Classification of postjunctional beta adrenoceptors mediating relaxation of canine bronchi.
Adrenoceptors mediating relaxant responses to exogenously added or endogenously released catecholamines in isolated canine bronchi (3rd-6th order) were characterized using selective beta receptor agonists and antagonists. Norepinephrine (3 x 10(7) to 3 x 10(-5) M) or isoproterenol (3 x 10(-8) to 10(-6) M) fully relaxed tissues precontracted with 3 x 10(-7) M carbachol (Cch). Salbutamol (Sal) also relaxed Cch-precontracted tissues, but this relaxant effect was extremely sensitive to the concentration of precontracting agent used: the maximal effect of Sal was 100, 79 and 28% reversal of tone in tissues precontracted with 2 x 10(-8), 10(-7) and 3 x 10(-7) M Cch. The effects of isoproterenol were antagonized by propranolol. Norepinephrine relaxations were antagonized by the beta-1-selective antagonist ICI 89,406 (pA2 = 7.70) and the beta-2-selective antagonist ICI 118,551 (pA2 = 6.33). Sal-relaxations were antagonized by ICI 118,551 (pA2 = 8.91). Field stimulation in tissues precontracted with McNeil A343 (M1-selective muscarinic agonist) produced transient relaxations which were antagonized by ICI 89,406 but not ICI 118,551 (both 10(-9) to 10(-7) M). Thus, exogenous and endogenous catecholamines relax canine bronchial smooth muscle by activating both beta-1 and beta-2 adrenoceptors, although the latter seen to play a significant role only when low concentrations of Cch were used.


Skills assessment using a virtual reality simulator, LapSim, after training to develop fundamental skills for endoscopic surgery.
Education and training to maintain medical safety are very important within clinical settings. We have established a training center for endoscopic surgery and we regularly hold a unique training course, which focuses on the development of fundamental skills. One hundred and ninety-four surgeons who participated in our training course were divided into four groups according to their experience in performing laparoscopic procedures. Group 1: 0-19 laparoscopic procedures (n=44). Group 2: 20-49 laparoscopic procedures (n=53). Group 3: 50-99 laparoscopic procedures (n=46). Group 4: more than 100 laparoscopic procedures (n=55). All subjects underwent evaluation for "Lifting & Grasping" using a virtual reality (VR) simulator, LapSim, before and after the training course. The mean efficiency score, time to completion and tissue damage after training were significantly improved after the training as compared with before training. Before training, subjects with greater experience had better scores. However, the only significant difference in the score was between the low experience group and greatest experience group. After training, the score increased in all groups compared with that before training, and there was no significant difference between groups. This study demonstrates the feasibility of using a VR simulator to assess fundamental skills for endoscopic surgery after training. We found that the scores for the task were associated with the level of experience of the surgeons.


5-Year cost/benefit analysis of revision of failed unicompartmental knee replacements (UKRs); not "just" a primary total knee replacement (TKR).
A number of studies suggest that one advantage of a unicompartmental knee replacement (UKR) is ease of revision to a total knee replacement (TKR). We aimed to perform a cost/benefit analysis of patients undergoing this procedure at our centre to evaluate its economic viability. From our own prospective joint replacement database we identified 812 consecutive tibio-femoral UKRs performed (1994-2007) of which 23 were revised to TKR (2005-2008). These were then matched to a cohort of primary TKRs (42 patients). Data were collected regarding patient demographics, cost of surgery, clinical outcome (OKS) and follow-up costs at five years. There was no significant difference in implant costs or in length of stay, however tourniquet time was significantly higher in the revision group (average 93 min (UKR) vs 75 min (TKR) p<0.0001). At five years there was no significant difference in clinical outcome between the revision UKR and primary TKR groups, mean OKS 27 and 32 respectively (p=0.20). The revision group had a greater complication and revision rate, attending significantly more follow-up appointments (average 6 (UKR) vs 2 (TKR) p<0.0001) and consultant appointments (average 4 (UKR) vs 0.4 (TKR) p<0.0001). This was translated to significantly higher follow-up costs. Revision of UKR to TKR is not universally a straightforward procedure comparable to a standard primary replacement. Despite cost of components not being significantly higher than primary TKR there are multiple hidden follow-up costs. The clinical outcomes are however similar at 5 years.


MacuFix® versus Amsler grid for metamorphopsia categorization for macular diseases.
Macular diseases often lead to metamorphopsia, which is traditionally tested using the Amsler grid. This study evaluates a novel method for assessing metamorphopsia, based on the software AMD-A Metamorphopsia Detector, application MacuFix®. In this observational study, the usability of a new smartphone-based testing method to assess metamorphopsia was evaluated in 45 patients experiencing metamorphopsia in at least one eye using the questionnaire "System Usability Score (SUS)." Additionally, the diagnostic adherence of self-monitoring with the Amsler grid was compared to self-monitoring with the novel software MacuFix®. The average score of the SUS questionnaire in this study was 76.7 ± 15.5, corresponding to the "good" score on the grading scale. The average interval between two home administered tests was significantly shorter (6 days) when the application was used as compared to using the Amsler grid (19 days). The odds ratio of the frequency of patients using the application to the patients using the home test was 4. MacuFix® application can help in effective home monitoring of macular function as high user satisfaction and increased testing frequency was observed in its use in patients with macular diseases.


Head-related transfer functions of rabbits within the front horizontal plane.
The head-related transfer function (HRTF) describes the direction-dependent acoustic filtering by the head that occurs between a source signal in free-field space and the signal at the tympanic membrane. HRTFs contain information on sound source location via interaural differences of their magnitude or phase spectra and via the shapes of their magnitude spectra. The present study characterized HRTFs for source locations in the front horizontal plane for nine rabbits, which are a species commonly used in studies of the central auditory system. HRTF magnitude spectra shared several features across individuals, including a broad spectral peak at 2.6kHz that increased gain by 12 to 23dB depending on source azimuth; and a notch at 7.6kHz and peak at 9.8kHz visible for most azimuths. Overall, frequencies above 4kHz were amplified for sources ipsilateral to the ear and progressively attenuated for frontal and contralateral azimuths. The slope of the magnitude spectrum between 3 and 5kHz was found to be an unambiguous monaural cue for source azimuths ipsilateral to the ear. Average interaural level difference (ILD) between 5 and 16kHz varied monotonically with azimuth over ±31dB despite a relatively small head size. Interaural time differences (ITDs) at 0.5kHz and 1.5kHz also varied monotonically with azimuth over ±358 μs and ±260 μs, respectively. Remeasurement of HRTFs after pinna removal revealed that the large pinnae of rabbits were responsible for all spectral peaks and notches in magnitude spectra and were the main contribution to high-frequency ILDs (5-16kHz), whereas the rest of the head was the main contribution to ITDs and low-frequency ILDs (0.2-1.5kHz). Lastly, inter-individual differences in magnitude spectra were found to be small enough that deviations of individual HRTFs from an average HRTF were comparable in size to measurement error. Therefore, the average HRTF may be acceptable for use in neural or behavioral studies of rabbits implementing virtual acoustic space when measurement of individualized HRTFs is not possible.


Congenital microarteriovenous shunts. Angiographic and Doppler ultrasonographic identification.
We describe herein two cases of vascular malformations, one classified as hemangioma and the other as Klippel-Trenaunay syndrome. Clinical investigation in each case failed to demonstrate the presence of arteriovenous (AV) shunting. Arteriographic findings revealed only indirect evidence of AV shunting in each case. In contrast, systematic scanning with a Doppler ultrasonographic probe of the involved extremities provided evidence of AV shunting and pinpointed it in suspected arteriographic areas. Good correlation between the two methods was confirmed in the hemangioma case both preoperatively and intraoperatively. In the case of Klippel-Trenaunay syndrome, evidence of multiple AV shunts was obtained primarily with Doppler ultrasonography. In addition to arteriography, serial phlebography, when indicated, is also necessary for complete evaluation of concomitant venous malformations. The pathogenic mechanism of these vascular malformations was briefly reviewed, emphasizing AV shunting as a common link between the various anatomicoclinical forms.


Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer.
Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing. In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance. Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.


LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study.
Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM. We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed. LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM. LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM. This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.


What Is the Evidence on Natural Recovery Over the Year Following Sports-Related and Non-sports-Related Mild Traumatic Brain Injury: A Scoping Review.
Background: Treatment approaches often differ dependent upon whether a person experiences a sports-related or a non-sports-related mild traumatic brain injury. It remains unclear if recovery from these injuries is comparable or unique to context of the injury. Objective: To identify knowledge gaps on self-reported outcomes and trajectories between sports- and non-sports-related mild traumatic brain injuries and how they are assessed in adults. Methods: This scoping review used a systematic search of key electronic databases, including PubMed, SPORTDiscus, Embase, MEDLINE, and CINAHL for articles published in 1937 until March 10, 2021. Articles were included if they were available in English; full text published in a peer-reviewed journal; had a prospective or retrospective study design; reported data on mild TBI cases >16 years of age, and included data from at least two time points on self-reported outcomes within 12 months post-injury. A standardized data extraction spreadsheet was used to determine the participant characteristics, definitions, assessment methods, outcomes, and recovery time frames. Results: Following removal of duplicates, the search strategy elicited 6,974 abstracts. Following abstract review, 174 were retained for full text review. Of the 42 articles that met inclusion criteria, 18 were sports related (15 in the USA and three in Canada) and 24 were general population studies (six in USA, three in Canada, three in Australasia, nine in Europe, two in Taiwan, and one in Morocco). Direct comparison in recovery trajectories between the sport and general population studies was difficult, given notable differences in methodology, definitions, types of outcome measures, and timing of follow-up assessments. Only one article reported on both sports-related and non-sports-related traumatic brain injuries separately at comparable timepoints. This study revealed no differences in recovery time frames or overall symptom burden. Discussion: Whilst there is a clear benefit in researching specific subpopulations in detail, standardized outcome measures and follow-up time frames are needed across contexts to facilitate understanding of similarities and differences between sports- and non-sports-related mild traumatic brain injuries to inform clinical treatment.


