations to eliminate reward shaping in reinforcement learning (RL). In addition to reducing the data required for training, the self-supervised nature of RL, in conjunction with expert knowledge-driven rewards, produces more generalizable policies tolerant to dynamic environment changes. A multimodal representation for interaction enables learning complex contact-rich surgical maneuvers. The effectiveness of the approach is shown using the cricothyroidotomy task, as it is a standard procedure seen in critical care to open the airway. In addition, we also provide a method for segmenting the teleoperator's demonstration into subtasks and classifying the subtasks using sequence modeling. A database of demonstrations for the cricothyroidotomy task was collected, comprising six fundamental maneuvers referred to as surgemes. The dataset was collected by teleoperating a collaborative robotic platform-SuperBaxter, with modified surgical grippers. Then, two learning models are developed for processing the dataset-one for automatic segmentation of the task demonstrations into a sequence of surgemes and the second for classifying each segment into labeled surgemes. Finally, a multimodal off-policy RL with rewards learned from demonstrations was developed to learn the surgeme execution from these demonstrations. The task segmentation model has an accuracy of 98.2%. The surgeme classification model using the proposed interaction features achieved a classification accuracy of 96.25% averaged across all surgemes compared to 87.08% without these features and 85.4% using a support vector machine classifier. Finally, the robot execution achieved a task success rate of 93.5% compared to baselines of behavioral cloning (78.3%) and a twin-delayed deep deterministic policy gradient with shaped rewards (82.6%). Results indicate that the proposed interaction features for the segmentation and classification of surgical tasks improve classification accuracy. The proposed method for learning surgemes from demonstrations exceeds popular methods for skill learning. The effectiveness of the proposed approach demonstrates the potential for future remote telemedicine on battlefields.


Sevelamer revisited: pleiotropic effects on endothelial and cardiovascular risk factors in chronic kidney disease and end-stage renal disease.
Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent independent-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, independent-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.


Melatonin receptors in rat hippocampus: molecular and functional investigations.
Since binding sites for melatonin have been found in the hippocampus of several mammals, it has been suggested that the pineal hormone melatonin is able to modulate neuronal functions of hippocampal cells. In order to get more insight into the role of melatonin for the functions of hippocampal cells, the following experiments were performed: male rats, maintained under a 12/12-h light-dark cycle, were sacrificed by decapitation at zeitgeber times (h) ZT2, ZT8, and ZT15 (ZT0 = lights on); for experiment 1, gene expression for melatonin receptors was detected in the hippocampus and in hippocampal subfields by means of the RT-PCR technique; for experiment 2, electrophysiological and pharmacological properties of melatonin receptors heterologously expressed in Xenopus oocytes after injection of mRNA from the hippocampus were analyzed by means of voltage clamp technique; and for experiment 3, effects of melatonin on the spontaneous firing rate of action potentials in the CA1 regions of hippocampal slices were analyzed by means of extracellular recordings. The RT-PCR data revealed that transcripts for both the MT1 and MT2 melatonin receptors are present in the dentate gyrus, CA3, and CA1 regions, and the subiculum of the hippocampus. Injection of mRNA from rat hippocampus into the Xenopus oocytes led to the functional reconstitution of melatonin-sensitive receptors, which activates calcium-dependent chloride inward currents. The melatonin responses were abolished by simultaneous administration of the antagonists 2-phenylmelatonin and luzindole, and were unaffected by the MT2 antagonist 4-phenyl-2-propionamidotetralin. Bath-applied melatonin (1 micromol/l) enhances the firing rate of neurons in the CA1 region. The effect was small in experiments performed at ZT8 (<2 times the initial level) and large in experiments performed at ZT15 (>6 times). The changes of neuronal firing rate induced by melatonin were completely suppressed with simultaneous administration of the melatonin receptor antagonist luzindole (10 micromol/l). The results indicate that melatonin may play an important role in modulating neuronal excitability in the hippocampus.