Mini-open compared with the trans-tubular approach in patients with spinal metastases underwent decompression surgery---a retrospective cohort study.
This study aimed to evaluate the perioperative safety and efficacy of the Mini-open and trans-tubular approach in patients with spinal metastases who underwent decompression surgery. 37 consecutive patients with spinal metastases who underwent decompression surgery through a Mini-open or trans-tubular approach were retrospectively reviewed between June 2017 and June 2022. Thirty-four patients were included in this study. 19 underwent decompression surgery through the Mini-open approach, and 15 underwent the Trans-tubular approach. T-test and chi-square test were used to evaluate the difference between baseline data and primary and secondary outcomes. Baseline characteristics did not differ significantly between Trans-tubular and Mini-open groups except for the Ambulatory status (P < 0.001). There was no significant difference in blood loss between the two groups (P = 0.061). Operative time, intraoperative blood transfusion, intraoperative complication (dural tear), and postoperative hospitalization were comparable in the two groups (P > 0.05). The trans-tubular group had significantly less amount of postoperative drainage (133.5 ± 30.9 ml vs. 364.5 ± 64.2 ml, p = 0.003), and the time of drainage (3.1 ± 0.2 days vs. 4.6 ± 0.5 days, p = 0.019) compared with Mini-open group (P < 0.05). Sub-group analysis showed that for patients with hypo-vascular tumors, the Trans-tubular group had significantly less blood loss than the Mini-open group (951.1 ± 171.7 ml vs. 1599.1 ± 105.7 ml, P = 0.026). Decompression through Mini-open or Trans-tubular was safe and effective for patients with spinal metastases. The trans-tubular approach might be more suitable for patients with hypo-vascular tumors.


A 3D Convolutional Neural Network to Model Retinal Ganglion Cell's Responses to Light Patterns in Mice.
Deep Learning offers flexible powerful tools that have advanced our understanding of the neural coding of neurosensory systems. In this work, a 3D Convolutional Neural Network (3D CNN) is used to mimic the behavior of a population of mice retinal ganglion cells in response to different light patterns. For this purpose, we projected homogeneous RGB flashes and checkerboards stimuli with variable luminances and wavelength spectrum to mimic a more naturalistic stimuli environment onto the mouse retina. We also used white moving bars in order to localize the spatial position of the recorded cells. Then recorded spikes were smoothed with a Gaussian kernel and used as the output target when training a 3D CNN in a supervised way. To find a suitable model, two hyperparameter search stages were performed. In the first stage, a trial and error process allowed us to obtain a system that is able to fit the neurons firing rates. In the second stage, a systematic procedure was used to compare several gradient-based optimizers, loss functions and the model's convolutional layers number. We found that a three layered 3D CNN was able to predict the ganglion cells firing rates with high correlations and low prediction error, as measured with Mean Squared Error and Dynamic Time Warping in test sets. These models were either competitive or outperformed other models used already in neuroscience, as Feed Forward Neural Networks and Linear-Nonlinear models. This methodology allowed us to capture the temporal dynamic response patterns in a robust way, even for neurons with high trial-to-trial variable spontaneous firing rates, when providing the peristimulus time histogram as an output to our model.


Peripheral synthesis and isoform distribution of dog apoprotein E. An in vivo approach.
Purified dog plasma apo-E is composed of four major isoforms with the following pI values: 5.40, 5.31, 5.26, and 5.22. Treatment with neuraminidase suggests that the multiple forms are due to progressive sialation. The acidic isoforms (pI = 5.22 and less), rarely detectable in plasma lipoprotein samples (except in the d less than 1.05 g/ml fraction of cholesterol-fed dogs), are present in high concentrations in the interstitial fluid high density lipoprotein fraction I (HDLI) of cholesterol-fed dogs, a lipoprotein recently described (Dory, L., Boquet, L.M., Hamilton, R.L., Sloop, C.H., and Roheim, P.S. (1985) J. Lipid Res. 26, 519-527). Apo-Es0 (the most basic isoform) is a major constituent of the plasma d less than 1.05 g/ml fraction, but it is usually only a minor component of other plasma or interstitial fluid lipoproteins. This is likely a reflection of the prolonged residence time of a specific lipoprotein species in this density range, resulting in more extensive desialation. Peripheral apo-E synthesis has been measured under in vivo conditions using a hindlimb cannulation of the lymphatics and collection of prenodal peripheral lymph. Following injection of [3H]leucine or [35S]methionine into the dorsal skin of the toes, the specific activity of the interstitial fluid apo-E far exceeded that of plasma apo-E at all time points examined. Incorporation was measurable 30 min after the isotope injection and peaked at 150 min in control dogs and between 120-150 min in cholesterol-fed dogs. The rate of peripheral synthesis of apo-E in cholesterol-fed dogs appeared to be twice that of control dogs. The newly synthesized and secreted apo-E preferentially associated with the disc-shaped HDLI of the interstitial fluid; less than 15% of the apo-E-associated radioactivity was recovered in the d less than 1.05 g/ml fraction, despite the fact that this fraction contains well over 50% of the total interstitial fluid apo-E mass. The newly secreted, HDLI-associated apo-E can be converted by neuraminidase into apo-Es0.


HR-MAS DREAMTIME NMR for Slow Spinning ex Vivo and in Vivo Samples.
HR-MAS NMR is a powerful tool, capable of monitoring molecular changes in intact heterogeneous samples. However, one of the biggest limitations of 1H NMR is its narrow spectral width which leads to considerable overlap in complex natural samples. DREAMTIME NMR is a highly selective technique that allows users to isolate suites of metabolites from congested spectra. This permits targeted metabolomics by NMR and is ideal for monitoring specific processes. To date, DREAMTIME has only been employed in solution-state NMR, here it is adapted for HR-MAS applications. At high spinning speeds (>5 kHz), DREAMTIME works with minimal modifications. However, spinning over 3-4 kHz leads to cell lysis, and if maintaining sample integrity is necessary, slower spinning (<2.5 kHz) is required. Very slow spinning (≤500 Hz) is advantageous for in vivo analysis to increase organism survival; however, sidebands from water pose a problem. To address this, a version of DREAMTIME, termed DREAMTIME-SLOWMAS, is introduced. Both techniques are compared at 2500, 500, and 50 Hz, using ex vivo worm tissue. Following this, DREAMTIME-SLOWMAS is applied to monitor key metabolites of anoxic stress in living shrimp at 500 Hz. Thus, standard DREAMTIME works well under MAS conditions and is recommended for samples reswollen in D2O or spun >2500 Hz. For slow spinning in vivo or intact tissue samples, DREAMTIME-SLOWMAS provides an excellent way to target process-specific metabolites while maintaining sample integrity. Overall, DREAMTIME should find widespread application wherever targeted molecular information is required from complex samples with a high degree of spectral overlap.


Tumor necrosis factor-alpha in pregnant cattle after intravenous or subcutaneous vaccination with Brucella abortus strain RB51.
To determine the influence of brucellosis vaccination on tumor necrosis factor-alpha (TNF-alpha) concentrations in pregnant cattle and the possible role of the bovine placenta in TNF-alpha production. Polled Hereford heifers obtained from a nonvaccinated, brucellosis-free herd and bred at 16 to 27 months at age. All cattle were seronegative for Brucella abortus by results of the standard tube agglutination test. At 6 months' gestation, cattle were vaccinated i.v. with B abortus strain RB51 (n = 10), s.c. with B abortus strain RB51 (n = 5), or s.c. with B abortus strain 19 (n = 5); controls received pyrogen-free saline solution s.c. (n = 2). Blood samples were collected periodically for TNF-alpha assays. At necropsy, 8 to 12 weeks after vaccination, placental fluids and fetal blood were collected for TNF-alpha analysis and placental tissues were collected for immunohistochemical detection of TNF-alpha. Radioimmunoassays indicated no increase in TNF-alpha concentration in blood from i.v. or s.c. vaccinated cattle, compared with controls. Similarly, TNF-alpha concentrations in amniotic and allantoic fluids from s.c. vaccinated cattle were not different from values for controls. Although only i.v. vaccinated cattle developed placentitis, immunohistochemical analysis for TNF-alpha revealed increased immunoreactivity within placental trophoblastic epithelial cells of s.c. and i.v. vaccinated cattle. s.c. vaccination for prevention of brucellosis, using recommended adult dosages, does not result in increase of TNF-alpha concentration in plasma, serum, or placental fluids; however, vaccination of pregnant cattle stimulates trophoblastic epithelial cells to express TNF-alpha, although the physiologic and quantitative importance of this expression remains unknown.


Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options.
Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by drastic alterations in mood, emotions, social abilities and cognition. Notably, one aspect of PTSD, particularly in veterans, is its comorbidity with suicide. Elevated aggressiveness predicts high-risk to suicide in humans and despite the difficulty in reproducing a complex human suicidal behavior in rodents, aggressive behavior is a well reproducible behavioral trait of suicide. PTSD animal models are based on a peculiar phenotype, including exaggerated fear memory and impaired fear extinction associated with neurochemical dysregulations in the brain circuitry regulating emotion. The endocannabinoid and the neurosteroid systems regulate emotions and stress responses, and recent evidence shows these two systems are interrelated and critically compromised in neuropsychiatric disorders. For instance, levels of the neurosteroid, allopregnanolone, as well as those of the endocannabinoids, anandamide and its congener, palmitoylethanolamide are decreased in PTSD. Similarly, the endocannabinoid system and neurosteroid biosynthesis are altered in suicidal individuals. Selective serotonin reuptake inhibitors (SSRIs), the only FDA-approved treatments for PTSD, fail to help half of the treatment-seeking patients. This highlights the need for developing biomarker-based efficient therapies. One promising alternative to SSRIs points to stimulation of allopregnanolone biosynthesis as a treatment and a valid end-point to predict treatment response in PTSD patients. This review highlights running findings on the role of the endocannabinoid and neurosteroid systems in PTSD and suicidal behavior both in a preclinical and clinical perspective. A specific focus is given to predictive PTSD/suicide animal models. Ultimately, we discuss the idea that disruption of neurosteroid and endocannabinoid biosynthesis may offer a novel promising biomarker axis to develop new treatments for PTSD and, perhaps, suicidal behavior.


Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival.
The most accurate predictor of disease recurrence in patients treated for head and neck squamous cell carcinoma is, at present, the extent of regional lymph node metastasis. Since elevated levels of epidermal growth factor receptor (EGFR) and of its ligand, transforming growth factor-alpha (TGF-alpha), have been detected in primary tumors of patients with head and neck squamous cell carcinoma, we determined whether tumor levels of these proteins were of prognostic importance. Monoclonal antibodies specific for EGFR and TGF-alpha were used for immunohistochemical detection of each protein in tissue sections of primary tumors from 91 patients who were treated by surgical resection. Levels of immunoreactive EGFR and TGF-alpha were quantified by use of a computerized image analysis system and were normalized to appropriate standards. The logrank test and proportional hazards regression analysis were used to calculate the probability that EGFR and TGF-alpha levels were associated with disease-free survival (i.e., no recurrence of cancer) and cause-specific survival (i.e., patients do not die of their disease). All P values were two-sided. When tumor levels of EGFR or TGF-alpha were analyzed as continuous variables, disease-free survival and cause-specific survival were reduced among patients with higher levels of EGFR (both P = .0001) or TGF-alpha (both P = .0001). In a multivariate analysis, tumor site, tumor level of EGFR, and tumor level of TGF-alpha were statistically significant predictors of disease-free survival; in a similar analysis, regional lymph node stage and tumor levels of EGFR and of TGF-alpha were significant predictors of cause-specific survival. Quantitation of EGFR and TGF-alpha protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy.


Geophysical evidence for an enriched molten silicate layer above Mars's core.
The detection of deep reflected S waves on Mars inferred a core size of 1,830 ± 40 km (ref. 1), requiring light-element contents that are incompatible with experimental petrological constraints. This estimate assumes a compositionally homogeneous Martian mantle, at odds with recent measurements of anomalously slow propagating P waves diffracted along the core-mantle boundary2. An alternative hypothesis is that Mars's mantle is heterogeneous as a consequence of an early magma ocean that solidified to form a basal layer enriched in iron and heat-producing elements. Such enrichment results in the formation of a molten silicate layer above the core, overlain by a partially molten layer3. Here we show that this structure is compatible with all geophysical data, notably (1) deep reflected and diffracted mantle seismic phases, (2) weak shear attenuation at seismic frequency and (3) Mars's dissipative nature at Phobos tides. The core size in this scenario is 1,650 ± 20 km, implying a density of 6.5 g cm-3, 5-8% larger than previous seismic estimates, and can be explained by fewer, and less abundant, alloying light elements than previously required, in amounts compatible with experimental and cosmochemical constraints. Finally, the layered mantle structure requires external sources to generate the magnetic signatures recorded in Mars's crust.


Hypersensitivity to non-steroidal anti-inflammatory drugs in childhood.
Although largely investigated in adults, the issue of hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) in childhood is unsettled due to lack of sufficient data. The purpose of this study is to examine the clinical syndromes of hypersensitivity to NSAIDs in children and adolescents. We performed a review of relevant papers on cutaneous and respiratory adverse reactions triggered by NSAIDs in pediatric patients, and a recount of our own experience in 43 well-characterized NSAID-sensitive children with cutaneous reactions who were submitted to controlled oral challenges with NSAIDs and the new inhibitors of the enzyme isoform cyclooxygenase-2 (COX-2). Although it has been suggested that allergic and pseudoallergic reactions to NSAIDs in children occur rarely, their prevalence remains largely unknown due to the scarcity of studies. About 23% of NSAID-sensitive patients seen in our institutions are young patients aged 8-18 yr who more frequently develop facial angioedema as their main clinical manifestation. Most patients are atopic and show reactions to more than one drug (cross-reactors). Drugs that inhibit COX-2 with higher specificity than classic NSAIDs are better tolerated in young NSAID-hypersensitive patients.


Variation in promiscuity and sexual selection drives avian rate of Faster-Z evolution.
Higher rates of coding sequence evolution have been observed on the Z chromosome relative to the autosomes across a wide range of species. However, despite a considerable body of theory, we lack empirical evidence explaining variation in the strength of the Faster-Z Effect. To assess the magnitude and drivers of Faster-Z Evolution, we assembled six de novo transcriptomes, spanning 90 million years of avian evolution. Our analysis combines expression, sequence and polymorphism data with measures of sperm competition and promiscuity. In doing so, we present the first empirical evidence demonstrating the positive relationship between Faster-Z Effect and measures of promiscuity, and therefore variance in male mating success. Our results from multiple lines of evidence indicate that selection is less effective on the Z chromosome, particularly in promiscuous species, and that Faster-Z Evolution in birds is due primarily to genetic drift. Our results reveal the power of mating system and sexual selection in shaping broad patterns in genome evolution.


A Proposed Molecular Mechanism of High-Dose Vitamin D3 Supplementation in Prevention and Treatment of Preeclampsia.
A randomized prospective clinical study performed on a group of 74 pregnant women (43 presenting with severe preeclampsia) proved that urinary levels of 15-F(2t)-isoprostane were significantly higher in preeclamptic patients relative to the control (3.05 vs. 2.00 ng/mg creatinine). Surprisingly enough, plasma levels of 25-hydroxyvitamin D3 in both study groups were below the clinical reference range with no significant difference between the groups. In vitro study performed on isolated placental mitochondria and placental cell line showed that suicidal self-oxidation of cytochrome P450scc may lead to structural disintegration of heme, potentially contributing to enhancement of oxidative stress phenomena in the course of preeclampsia. As placental cytochrome P450scc pleiotropic activity is implicated in the metabolism of free radical mediated arachidonic acid derivatives as well as multiple Vitamin D3 hydroxylations and progesterone synthesis, we propose that Vitamin D3 might act as a competitive inhibitor of placental cytochrome P450scc preventing the production of lipid peroxides or excess progesterone synthesis, both of which may contribute to the etiopathogenesis of preeclampsia. The proposed molecular mechanism is in accord with the preliminary clinical observations on the surprisingly high efficacy of high-dose Vitamin D3 supplementation in prevention and treatment of preeclampsia.


Nephron-sparing surgery.
This retrospective study examines partial nephrectomies performed over a period of approximately three years to confirm the feasibility of the procedure for suspected renal cell carcinoma. The surgeries were done primarily at a 1000-bed, university-affiliated hospital by members of a private urologic surgery practice. We examined whether recent advances in diagnosis and surgical therapy increased the viability of partial nephrectomy as an alternative to radical nephrectomy in certain carefully selected patients. Patients underwent preoperative evaluation to confirm suitability for partial nephrectomy. Surgeons used an extraperitoneal approach and mobilized the kidney after incising Gerota's fascia. Nearly one-third of the procedures involved renal cooling. Because three masses turned out to be benign cysts, and one tumor was an oncocytoma, four patients with benign disease were spared unnecessary radical nephrectomy. With an average follow-up of 32 months, all patients remain free of disease and are not dependent on dialysis. Our findings are consistent with those of national studies that show partial nephrectomy does not compromise disease-free survival in properly selected patients. The success of nephron-sparing surgery in this sample opens the door for exploration of more advanced, less invasive techniques for management of renal cell carcinoma.


Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under wartime conditions and with limited resources.
1) To determine the proportions of patients with visceral leishmaniasis who had various treatment outcomes when cared for under wartime conditions and with limited resources and 2) to identify patient characteristics associated with the outcomes. Cohort study. Médecins sans Frontières-Holland's treatment center in Duar, Western Upper Nile Province, an area in southern Sudan that has been severely affected by Sudan's civil war and a massive epidemic of visceral leishmaniasis. 3076 consecutive patients who had visceral leishmaniasis, were admitted to the treatment center the first year the center was operational (August 1990 to July 1991), and were treated with the pentavalent antimonial compound sodium stibogluconate. Patient characteristics on admission and four mutually exclusive treatment outcomes (default during first admission, death during first admission, discharge and readmission for retreatment [relapse], and discharge and no readmission for retreatment [successful treatment]). The patients had a median age of 15 years and were notably anemic (median hemoglobin level, 77g/L) and malnourished (median body mass index of adults [> or = 18 years of age], 15.2 kg/m2); most (91.0%) had been sick less than 5 months. Although patients could not be monitored after treatment to document cure, most (2562 [83.3%]) were successfully treated; 336 (10.9%) died during their first admission, and 79 are known to have relapsed (3.0% of those discharged alive [that is, those whose final treatment outcome was successful treatment or relapse]). In univariable analysis, young and older age (<5 or > or = 45 years of age), long duration of illness (> or = 5 months), markedly low hemoglobin level or body mass index, large spleen, high parasite density, and vomiting at least once during the treatment course were associated with death. In multiple logistic regression analysis of data for a subgroup of 1207 adults (those who did not default or relapse and for whom data were recorded on age, sex, duration of illness, hemoglobin level, body mass index, and spleen size), the approximate risk ratios for death were 2.2 (95% Cl, 1.4 to 3.6) for those with a long duration of illness, 3.6 (Cl, 2.1 to 5.9) for those 45 years of age or older, 4.6 (Cl, 2.2 to 9.4) for those with a hemoglobin level less than 60 g/L, and 12.2 (Cl, 3.2 to 47.2) for those with a body mass index less than 12.2 kg/m2. CONCLUSION; Despite the severe debility of the patients and the exceptionally difficult circumstances under which they were treated, most fared remarkably well.


Benefits of Bullying? A Test of the Evolutionary Hypothesis in Three Cohorts.
Recent work on bullying perpetration includes the hypothesis that bullying carries an evolutionary advantage for perpetrators in terms of health and reproductive success. We tested this hypothesis in the National Child Development Study (n = 4998 male, n = 4831 female), British Cohort Study 1970 (n = 4261 male, n = 4432 female), and TRacking Adolescents' Individual Lives Survey (n = 486 male, n = 521 female), where bullying was assessed in adolescence (NCDS, BCS70: age 16, TRAILS: age 14) and outcomes in adulthood. Partial support for the evolutionary hypothesis was found as bullies had more children in NCDS and engaged in sexual intercourse earlier in TRAILS. In contrast, bullies reported worse health in NCDS and BCS70.


[Participants-centered Design of Annual Meeting: From the Perspectives of Instructional Systems].
This paper examines the reform experience of the 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences from Instructional Systems perspectives, to check whether it was effective, efficient, and appealing for participants. "Instructional Systems" has been a research area in educational technology for the past 50 years, and has also been applied to training and human resource development in healthcare domains. If an annual meeting is to be designed for participants' learning, then perspectives of Instructional Systems can be applied to interpret the effort of the reform. First, fill in the gaps of participants' knowledge, using before-and-after comparison. Design a conference to meet the needs of its participants by checking why they attend (expectations) and what they bring in (starting status). Second, design the conference as a process of innovation. The bigger the expected changes, the more carefully participants should be prepared to accommodate them. Third, follow plan-do-check-action cycles with data for confirming and revising the new ways of running the meeting. Plan to check "exportability" of the new ways, to assess whether it can be generalized to future meetings.


Grief During the COVID-19 Pandemic: Considerations for Palliative Care Providers.
The COVID-19 pandemic is anticipated to continue spreading widely across the globe throughout 2020. To mitigate the devastating impact of COVID-19, social distancing and visitor restrictions in health care facilities have been widely implemented. Such policies and practices, along with the direct impact of the spread of COVID-19, complicate issues of grief that are relevant to medical providers. We describe the relationship of the COVID-19 pandemic to anticipatory grief, disenfranchised grief, and complicated grief for individuals, families, and their providers. Furthermore, we provide discussion regarding countering this grief through communication, advance care planning, and self-care practices. We provide resources for health care providers, in addition to calling on palliative care providers to consider their own role as a resource to other specialties during this public health emergency.


Multibeam ptychography with synchrotron hard X-rays.
We report the first demonstration of multibeam ptychography using synchrotron hard X-rays, which can enlarge the field of view of the reconstructed image of objects by efficiently using partially coherent X-rays. We measured the ptychographic diffraction patterns of a Pt test sample and MnO particles using three mutually incoherent coherent beams with a high intensity that were produced by using both the multiple slits and a pair of focusing mirrors. We successfully reconstructed the phase map of the samples at a spatial resolution of 25 nm in a field of view about twice as wide as that in the single-beam ptychography. We also computationally simulated a feasible experimental setup using random modulators to further enlarge the field of view by increasing the number of available beams. The present method has the potential to enable the high spatial resolution and large field-of-view observation of specimens in materials science and biology.


An integrative phylogenomic approach illuminates the evolutionary history of Old World tree frogs (Anura: Rhacophoridae).
Rhacophoridae are one of the most speciose and ecologically diverse families of amphibians. Resolution of their evolutionary relationships is key to understanding the accumulation of biodiversity, yet previous hypotheses based on Sanger sequencing exhibit much discordance amongst generic relationships. This conflict precludes the making of sound macroevolutionary conclusions. Herein, we conduct the first phylogenomic study using broad-scale sampling and sequences of 352 nuclear DNA loci obtained using anchored hybrid enrichment targeted sequencing. The robust time-calibrated phylogenetic hypothesis clarifies several long-disputed relationships and facilitates the testing of evolutionary hypotheses on spatiotemporal diversification and reproductive modes. The major extant lineages of Rhacophoridae appear to have radiated in mainland Asia, and the spatiotemporal process corresponds with several common accumulations of biodiversity in Asia. Analyses do not detect any case of "Out of Himalaya" in Rhacophoridae. All transitions of reproductive modes appear to have evolved in an ordered, gradual sequence associated with gaining independence of standing water for larval development. The different reproductive modes are phylogenetically conserved and the completion of their transitions appear to have occurred over a period of ~30 Ma, which does not fit a pattern of a rapid burst of diversification. Innovations in reproductive modes associate statistically with the uneven distribution of species-richness between clades, where higher diversification is linked to increased terrestrial modes of reproduction. These results strengthen the hypothesis that breeding innovations drive diversification by providing new opportunities for ecological release and dispersion.


[Herbal remedies in depression--state of the art].
Recent decades have seen development of research and an increased interest in the psychopharmacology of natural remedies. More than 20 herbal remedies have been identified that may potentially be applied in medicine as antidepressive, anxiety relieving or sleep-inducing agents. Patients often prefer to take herbal remedies and often take them on their own, without consulting a physician. The aim of the study is to present the state of the art concerning the use of natural remedies in the treatment of depression. Following a literature review, 7 herbal remedies for which preclinical and clinical trials suggest their antidepressive influence have been identified: hypericum, lavender, borage, roseroot, chamomile, saffron and ginseng. For two of these, i.e. hypericum and saffron extracts, antidepressive effect in subjects with mild or moderate depression has been confirmed in controlled randomized clinical trials.


High normal blood pressure, hypertension, and the risk of type 2 diabetes in Japanese men. The Osaka Health Survey.
To investigate the relationship between high normal blood pressure or hypertension and the risk of developing type 2 diabetes in a large Japanese cohort. We enrolled 7,594 Japanese men aged 35-60 years who did not have diabetes or impaired fasting glucose at study entry. Type 2 diabetes was defined as a fasting plasma glucose level of > or = 126 mg/dl or a 2-h postload plasma glucose level of > or = 200 mg/dl. High normal blood pressure was defined as no history of hypertension and a systolic blood pressure of > or = 130 and < 140 mmHg or a diastolic blood pressure of > or = 85 and < 90 mmHg. Subjects were considered to have hypertension if they had a systolic blood pressure > or = 140 mmHg, if they had a diastolic blood pressure > or = 90 mmHg, or if they were taking anti-hypertensive medications. We confirmed 600 cases of type 2 diabetes during the 72,946 person-years of follow-up. Both high normal blood pressure and hypertension were associated with the risk of type 2 diabetes. Compared with normotensive men, men with high normal blood pressure had a multiple adjusted relative risk (RR) of 1.39 (95% CI 1.14-1.69), and men with hypertension had a multiple adjusted RR of 1.76 (1.43-2.16). Even among lean men (BMI < 22.7 kg/m2), men with high normal blood pressure had a multiple adjusted RR of 1.71 (1.20-2.42), and men with hypertension had a multiple adjusted RR of 2.02 (1.34-3.05) compared with normotensive men. High normal blood pressure and hypertension are associated with an increased risk of developing type 2 diabetes.