[Severe aplastic anaemia in six children after non-A-E hepatitis without hepatic failure].
Aplastic anaemia can coincide with non-A-E hepatitis. Treatment follows a standardised study protocol of the German Society of Paediatric Oncology and Haematology (GPOH). Patients receive immunosuppression and/or bone marrow transplantation. We present six cases of aplastic anaemia after non-A-E hepatitis with different courses. In four of these children illness first presented with acute gastroenteritis. Five out of six children fully recovered, two of these with immunosuppression alone, three after bone marrow transplantation. One patient died due to complications of the bone marrow transplantation. In two patients steroid therapy was carried out to treat the hepatitis. This did not have any effect on the course of their aplastic anemia. We emphasise this common combination of aplastic anemia following non-A-E hepatitis. This overview underlines the necessity of regular blood testing after non-A-E hepatitis. Often gastroenteritis seems to precede illness thus perhaps indicating an infectious trigger.


CAV1 and KRT5 are potential targets for prostate cancer.
Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis.


Influence of Temperature and Electrolyte Concentration on the Structure and Catalytic Oxygen Evolution Activity of Nickel-Iron Layered Double Hydroxide.
NiFe layered double hydroxide (LDH) is inarguably the most active contemporary catalyst for the oxygen evolution reaction under alkaline conditions. However, the ability to sustain unattenuated performance under challenging industrial conditions entailing high corrosivity of the electrolyte (≈30 wt. % KOH), high temperature (>80 °C) and high current densities (>500 mA cm-2 ) is the ultimate criterion for practical viability. This work evaluates the chemical and structural stability of NiFe LDH at conditions akin to practical electrolysis, in 30 % KOH at 80 °C, however, without electrochemical polarization, and the resulting impact on the OER performance of the catalyst. Post-analysis of the catalyst by means of XRD, TEM, FT-IR, and Raman spectroscopy after its immersion into 7.5 m KOH at 80 °C for 60 h revealed a transformation of the structure from NiFe LDH to a mixture of crystalline β-Ni(OH)2 and discrete predominantly amorphous FeOOH containing minor non-homogeneously distributed crystalline domains. These structural and compositional changes led to a drastic loss of the OER activity. It is therefore recommended to study catalyst stability at industrially relevant conditions.


Risk Prediction Models for Lung Cancer: A Systematic Review.
Many lung cancer risk prediction models have been published but there has been no systematic review or comprehensive assessment of these models to assess how they could be used in screening. We performed a systematic review of lung cancer prediction models and identified 31 articles that related to 25 distinct models, of which 11 considered epidemiological factors only and did not require a clinical input. Another 11 articles focused on models that required a clinical assessment such as a blood test or scan, and 8 articles considered the 2-stage clonal expansion model. More of the epidemiological models had been externally validated than the more recent clinical assessment models. There was varying discrimination, the ability of a model to distinguish between cases and controls, with an area under the curve between 0.57 and 0.879 and calibration, the model's ability to assign an accurate probability to an individual. In our review we found that further validation studies need to be considered; especially for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial 2012 Model Version (PLCOM2012) and Hoggart models, which recorded the best overall performance. Future studies will need to focus on prediction rules, such as optimal risk thresholds, for models for selective screening trials. Only 3 validation studies considered prediction rules when validating the models and overall the models were validated using varied tests in distinct populations, which made direct comparisons difficult. To improve this, multiple models need to be tested on the same data set with considerations for sensitivity, specificity, model accuracy, and positive predictive values at the optimal risk thresholds.


Multipolymer systems.
Different polymers can be combined to yield a wide variety of composite materials: layered sheets and films, homogeneous and heterogeneous blends, interpenetrating polymer networks, bicomponent fibers, and others. Some properties of a multipolymer material are roughly additive, but synergistic interactions can yield properties and performances superior to those of the individual constituents. Consequently, the use of polymers in combination is a rapidly growing component of polymer materials technology.


A new locus for autosomal recessive congenital cataract identified in a Pakistani family.
To identify the disease locus for autosomal recessive congenital cataract in a consanguineous Pakistani family. All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and logarithm of odds (LOD) scores were calculated. The clinical records and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Maximum LOD scores of 5.01, 4.38, and 4.17 at theta=0 were obtained with markers D7630, D7S657, and D7S515, respectively. Fine mapping refined the critical interval and suggested that markers in a 27.78 cM (27.96 Mb) interval are flanked by markers D7S660 and D7S799, which co-segregate with the disease phenotype in family PKCC108. We have identified a new locus for autosomal recessive congenital cataract, localized to chromosome 7q21.11-q31.1 in a consanguineous Pakistani family.


Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure.
The median latency of 2 degrees MDS/AL is 4 to 5 years. A high percentage of patients with 2 degrees MDS/AL convert to 2 degrees AL. Survival of either is less than 1 year. A constellation of morphologic abnormalities from all 3 cell lines produces a unique appearance. Both 2 degrees MDS and 2 degrees AL are difficult to classify by the FAB system. With the exception of the identification of karyotypic abnormalities, the biology of 2 degrees MDS/AL remains largely unexplored. Alterations of chromosomes 5 and 7 predominate, but other associated cytogenetic abnormalities are being increasingly recognized. A synthesis of data regarding 2 degrees MDS/AL resulting from the treatment of several primary malignancies generates the tentative conclusions that (a) many of the alkylating agents, and the nonclassic alkylating agent procarbazine, are leukemogens; (b) melphalan is a more potent leukemogen than cyclophosphamide. None of the other alkylating agents has been clearly established to be more or less potent than another; (c) increasing duration or amount of alkylator-based chemotherapy increases the risk of leukemogenesis; (d) low doses of radiation delivered to large volumes of bone marrow are weakly leukemogenic. High doses of radiation delivered to small volumes are not. Due to the latter, there is minimal additive risk for 2 degrees MDS/AL among studies using alkylator-based chemotherapy and radiotherapy, either concurrently or sequentially; (e) the older patient (greater than 40) is at increased risk for 2 degrees MDS/AL, at least in Hodgkin's disease. Children may be at lesser risk than adults, and younger children at lesser risk than older children; (f) the risk of 2 degrees MDS/AL peaks within the first decade after treatment for the primary malignancy. The incidence rates during the second decade are low. Identified occupational/environmental risks for 2 degrees MDS/AL include benzene, ambient and diagnostic radiation exposure, and perhaps ethylene oxide. The similarities in karyotype abnormalities among leukemic cells of those whose occupations expose them to chemical hazard, and those who are exposed to cytotoxic agents, suggest that many more environmental leukemogens have yet to be discovered. Karyotype is an important prognostic factor for both achievement of CR and for survival. Nonaggressive treatment approaches have not proven useful, although the use of hematopoietic growth factors offers promise in this area. Combination chemotherapy is justified in patients with adequate performance statuses and "favorable" karyotypes. Allogeneic bone marrow transplantation is currently the only curative approach, and can be applied without attempts to first reduce the leukemic burden.


Integrative modelling of the influence of MAPK network on cancer cell fate decision.
The Mitogen-Activated Protein Kinase (MAPK) network consists of tightly interconnected signalling pathways involved in diverse cellular processes, such as cell cycle, survival, apoptosis and differentiation. Although several studies reported the involvement of these signalling cascades in cancer deregulations, the precise mechanisms underlying their influence on the balance between cell proliferation and cell death (cell fate decision) in pathological circumstances remain elusive. Based on an extensive analysis of published data, we have built a comprehensive and generic reaction map for the MAPK signalling network, using CellDesigner software. In order to explore the MAPK responses to different stimuli and better understand their contributions to cell fate decision, we have considered the most crucial components and interactions and encoded them into a logical model, using the software GINsim. Our logical model analysis particularly focuses on urinary bladder cancer, where MAPK network deregulations have often been associated with specific phenotypes. To cope with the combinatorial explosion of the number of states, we have applied novel algorithms for model reduction and for the compression of state transition graphs, both implemented into the software GINsim. The results of systematic simulations for different signal combinations and network perturbations were found globally coherent with published data. In silico experiments further enabled us to delineate the roles of specific components, cross-talks and regulatory feedbacks in cell fate decision. Finally, tentative proliferative or anti-proliferative mechanisms can be connected with established bladder cancer deregulations, namely Epidermal Growth Factor Receptor (EGFR) over-expression and Fibroblast Growth Factor Receptor 3 (FGFR3) activating mutations.


A novel single-fluorophore-based ratiometric fluorescent probe for direct detection of isocyanates in air.
A ratiometric fluorescent probe based on anthracene carboximide was developed for direct detection of isocyanates in air. The sensing mechanism was illustrated to be variation in the photophysical properties caused by the nucleophilic reaction of the probe molecule. A number of isocyanates were conveniently detected by a test paper.