Plasmablastic lymphoma in the ano-rectal junction presenting in an immunocompetent man: a case report.
Plasmablastic lymphoma is an aggressive non-Hodgkin lymphoma classically occurring in individuals infected with HIV. Plasmablastic lymphoma has a predilection for the oral cavity and jaw. However, recent case reports have shown lymphoma in the stomach, lung, nasal cavity, cervical lymph nodes and jejunum in HIV-negative individuals. We report what is, to the best of our knowledge, the first case of plasmablastic lymphoma occurring in the ano-rectal junction of an HIV-negative man. A previously healthy 59-year-old Caucasian man presented with painless rectal bleeding. Colonoscopy revealed a lesion in the ano-rectal junction, with pathological examination demonstrating atypical lymphoid cells consisting primarily of plasmablasts with rounded nuclei, coarse chromatin, small nucleoli and multiple mitotic figures. Immunohistochemical analysis showed the atypical cells were negative for CD45, CD20, CD79a and immunoglobulin light chains, but were strongly positive for CD138 and EBV-encoded RNA. The results were consistent with a diagnosis of plasmablastic lymphoma. Aggressive systemic chemotherapy and involved field radiation therapy resulted in complete clinical and pathological remission. Increasing awareness of plasmablastic lymphoma in HIV-negative individuals and in this location is warranted.


Comorbidity and continuity of attention deficit hyperactivity disorder (ADHD) from childhood to adolescence in Turkey.
The aim of this study was to examine clinical outcomes, psychiatric comorbidity and neuropsychological characteristics in Turkish adolescents with an attention deficit hyperactivity disorder (ADHD) diagnosis in childhood. A total of 45 children with ADHD diagnosis and 28 children with a psychiatric diagnosis other than ADHD in a 1-year cohort of 7-10-year-olds were reevaluated 6 years later using Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version and Wechsler Intelligence Scale for Children-Revised and Stroop Test TBAG version. This study shows that the clinical outcomes and the comorbidity patterns for ADHD from childhood to adolescence in Turkey are similar to reported rates in the Western countries. In the ADHD group, 75.6 % still has impairing ADHD symptoms and 46.6 % has comorbid psychiatric disorders. The main difference is anxiety disorders being the most common comorbid disorders (37.8 %) in Turkish ADHD youth. These findings stress the high comorbidity associated with ADHD and support the importance of assessment and treatment for ADHD and comorbidities during adolescence.


Single-shot extreme ultraviolet laser imaging of nanostructures with wavelength resolution.
We have demonstrated near-wavelength resolution microscopy in the extreme ultraviolet. Images of 50 nm diameter nanotubes were obtained with a single ~1 ns duration pulse from a desktop-size 46.9 nm laser. We measured the modulation transfer function of the microscope for three different numerical aperture zone plate objectives, demonstrating that 54 nm half-period structures can be resolved. The combination of near-wavelength spatial resolution and high temporal resolution opens myriad opportunities in imaging, such as the ability to directly investigate dynamics of nanoscale structures.


Scientometric characterization of Medwave's scientific production 2010-2014.
The use of bibliometric indicators for the evaluation of science allows an analysis of scientific production both from a quantitative and qualitative point of view. To characterize the scientific production of Medwave during the period 2010 to 2014 in terms of visibility and productivity. A bibliometric study was carried out. Variables analyzed were offered by the "Publish or Perish" program working with the Google Scholar database. The number of articles published were related to the number of authors involved in each research work. The articles cited, number of citations, authors and year were reported. Indicators were obtained by placing in name of the journal and its International Standard Serial Number (ISSN) in the navigation box of Publish or Perish. There were 481 articles published with 220 citations; at a rate of more than 36 citations per year and 20 citations per author and year. An index h = 5 and index g = 6 were achieved. There was an average of two authors per article. Only five articles had more citations than the total they provided. The scientometric indicators found place the journal in a favorable position relative to other medical journals of the region, in terms of visibility and productivity. There was a low rate of cooperation since articles with individual authors prevailed. A low number of articles contributed to the productivity of the journal despite having significant number of citations.


Stepwise approach to establishing multiple outreach laboratory information system-electronic medical record interfaces.
Clinical laboratory outreach business is changing as more physician practices adopt an electronic medical record (EMR). Physician connectivity with the laboratory information system (LIS) is consequently becoming more important. However, there are no reports available to assist the informatician with establishing and maintaining outreach LIS-EMR connectivity. A four-stage scheme is presented that was successfully employed to establish unidirectional and bidirectional interfaces with multiple physician EMRs. This approach involves planning (step 1), followed by interface building (step 2) with subsequent testing (step 3), and finally ongoing maintenance (step 4). The role of organized project management, software as a service (SAAS), and alternate solutions for outreach connectivity are discussed.


[Status of the blood and lung antioxidant system of the rat in toxic pulmonary edema].
The state of enzymatic and non-enzymatic components of antioxidant system and also lipid peroxidation processes in blood and lungs of rats with toxic pulmonary edema induced by inhalation of nitric oxides were investigated. The changes in the state of blood and lung antioxidant system components accompany the development of toxic pulmonary edema and coincide in time-course of edema manifestation. The determined changes were more pronounced in blood than in lungs.


The effect of acute physical pain on subsequent negative emotional affect: A meta-analysis.
Although it is clear that most people attempt to avoid pain and often find it unpleasant in the moment, research suggests that changes in affect after pain are not universally negative. To help advance our understanding of pain-affect relationships, the goal of the current study was to conduct a meta-analysis of studies examining changes in negative affect, as defined by subjective experience and psychophysiology, after the experience of acute laboratory pain. We identified 22 effect sizes from 17 different studies (N = 1,717). We tested several different hypotheses based primarily on theories of nonsuicidal self-injury (NSSI), with mixed support. Our main findings were that pain had a small to medium effect in reducing negative affect (dav = -0.35, 95% confidence interval [CI] [-0.58, -0.12]), and most robustly regulated negative affect in the context of a negative affect induction (dav = -0.37, 95% CI [-0.73, -0.02]) relative to neutral affect induction (dav = 0.08, 95% CI [-0.09, 0.26]). Similar reductions were also seen after painful and nonpainful stimulation, calling into question whether pain is necessary or whether any stimulation is sufficient. The results lead to several questions to be addressed in future research. (PsycINFO Database Record


Arterial bullet embolism.
An arterial bullet embolus is reported in an asymptomatic patient. Emphasis is placed on the need for an aggressive search for any unaccounted-for bullets, confirmation of diagnosis by arteriography and early operative extraction of the embolus.


Does correction of preoperative coronal imbalance make a difference in outcomes of adult patients with deformity?
Retrospective study with prospectively collected outcomes data. Determine the significance of coronal balance on spinal deformity surgery outcomes. Sagittal balance has been confirmed as an important radiographic parameter correlating with adult deformity treatment outcomes. The significance of coronal balance on functional outcomes is less clear. Eighty-five patients with more than 4 cm of coronal imbalance who underwent reconstructive spinal surgery were evaluated to determine the significance of coronal balance on functional outcomes as measured with the Oswestry Disability Index (ODI) and Scoliosis Research Society outcomes questionnaires. Sixty-two patients had combined coronal (>4 cm) and sagittal imbalance (>5 cm), while 23 patients had coronal imbalance alone. Postoperatively, 85% of patients demonstrated improved coronal balance. The mean improvement in the coronal C7 plumb line was 26 mm for a mean correction of 42%. The mean preoperative sagittal C7 plumb line in patients with combined coronal and sagittal imbalance was 118 mm (range, 50-310 mm) and improved to a mean 49 mm. The mean preoperative and postoperative ODI scores were 42 (range, 0-90) and 27 (range, 0-78), for a mean improvement of 15 (36%) (P = 0.00001; 95% CI, 12-20). The mean Scoliosis Research Society scores improved by 17 points (29%) (P = 0.00). Younger age (P = 0.008) and improvement in sagittal balance (P = 0.014) were positive predictors for improved ODI scores. Improvement in sagittal balance (P = 0.010) was a positive predictor for improved Scoliosis Research Society scores. In patients with combined coronal and sagittal imbalance, improvement in sagittal balance was the most significant predictor for improved ODI scores (P = 0.009). In patients with preoperative coronal imbalance alone, improvement in coronal balance trended toward, but was not a significant predictor for improved ODI (P = 0.092). Sagittal balance improvement is the strongest predictor of improved outcomes in patients with combined coronal and sagittal imbalance. In patients with coronal imbalance alone, improvement in coronal balance was not a factor for predicting improved functional outcomes.


Alterations in positive affect: Relationship to symptoms, traumatic experiences, and affect ratings.
Intrusive negative affect and concurrent deficits in positive affect are hallmarks of posttraumatic stress disorder (PTSD). We sought to further extend the extant literature by exploring the experience of negative affect intrusion upon potentially positive situations (here termed, "negative affect interference," NAI). Two studies with adults endorsing at least 1 traumatic event (Study 1, N = 294; Study 2, N = 286) examined how NAI and more general hedonic deficits (HD) relate to psychopathology, trauma exposure characteristics, and ratings of normed visual stimuli. Study 1 found that NAI and HD were positively correlated with PTSD symptoms and childhood trauma, and NAI incremented over depressive symptoms in predicting PTSD severity. Study 2 results indicated additional strong positive correlations between NAI and HD and anhedonia, affect regulation problems, negative affect, and neuroticism. NAI and HD were found to increment over trait NA in predicting PTSD symptoms. Individuals endorsing elevated NAI and HD rated positively valenced pictures (including food and erotic images) as less arousing, although not more negative. These findings expand conceptualizations of anhedonia and emotional numbing by drawing attention to negative affect in otherwise positive contexts. (PsycINFO Database Record


Chemoprophylaxis for Venous Thromboembolism in Operative Treatment of Fractures of the Tibia and Distal Bones: A Systematic Review and Meta-analysis.
Clinical practice has shifted from therapeutic anticoagulation of any lower extremity venous thromboembolism (VTE) to only thromboses with risk of proximal extension or embolization-clinically important VTE (CIVTE). Isolated operative fractures of the tibia or distal bone of the lower extremity are associated with low-to-intermediate VTE risk, and there is wide variability in the choice to anticoagulate as well as anticoagulant. We sought to evaluate the role for chemoprophylaxis of VTE and CIVTE in these injuries by meta-analysis of Level I evidence. Articles in English, Chinese, French, and German in MEDLINE, Biosis, and EMBASE from 1988 to 2016. Randomized controlled trials describing chemoprophylaxis of VTE after operative management of fractures of the tibia and distal bones. Independent review of 1502 citations yielded 5 studies (1181 patients) meeting inclusion criteria. Chemoprophylaxis regimen, VTE, CIVTE, and major bleeding events were recorded. Study quality was assessed with regard to randomization, outcome assessment allocation and treatment concealment, and commercial funding. A random-effects model meta-analysis determined that chemoprophylaxis with a low-molecular-weight heparin (LMWH) compared with placebo or no intervention significantly reduced the risk of any VTE [pooled relative risk (RR) = 0.696, 95% confidence interval (0.490-0.989), P = 0.043; homogeneity P = 0.818, I = 0%]. However, chemoprophylaxis with a LMWH compared with placebo did not significantly reduce the risk of CIVTE [RR = 0.865, 95% confidence interval (pooled RR = 0.112-3.863), P = 0.790; homogeneity P = 0.718, I = 0%]. No major bleeding events occurred. Funnel plots did not suggest publication bias. The number needed to treat was 31 patients treated with chemoprophylaxis using a LMWH to prevent 1 VTE and 584 patients to prevent 1 CIVTE. Meta-analysis of Level I evidence suggests that routine postoperative anticoagulation after surgical management of an isolated fracture of the tibia or distal bone in patients without risk factors for VTE is unlikely to provide a clinical benefit, based on the absence of a treatment effect for preventing VTE warranting therapeutic anticoagulation. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Permanent draft genome sequence of Geobacillus thermocatenulatus strain GS-1.
Geobacillus thermocatenulatus strain GS-1 is a thermophilic bacillus having a growth optimum at 60°C, capable of degrading alkanes. It was isolated from the formation water of a high-temperature deep oil reservoir in Qinghai oilfield, China. Here, we report the draft genome sequence with an estimated assembly size of 3.5Mb. A total of 3371 protein-coding sequences, including monooxygenase, alcohol dehydrogenase, aldehyde dehydrogenase, fatty acid-CoA ligase, acyl-CoA dehydrogenase, enoyl-CoA hydrogenase, hydroxyacyl-CoA dehydrogenase and thiolase, were detected in the genome, which are involved in the alkane degradation pathway. Our results may provide insights into the genetic basis of the adaptation of this strain to high-temperature oilfield ecosystems.


Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors.
Caseinolytic protease P (ClpP) responsible for the proteolysis of damaged or misfolded proteins plays a critical role in proteome homeostasis. MtbClpP1P2, a ClpP enzyme complex, is required for survival in Mycobacterium tuberculosis, and it is therefore considered as a promising target for the development of antituberculosis drugs. Here, we discovered that cediranib and some of its derivatives are potent MtbClpP1P2 inhibitors and suppress M. tuberculosis growth. Protein pull-down and loss-of-function assays validated the in situ targeting of MtbClpP1P2 by cediranib and its active derivatives. Structural and mutational studies revealed that cediranib binds to MtbClpP1P2 by binding to an allosteric pocket at the equatorial handle domain of the MtbClpP1 subunit, which represents a unique binding mode compared to other known ClpP modulators. These findings provide us insights for rational drug design of antituberculosis therapies and implications for our understanding of the biological activity of MtbClpP1P2.


Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study.
Objectives To assess the impact of in utero co-exposure to psychotropic medications and opioids on the incidence and severity of neonatal drug withdrawal.Design Observational cohort study.Setting Nationwide sample of pregnancies in publicly insured women in the US, nested in the Medicaid Analytic eXtract (2000-10).Participants 201 275 pregnant women with public insurance who were exposed to opioids around the time of delivery and their liveborn infants.Interventions In utero exposure to psychotropic medications, in particular antidepressants, atypical antipsychotics, benzodiazepines, gabapentin, and non-benzodiazepine hypnotics (Z drugs), with prescriptions filled within the same time window as prescriptions for opioids.Main outcome measure Diagnosis of neonatal drug withdrawal in infants exposed in utero to opioids and psychotropic medications compared with opioids alone.Results The absolute risk for neonatal drug withdrawal ranged from 1.0% in infants exposed in utero to prescription opioids alone to 11.4% for those exposed to opioids co-prescribed with gabapentin. Among neonates exposed in utero to prescription opioids, the relative risk adjusted for propensity score was 1.34 (95% confidence interval 1.22 to 1.47) with concomitant exposure to antidepressants, 1.49 (1.35 to 1.63) with benzodiazepines, 1.61 (1.26 to 2.06) with gabapentin, 1.20 (0.95 to 1.51) with antipsychotics, and 1.01 (0.88 to 1.15) with Z drugs. In utero exposure to two or more psychotropic medications along with opioids was associated with a twofold increased risk of withdrawal (2.05, 1.77 to 2.37). The severity of the withdrawal seemed increased in neonates exposed to both opioids and psychotropic medications compared with opioids alone.Conclusions During pregnancy, the use of psychotropic medications in addition to prescription opioids is common, despite a lack of safety data. The current findings suggest that these drugs could further increase the risk and severity of neonatal drug withdrawal.


Minimally invasive management of the calcified ureteral stent.
The double "J" ureter stent has become one of the most basic and valuable tools in urology, but it can cause complications. Stent encrustation is one of its most difficult complications to manage. An evaluation and treatment algorithm that stratifies the treatment based upon the function of the stented kidney and the presence or absence of concomitant ureteral obstruction is presented. Minimally invasive surgery using ESWL and cystolitholapaxy is recommended as the first line of treatment of the extensively encrusted ureteral stent when the kidney has greater than 10% function.


Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling.
In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng-/- mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng+/+ mice, the frequency-response curve of Ng-/- shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng-/- slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+ ([Ca2+]i) response in Ng+/+ compared with Ng-/- mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng-/- mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+]i by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+]i at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.


Maxwell equations and the k function
We use a general solution to the eikonal equation to define generalized coordinates in terms of which the Maxwell equations are then cast. These coordinates are then used to obtain expressions for the electric and magnetic field vectors and the Poynting vector. An arbitrary vector function V is introduced that is subject to certain side conditions derived in this process. The k function, the arbitrary function that arises in the solution of the eikonal equation, contains only information descriptive of the geometry of a wave-front train. The vector function V contains information pertaining to the physics of the propagating energy that is distinct from the geometry of the wave-front train.


Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.
Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.


Working at higher magnifications in scanning electron microscopy with secondary and backscattered electrons on metal coated biological specimens and imaging macromolecular cell membrane structures.
Membrane structures of macromolecular dimensions were imaged with high resolution secondary electron type I (SE-I) signal contrasts on metal coated biological specimens. The quality of the surface information was strongly dependent on the signal used for microscopy and on the properties of metal films, i.e., thickness, continuity, structure and decoration effects. Films of 10 nm thickness produced so much type II electrons that identical images were obtained with the conventional SE-II and BSE-II signals. In such images, the type I SE signal was so low that only very weak contrasts were recognizable. If the films--continuous or discontinuous--were composed of large metal aggregates (gold and platinum) a strong micro-roughness contrast was produced by the type II signal. At high magnifications (100,000 x) this background signal greatly reduced the S/N ratio of the SE-I signal. A similar effect was previously shown to be produced by the type III background signal. The type II background signal minimized when continuous films of small aggregates (tantalum and chromium) were applied. SE-I contrast dominated in the image if the film thickness was limited to 1 nm. Additionally, it was found that gold and platinum decorated membrane surface structures, less than 20 nm in size, and did not reveal all the topographic information available (size, shape, orientation spacing of small surface features) but merely displayed center-to-center distances. These decoration effects were avoided and extensive topographic information was obtained through surface coating with Ta or Cr.