Time-lapse fluorescence imaging of Arabidopsis root growth with rapid manipulation of the root environment using the RootChip.
The root functions as the physical anchor of the plant and is the organ responsible for uptake of water and mineral nutrients such as nitrogen, phosphorus, sulfate and trace elements that plants acquire from the soil. If we want to develop sustainable approaches to producing high crop yield, we need to better understand how the root develops, takes up a wide spectrum of nutrients, and interacts with symbiotic and pathogenic organisms. To accomplish these goals, we need to be able to explore roots in microscopic detail over time periods ranging from minutes to days. We developed the RootChip, a polydimethylsiloxane (PDMS)- based microfluidic device, which allows us to grow and image roots from Arabidopsis seedlings while avoiding any physical stress to roots during preparation for imaging(1) (Figure 1). The device contains a bifurcated channel structure featuring micromechanical valves to guide the fluid flow from solution inlets to each of the eight observation chambers(2). This perfusion system allows the root microenvironment to be controlled and modified with precision and speed. The volume of the chambers is approximately 400 nl, thus requiring only minimal amounts of test solution. Here we provide a detailed protocol for studying root biology on the RootChip using imaging-based approaches with real time resolution. Roots can be analyzed over several days using time lapse microscopy. Roots can be perfused with nutrient solutions or inhibitors, and up to eight seedlings can be analyzed in parallel. This system has the potential for a wide range of applications, including analysis of root growth in the presence or absence of chemicals, fluorescence-based analysis of gene expression, and the analysis of biosensors, e.g. FRET nanosensors(3).


Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies.
To describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs). Patients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents. We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy. Neuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.


Both hemolytic anemia and malaria parasite-specific factors increase susceptibility to Nontyphoidal Salmonella enterica serovar typhimurium infection in mice.
Severe pediatric malaria is an important risk factor for developing disseminated infections with nontyphoidal Salmonella serotypes (NTS). While recent animal studies on this subject are lacking, early work suggests that an increased risk for developing systemic NTS infection during malaria is caused by hemolytic anemia, which leads to reduced macrophage microbicidal activity. Here we established a model for oral Salmonella enterica serotype Typhimurium challenge in mice infected with Plasmodium yoelii nigeriensis. Initial characterization of this model showed that 5 days after coinoculation, P. yoelii nigeriensis infection increased the recovery of S. Typhimurium from liver and spleen by approximately 1,000-fold. The increased bacterial burden could be only partially recapitulated by antibody-mediated hemolysis, which increased the recovery of S. Typhimurium from liver and spleen by 10-fold. These data suggested that both hemolysis and P. yoelii nigeriensis-specific factors contributed to the increased susceptibility to S. Typhimurium. The mechanism by which hemolysis impaired resistance to S. Typhimurium was further investigated. In vitro, S. Typhimurium was recovered 24 h after infection of hemophagocytic macrophages in 2-fold-higher numbers than after infection of mock-treated macrophages, making it unlikely that reduced macrophage microbicidal activity was solely responsible for hemolysis-induced immunosuppression during malaria. Infection with P. yoelii nigeriensis, but not antibody-mediated hemolysis, reduced serum levels of interleukin-12p70 (IL-12p70) in response to S. Typhimurium challenge. Collectively, studies establishing a mouse model for this coinfection suggest that multiple distinct malaria-induced immune defects contribute to increased susceptibility to S. Typhimurium.


Hydrophilic tripeptide-functionalized magnetic metal-organic frameworks for the highly efficient enrichment of N-linked glycopeptides.
Hydrophilic interaction liquid chromatography (HILIC) is a useful tool in glycoproteomic analysis. Glutathione (GSH) is a well-known zwitterionic tripeptide with great hydrophilicity and biocompatibility and is ubiquitous in biological activities. In this study, a hydrophilic metal-organic framework (denoted as mMOF@Au@GSH) was synthesized by grafting glutathione on Au-immobilized magnetic MOFs via the affinity between the thiol group in glutathione and Au. Endowed with the high hydrophilicity of glutathione, the large surface area of the MOF and strong magnetic responsiveness of magnetic nanoparticles, the as-prepared mMOF@Au@GSH exhibited high selectivity (1 : 100) and great sensitivity (0.5 fmol μL-1) towards glycopeptides. Furthermore, it also achieved outstanding performance in enriching glycopeptides from complex biological samples. In all, 273 glycopeptides corresponding to 94 glycoproteins were identified from only 2 μL human serum.