Characterization of Tetragenococcus strains from sugar thick juice reveals a novel species, Tetragenococcus osmophilus sp. nov., and divides Tetragenococcus halophilus into two subspecies, T. halophilus subsp. halophilus subsp. nov. and T. halophilus subsp. flandriensis subsp. nov.
Most bacteria recovered so far from sugar thick juice during storage represent strains of the species Tetragenococcus halophilus. Recently, several Gram-positive, non-motile, non-spore-forming cocci with other physiological and genetic traits were isolated from sugar thick juice samples from different origins. In this study, representative isolates were investigated using a polyphasic taxonomic approach. The 16S rRNA gene sequence similarity between these isolates and their closest relative, Tetragenococcus muriaticus, was 97.4%. The level of DNA-DNA relatedness between isolate T1(T), representing the newly found Tetragenococcus isolates, and T. muriaticus was 57%. Isolate T1(T) had a DNA G+C content of 36.7 mol%. Phylogenetic data and genomic and phenotypic features demonstrated that the isolates represent a novel species, for which the name Tetragenococcus osmophilus sp. nov. is proposed with T1(T) as the type strain (=LMG 26041(T) =DSM 23765(T)). Additionally, T. halophilus isolates from high-salt and high-sugar environments showed clear differences in several physiological and genetic characteristics like RAPD fingerprints and 16S rRNA gene sequences. DNA-DNA hybridizations, however, showed 79 to 80% relatedness between osmophilic and halophilic T. halophilus isolates, demonstrating that the different strains belong to the same species. Based on the phenotypic and genotypic differences observed, as well as the different origins of the strains and the industrial relevance of thick juice degradation, two subspecies of T. halophilus are described in this manuscript: T. halophilus subsp. halophilus subsp. nov. for the strains isolated from salt media and T. halophilus subsp. flandriensis subsp. nov. for the strains isolated from sugar-rich environments, which were first isolated in Flanders, Belgium. The type strains for the subspecies are IAM 1676(T) (=LMG 11490(T) =DSM 20339(T)) and T5(T) (=LMG 26042(T) =DSM 23766(T)), respectively.


Interplay of catalysis, fidelity, threading, and processivity in the exo- and endonucleolytic reactions of human exonuclease I.
Human exonuclease 1 (hExo1) is a member of the RAD2/XPG structure-specific 5'-nuclease superfamily. Its dominant, processive 5'-3' exonuclease and secondary 5'-flap endonuclease activities participate in various DNA repair, recombination, and replication processes. A single active site processes both recessed ends and 5'-flap substrates. By initiating enzyme reactions in crystals, we have trapped hExo1 reaction intermediates that reveal structures of these substrates before and after their exo- and endonucleolytic cleavage, as well as structures of uncleaved, unthreaded, and partially threaded 5' flaps. Their distinctive 5' ends are accommodated by a small, mobile arch in the active site that binds recessed ends at its base and threads 5' flaps through a narrow aperture within its interior. A sequence of successive, interlocking conformational changes guides the two substrate types into a shared reaction mechanism that catalyzes their cleavage by an elaborated variant of the two-metal, in-line hydrolysis mechanism. Coupling of substrate-dependent arch motions to transition-state stabilization suppresses inappropriate or premature cleavage, enhancing processing fidelity. The striking reduction in flap conformational entropy is catalyzed, in part, by arch motions and transient binding interactions between the flap and unprocessed DNA strand. At the end of the observed reaction sequence, hExo1 resets without relinquishing DNA binding, suggesting a structural basis for its processivity.


Vibrational dynamics in lead halide hybrid perovskites investigated by Raman spectroscopy.
Lead halide perovskite semiconductors providing record efficiencies of solar cells have usually mixed compositions doped in A- and X-sites to enhance the phase stability. The cubic form of formamidinium (FA) lead iodide reveals excellent opto-electronic properties but transforms at room temperature (RT) into a hexagonal structure which does not effectively absorb visible light. This metastable form and the mechanism of its stabilization by Cs+ and Br- incorporation are poorly characterized and insufficiently understood. We report here the vibrational properties of cubic FAPbI3 investigated by DFT calculations on phonon frequencies and intensities, and micro-Raman spectroscopy. The effects of Cs+ and Br- partial substitution are discussed. We support our results with the study of FAPbBr3 which expands the identification of vibrational modes to the previously unpublished low frequency region (<500 cm-1). Our results show that the incorporation of Cs+ and Br- leads to the coupling of the displacement of the A-site components and weakens the bonds between FA+ and the PbX6 octahedra. We suggest that the enhancement of α-FAPbI3 stability can be a product of the release of tensile stresses in the Pb-X bond, which is reflected in a red-shift of the low frequency region of the Raman spectrum (<200 cm-1).


The caries-preventive effect of chlorhexidine varnish in children and adolescents: a systematic review.
Our purpose was to systematically review the literature on the effectiveness of chlorhexidine varnish for preventing dental caries in children and adolescents and to determine its effectiveness compared to fluoride varnish. MEDLINE, EMBASE and the Cochrane Library were searched through December 2009 to identify relevant randomised trials with blind outcome assessment and a minimum duration of 1 year. The search was later updated in MEDLINE and the Cochrane Library to March 19th, 2010. Risk of bias of the included trials was assessed. The primary outcome was the caries increment. Twelve trials met the inclusion criteria for the review. There was considerable variation between trials in the concentration and frequency of application of the chlorhexidine varnish, in baseline caries levels and in background exposure to fluoride. Six parallel-group trials reported no statistically significant difference in caries increment in permanent teeth with the application of chlorhexidine varnish compared to placebo or no treatment. The results of 4 split-mouth trials were conflicting: 2 trials found no significant difference in caries increment and 2 reported statistically significant results in favour of chlorhexidine varnish. One trial of the effect of chlorhexidine varnish in primary teeth demonstrated a statistically significant reduction in caries increment. The results of 1 trial comparing chlorhexidine varnish with fluoride varnish for preventing caries in adolescents were equivocal. Evidence regarding the effectiveness of chlorhexidine varnish for preventing caries is inconclusive. Further well-conducted randomised trials are required before chlorhexidine varnish can be recommended for caries prevention.


A comparison of continuous flow and sequencing batch reactor plants concerning integrated operation of sewer systems and wastewater treatment plants.
Integrated operation strategies for combined sewer and WWTP are becoming more and more popular because of numerous benefits. One can find many examples in literature, but many of these studies deal with partly fictitious systems and/or were accomplished within the planning. Hence most of these studies do not have to deal with the restrictions given by already built constructions. The authors, who worked on several integrated projects, will discuss the requirements of SBR and CFR plants concerning an implementation of integrated operation.


C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice.
Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders. C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice. Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-alpha and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.


Neurodegeneration, Neuroregeneration, and Neuroprotection in Psychiatric Disorders.
Prevention of deterioration of brain function over time is important in the long-term management of chronic brain disorders such as dementia, schizophrenia, and mood disorders. Although the possibility of neurogenesis in the adult human brain is attractive, and there are psychiatric drugs proven to be effective inducers of neurogenesis in animals, we have yet to see their utility in clinical practice. The terms neurodegeneration and neuroregeneration are often used in a nonspecific manner. Neuroregeneration may mean neurogenesis, dendritogenesis, spinogenesis, or axonogenesis. The term "neuroprotection" is attractive clinically and may involve different mechanisms. Many causative and protective factors of neurodegeneration and neuroregeneration have been proposed. However, the specificity of these factors and agents and differential neuronal vulnerability factors have generally been ignored in past studies. It is also hard to separate disease-modifying from "neuroprotective" effects of a drug. The application of stringent long-term neuroanatomical, neurochemical, neurophysiological, and therapeutic efficacy criteria should improve future research in this important area.


Complete genomic structure of human rpS3: identification of functional U15b snoRNA in the fifth intron.
Analysis of the complete genomic structure of the human ribosomal protein S3 (rpS3) gene revealed the presence of a functional U15b snoRNA gene in its intron. Human ribosomal protein S3 (rpS3) gene of 6115 bp long has been identified to contain six introns and seven exons in this study. The first and fifth introns of human S3 gene contain functional U15 snoRNA genes. Although Xenopus and Fugu counterparts also have six introns and seven exons, S3 gene of Fugu contains two functional U15 snoRNAs in the fourth and sixth introns and two pseudo genes for U15 snoRNAs in the first and fifth introns. In Xenopus S1 gene encoding ribosomal protein S3, however, three of its six introns contain U15 snoRNA gene sequence. Sequence comparison of the U15 genes from Xenopus, Fugu and human revealed that the regions involved in binding to 28S rRNA and the consensus sequence (C, D and D' boxes) for snoRNAs are highly conserved among those genes from these three species. Human U15a and U15b RNAs which are derived from the first and the fifth introns, respectively, have been identified to be functional by microinjection of human U15a and U15b snoRNAs into Xenopus oocyte. Northern blot and primer extension analyses confirm that human U15b snoRNA is expressed in vivo.


Be yourself, believe in yourself, and be happy: self-efficacy as a mediator between personality factors and subjective well-being.
Research has shown close connections between personality and subjective well-being (SWB), suggesting that personality traits predispose individuals to experience different levels of SWB. Moreover, numerous studies have shown that self-efficacy is related to both personality factors and SWB. Extending previous research, we show that general self-efficacy functionally connects personality factors and two components of SWB (life satisfaction and subjective happiness). Our results demonstrate the mediating role of self-efficacy in linking personality factors and SWB. Consistent with our expectations, the influence of neuroticism, extraversion, openness, and conscientiousness on life satisfaction was mediated by self-efficacy. Furthermore, self-efficacy mediated the influence of openness and conscientiousness, but not that of neuroticism and extraversion, on subjective happiness. Results highlight the importance of cognitive beliefs in functionally linking personality traits and SWB.