The oligosaccharides of Xiasangju alleviates dextran sulfate sodium-induced colitis in mice by inhibiting inflammation.
Xiasangju (XSJ) is a traditional Chinese herbal formula consisted of Prunella spica, Mulberry leaf and Chrysanthemi indici flos, which can be used to treat fever, headache and ulcer. To explore the effects of oligosaccharides from XSJ (OX) on colitis, we used dextran sulfate sodium (DSS) to establish colitis mouse models. After administration of OX with different doses on the control and colitis mice, we measured their body weights, disease activity indexes (DAI), lengths and histopathologic changes of colons, spleen indexes. The inflammatory cytokines and oxidative stress-related factors in serum, and the intestinal microbial community in feces were also detected. We found that colitis mice with oral administration of OX showed higher body weights and lower levels of DAI and spleen index. Tissue damages induced by DSS were also alleviated by OX treatment. The colitis mice with OX treatment exhibited lower levels of AST, ALT, BUN, CR, MDA and a down-regulated expression of IL-6 and IL-1β, while the activity of SOD was up-regulated. Furthermore, OX improved the relative abundance of gut microbiota and restored the proportions of Bacteroidetes and Muribaculaceae. We found that oligosaccharides from XSJ alleviated the symptoms of colitis mice through its inhibitory effects on inflammation and oxidative stress, and also regulated the composition of intestinal flora, which indicates a beneficial role for patients with colitis.


Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing.
Circulating tumor cells (CTC) released into blood from primary cancers and metastases reflect the current status of tumor genotypes, which are prone to changes. Here, we conducted the first comprehensive genomic profiling of CTCs using array-comparative genomic hybridization (CGH) and next-generation sequencing. We used the U.S. Food and Drug Administration-cleared CellSearch system, which detected CTCs in 21 of 37 patients (range, 1-202/7.5 mL sample) with stage IV colorectal carcinoma. In total, we were able to isolate 37 intact CTCs from six patients and identified in those multiple colorectal cancer-associated copy number changes, many of which were also present in the respective primary tumor. We then used massive parallel sequencing of a panel of 68 colorectal cancer-associated genes to compare the mutation spectrum in the primary tumors, metastases, and the corresponding CTCs from two of these patients. Mutations in known driver genes [e.g., adenomatous polyposis coli (APC), KRAS, or PIK3CA] found in the primary tumor and metastasis were also detected in corresponding CTCs. However, we also observed mutations exclusively in CTCs. To address whether these mutations were derived from a small subclone in the primary tumor or represented new variants of metastatic cells, we conducted additional deep sequencing of the primary tumor and metastasis and applied a customized statistical algorithm for analysis. We found that most mutations initially found only in CTCs were also present at subclonal level in the primary tumors and metastases from the same patient. This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse.


The glycemic response is a personal attribute.
The Glycemic Index (GI) is a measure of the extent of the change in blood glucose content (glycemic response) following consumption of digestible carbohydrate, relative to a standard such as glucose. We have explored whether the reported GIs of foods are a sufficient guide to a person wishing to avoid large glycemic responses and thereby avoid hyperglycemia. For this purpose, volunteers carried out multiple tests of four foods, following overnight fasting, measuring the glycemic response over 2 H. The areas under the blood glucose/time curves (AUCs) were compared. Each food tester displayed individual, characteristic glycemic responses to each food, unrelated to any other tester's response. Wide variations (up to 5-fold) were seen between the average AUCs for the same test by different testers. The absolute magnitudes of the glycemic responses are important for individuals trying to control blood sugar and/or body weight, but using published GI lists as a guide to control the glycemic response is not fully informative. This is because in calculating the GI, individual glycemic responses to glucose are normalized to 100. GI values are, therefore, relative and are not necessarily a reliable guide to the person's actual individual AUC when consuming a food. Without knowledge of the person's characteristic blood glucose responses, reliance only on the GI may be misleading.


Estimating selection on the act of inbreeding in a population with strong inbreeding depression.
Inbreeding depression is widely regarded as a driving force in the evolution of dispersal, mate choice and sperm selection. However, due to likely costs of inbreeding avoidance, which are poorly understood, it is unclear to what extent selection to avoid inbreeding is expected in nature. Moreover, there are currently very few empirical estimates of the strength of selection against the act of inbreeding (mating with a relative), as opposed to the fitness costs of being inbred. Here, we use data from the individual-based study of red deer on the Scottish island of Rum, a strongly polygynous system which harbours a large inbreeding load, to estimate selection against the act of inbreeding for each sex. We use pedigree and genomic estimates of relatedness between individuals and measure fitness using both lifetime breeding success (number of calves born) and lifetime reproductive success (number of calves surviving to independence), with the latter incorporating inbreeding depression in calf survival. We find for both sexes that the repeatability of the act of inbreeding was low (< 0.1), suggesting little among-individual variation for this trait on which selection can act. Using the genomic measures, there was significant selection against the act of inbreeding in males, but not in females, and there was considerable uncertainty in the estimate in both sexes. We discuss possible explanations for these patterns and their implications for understanding the evolution of inbreeding avoidance in natural populations.


[Electrical characteristics of normal and transformed fibroblasts in tissue culture].
The two-electrode method of input resistance measuring was shown to give lower values of resistance compared with the one-electrode balance method. Gradual growth of estimates of input resistance and membrane potential in the cause of experiment is associated with decrease in the shunting effect of the electrode puncture. The mean values of steady Rin of sparse and confluent culture did not differ when the cells were electrically disconnected (38 plus or minus 1.2 MO and 41 plus or minus 1.8 MO respectively) and differed in electrically coupled fibroblasts (54 plus or minus 4.9 MO --sparse; 29 plus or minus 2.2 MO -- confluent culture). This difference is thought to be associated with shunting effect of electrical connections. The specific resistance of membrane was estimated in normal and transformed fibroblasts.


Inter-rater agreement in trait judgements from faces.
Researchers have long been interested in how social evaluations are made based upon first impressions of faces. It is also important to consider the level of agreement we see in such evaluations across raters and what this may tell us. Typically, high levels of inter-rater agreement for facial judgements are reported, but the measures used may be misleading. At present, studies commonly report Cronbach's α as a way to quantify agreement, although problematically, there are various issues with the use of this measure. Most importantly, because researchers treat raters as items, Cronbach's α is inflated by larger sample sizes even when agreement between raters is fixed. Here, we considered several alternative measures and investigated whether these better discriminate between traits that were predicted to show low (parental resemblance), intermediate (attractiveness, dominance, trustworthiness), and high (age, gender) levels of agreement. Importantly, the level of inter-rater agreement has not previously been studied for many of these traits. In addition, we investigated whether familiar faces resulted in differing levels of agreement in comparison with unfamiliar faces. Our results suggest that alternative measures may prove more informative than Cronbach's α when determining how well raters agree in their judgements. Further, we found no apparent influence of familiarity on levels of agreement. Finally, we show that, like attractiveness, both trustworthiness and dominance show significant levels of private taste (personal or idiosyncratic rater perceptions), although shared taste (perceptions shared with other raters) explains similar levels of variance in people's perceptions. In conclusion, we recommend that researchers investigating social judgements of faces consider alternatives to Cronbach's α but should also be prepared to examine both the potential value and origin of private taste as these might prove informative.


Equol inhibits prostate cancer growth through degradation of androgen receptor by S-phase kinase-associated protein 2.
Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S-phase kinase-associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.


Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: a mechanism for the intersection of coagulation and inflammation.
Preeclampsia (PE) is characterized by excessive thrombin generation, which has been implicated in the multiple organ damage associated with the disease. The biological effects of thrombin on coagulation and inflammation are mediated by protease-activated receptor-1 (PAR-1), a G protein-coupled receptor. The aim of this study was to determine whether preterm PE is associated with changes in placental expression of PAR-1. This cross-sectional study included two groups matched for gestational age at delivery: (1) patients with preterm PE (<37 weeks of gestation; n = 26) and (2) a control group of patients with preterm labor without intra-amniotic infection (n = 26). Placental tissue microarrays were immunostained for PAR-1. Immunoreactivity of PAR-1 in the villous trophoblasts was graded as negative, weak-positive, or strong-positive. (1) The proportion of cases with strong PAR-1 immunoreactivity was significantly higher in placentas of patients with PE than in placentas from the control group (37.5% (9/24) vs. 8.7% (2/23); p = 0.036, respectively). (2) PAR-1 immunoreactivity was found in the cellular compartments of the placental villous tree, mainly in villous trophoblasts and stromal endothelial cells. (3) PAR-1 was detected in 92.3% (24/26) of the placentas of women with PE and in 88.5% (23/26) of the placentas from the control group. Placentas from pregnancies complicated by preterm PE had a significantly higher frequency of strong PAR-1 expression than placentas from women with spontaneous preterm labor. This observation is consistent with a role for PAR-1 as a mediator of the effect of thrombin on coagulation and inflammation in PE. We propose that the effects of thrombin in PE are due to increased thrombin generation and higher expression of PAR-1, the major receptor for this enzyme.


Effect of a Cognitive Aid on Reducing Sugammadex Use and Associated Costs: A Time Series Analysis.
The authors observed increased pharmaceutical costs after the introduction of sugammadex in our institution. After a request to decrease sugammadex use, the authors implemented a cognitive aid to help choose between reversal agents. The purpose of this study was to determine if sugammadex use changed after cognitive aid implementation. The authors' hypothesis was that sugammadex use and associated costs would decrease. A cognitive aid suggesting reversal agent doses based on train-of-four count was developed. It was included with each dispensed reversal agent set and in medication dispensing cabinet bins containing reversal agents. An interrupted time series analysis was performed using pharmaceutical invoices and anesthesia records. The primary outcome was the number of sugammadex administrations. Secondary outcomes included total pharmaceutical acquisition costs of neuromuscular blocking drugs and reversal agents, adverse respiratory events, emergence duration, and number of neuromuscular blocking drug administrations. Before cognitive aid implementation, the number of sugammadex administrations was increasing at a monthly rate of 20 per 1,000 general anesthetics (P < 0.001). Afterward, the monthly rate was 4 per 1,000 general anesthetics (P = 0.361). One month after cognitive aid implementation, the number of sugammadex administrations decreased by 281 per 1,000 general anesthetics (95% CI, 228 to 333, P < 0.001). In the final study month, there were 509 fewer sugammadex administrations than predicted per 1,000 general anesthetics (95% CI, 366 to 653; P < 0.0001), and total pharmaceutical acquisition costs per 1,000 general anesthetics were $11,947 less than predicted (95% CI, $4,043 to $19,851; P = 0.003). There was no significant change in adverse respiratory events, emergence duration, or administrations of rocuronium, vecuronium, or atracurium. In the final month, there were 75 more suxamethonium administrations than predicted per 1,000 general anesthetics (95% CI, 32 to 119; P = 0.0008). Cognitive aid implementation to choose between reversal agents was associated with a decrease in sugammadex use and acquisition costs.


Complications of single and multistage operations for hypospadias: a comparative review.
From 1970 through 1975, 198 children with hypospadias were operated upon at our clinic. Three basic types of primary urethroplasty were used: 1) a modified 2-stage Cecil urethroplasty after separate straightening, 2) a modified 1-stage Denis Browne procedure after prior correction of chordee and 3) a 1-stage combined repair of hypospadias and chordee. A comparative review of early complications is presented.


Eggplant tissue homogenate-based bioselective membrane electrode for determination of catechol.
A novel eggplant tissue homogenate-based membrane electrode with high selective response to catechol (5 x 10(-6)-2.5 x 10(-5) M concentration) has been constructed by immobilizing tissue of eggplant (Solanum melangena L.) at dissolved oxygen probe. In order to optimize the stability of the electrode, general immobilization techniques are used to secure the eggplant tissue section physically in a gelatin-glutaraldehyde cross-linking matrix. The electrode response was maximum when 50 mM phosphate buffer was used at pH 7.0 and 35 degrees C. The sensor is stable for more than 3 months.