Phytochemical Analysis, Identification and Quantification of Antibacterial Active Compounds in Betel Leaves, Piper betle Methanolic Extract.
The problems of bacterial diseases in aquaculture are primarily controlled by antibiotics. Medicinal plants and herbs which are seemed to be candidates of replacements for conventional antibiotics have therefore gained increasing interest. Current study was performed to investigate the presence of phytochemical constituents, antibacterial activities and composition of antibacterial active compounds in methanolic extract of local herb, Piper betle . Qualitative phytochemical analysis was firstly carried out to determine the possible active compounds in P. betle leaves methanolic extract. The antibacterial activities of major compounds from this extract against nine fish pathogenic bacteria were then assessed using TLC-bioautography agar overlay assay and their quantity were determined simultaneously by HPLC method. The use of methanol has proved to be successful in extracting numerous bioactive compounds including antibacterial compounds. The TLC-bioautography assay revealed the inhibitory action of two compounds which were identified as hydroxychavicol and eugenol. The $-caryophyllene however was totally inactive against all the tested bacterial species. In this study, the concentration of hydroxychavicol in extract was found to be 374.72±2.79 mg g-1, while eugenol was 49.67±0.16 mg g-1. Based on these findings, it could be concluded that hydroxychavicol and eugenol were the responsible compounds for the promising antibacterial activity of P. betle leaves methanolic extract. This inhibitory action has significantly correlated with the amount of the compounds in extract. Due to its potential, the extract of P. betle leaves or it compounds can be alternative source of potent natural antibacterial agents for aquaculture disease management.


Charge-density analysis of YBa2Cu3O6.98. Comparison of theoretical and experimental results.
Using high-energy synchrotron radiation, structure factors of YBa(2)Cu(3)O(6.98) were measured at $\lambda$ = 0.124 A. Charge densities were derived using generalized structure factors and VALRAY and compared to densities refined from theoretical structure factors, which were calculated using the LAPW method and WIEN2k. Refinement agreement indices were R(F) = 0.0047 for the experimental and 0.0023 for the theoretical data set, respectively. Experimental and theoretical results generally agree well. A topological analysis shows that the structure is mainly ionic but depletion of charge density between Cu and O gives hints for covalency and confirms the general consensus of hole localization in these bonds.


Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4.
Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome. MDP reduced hepatic insulin resistance during obesity and low-level endotoxemia. NOD1-activating muropeptides worsened glucose tolerance. IRF4 distinguished opposing glycemic responses to different types of peptidoglycan and was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia. IRF4 was dispensable for exacerbated glucose intolerance via NOD1. Mifamurtide, an MDP-based drug with orphan drug status, was an insulin sensitizer at clinically relevant doses in obese mice.


Endogenous interleukin-10 constrains Th17 cells in patients with inflammatory bowel disease.
Th17 cells play a role in inflammation. Interleukin (IL)-10 is a potent anti-inflammatory cytokine. However, it is poorly understood whether and how endogenous IL-10 impacts the development of Th17 cells in human pathologies. We examined the relationship between IL-10 and Th17 cells in patients with Crohn's disease and in IL-10-deficient (IL-10-/-) mice. Th17 cells and dendritic cells (DCs) were defined by flow cytometry and evaluated by functional studies. We detected elevated levels of IL-17 and Th17 cells in the intestinal mucosa of patients with Crohn's disease. Intestinal DCs from Crohn's patients produced more IL-1β than controls and were superior to blood DCs in Th17 induction through an IL-1-dependent mechanism. Furthermore, IL-17 levels were negatively associated with those of IL-10 and were positively associated those of IL-1β in intestinal mucosa. These data point toward an in vivo cellular and molecular link among endogenous IL-10, IL-1, and Th17 cells in patients with Crohn's disease. We further investigated this relationship in IL-10(-/-) mice. We observed a systemic increase in Th17 cells in IL-10(-/-) mice when compared to wild-type mice. Similar to the intestinal DCs in patients with Crohn's disease, murine IL-10-/- DCs produced more IL-1β than their wild-type counterparts and promoted Th17 cell development in an IL-1-dependent manner. Finally, in vivo blockade of IL-1 receptor signaling reduced Th17 cell accumulation and inflammation in a mouse model of chemically-induced colitis. Endogenous IL-10 constrains Th17 cell development through the control of IL-1 production by DCs, and reaffirms the crucial anti-inflammatory role of IL-10 in patients with chronic inflammation.


Peptide toxin components of Amanita exitialis basidiocarps.
Eight peptide toxins were isolated and purified from basidiocarps of Amanita exitialis with high performance liquid chromatography and were subjected to ultraviolet, nuclear magnetic resonance and mass spectrometry. We identified seven peptide toxins, α-amanitin, β-amanitin, amaninamide, phallacin, phallacidin, phallisacin and desoxoviroidin. The molecular weight (729.5 Da) of the eighth compound did not match that of any reported Amanita toxins and, although the UV absorption spectrum indicated it to be a phallotoxin, further studies are required to identify this component. This is the first report of amaninamide, phallacin, phallisacin and desoxoviroidin in this lethal mushroom species.


Use of oxygen and opioids in the palliation of dyspnoea in hypoxic and non-hypoxic palliative care patients: a prospective study.
Dyspnoea is a complex experience of the body and the mind. Whereas the effects of opioids on dyspnoea in advanced disease have been the focus of studies for management of dyspnoea in palliative medicine, the role of oxygen is still unclear. The effects of symptomatic oxygen and opioid treatment on ventilation and palliation of dyspnoea in hypoxic (H) and non-hypoxic (NH) palliative care patients were assessed and compared. In a prospective, non-randomised study, 46 patients with mild to severe dyspnoea were included. Transcutaneous measurement (earlobe sensor) of carbon dioxide partial pressure (tcpaCO2), pulse oximetry oxygen saturation (SaO2) and pulse frequency (PF) were monitored with SenTec digital monitor. Compared was: baseline data of the continuously documented respiratory parameters for about 15 min in patients breathing room air at admission, 60 min during nasal O2 insufflation, and 30, 90 and 120 min after the first opioid application and without O2 insufflation. Whereas opioid application resulted in a significant decrease in the intensity of dyspnoea and respiratory rate, during the nasal O2 insufflation (4 l/min), there was no significant decrease in the intensity of dyspnoea neither in H (P = 0.564) nor in NH (P = 0.096) patients. There was no evidence of a significant correlation between the intensity of dyspnoea and oxygen saturation. The Spearman rank correlation in NH patients was -0.080 (P = 0.686) and in H patients P = 0.296 (P = 0.233). No significant differences between the groups of hypoxic and non-hypoxic patients with regard to tcpaCO2 increase (P = 0.075 NH; P = 0.346 H) or SaO2 decrease after opioid application (P = 0.077) were found. In this study, opioids worked significantly better than oxygen in reducing the intensity of dyspnoea even in hypoxic patients. There was no correlation between intensity of dyspnoea and oxygen saturation in H and NH patients. Oxygen should be seen as a pharmacological agent and not be given based on intuitive assumption of benefit.


[Effect of sodium fluoride on succinate dehydrogenase and NADH: cytochrome c-reductase of rat liver mitochondria].
It is established that sodium fluoride inhibits the activity of isolated soluble dehydrogenase and succinate dehydrogenase in the rat liver mitochondria in experiments in vitro. The degree of inhibition depends on the fluoride concentration and period of action. At the same time no changes are observed in the NADH-dehydrogenase activity of the mitochondria in the presence of 100 mM of sodium fluoride. With the intragastric administration of 35 and 24 mg/kg sodium fluoride to animals for 3 and 60 days, respectively, the succinate and NADH-dehydrogenase activities of the rat liver mitochondria lower significantly.


Synthetic aperture pulse-echo imaging with rectangular boundary arrays [acoustic imaging].
The effectiveness of a square boundary array in finite-range, pulse-echo imaging is investigated. The images produced by such an array are quite poor when no additional signal processing is used. It is demonstrated through simulations that a synthetic-aperture signal processing technique called image addition can be used to reduce the sidelobes associated with the square boundary array, thereby improving the image quality. Image addition was originally proposed for narrowband imaging of far-field scenes, but it is also useful for finite-range, pulse-echo imaging. The conclusions are expected to apply to other, nonsquare boundary array geometries.


The site-specific integration of genetic elements may modulate thermostable protease production, a virulence factor in Dichelobacter nodosus, the causative agent of ovine footrot.
The gram-negative anaerobe Dichelobacter nodosus is the causative agent of footrot in sheep. The authors have previously characterized two genetic elements, the intA (vap) and intB elements, which integrate into the genome of D. nodosus. In the virulent strain A198 there are two copies of the intA element. One copy is integrated into the 3' end of the tRNA-serGCU gene, close to the aspartokinase (askA) gene, and the second copy is integrated into the 3' end of the tRNA-serGGA gene, next to the polynucleotide phosphorylase (pnpA) gene. In this study, a new genetic element was identified in the benign strain C305, the intC element, integrated into the 3' end of the tRNA-serGCU gene, next to askA. The intC element was found in most D. nodosus strains, both benign and virulent, which were examined, and was integrated into tRNA-serGCU in most strains. Between the askA and tRNA-serGCU genes, a gene (designated glpA), was identified whose predicted protein product has very high amino acid identity with RsmA from the plant pathogen Erwinia carotovora. RsmA acts as a global repressor of pathogenicity in E. carotovora, by repressing the production of extracellular enzymes. In virulent strains of D. nodosus the intA element was found to be integrated next to pnpA, and either the intA or intC element was integrated next to glpA. By contrast, all but one of the benign strains had intB at one or both of these two positions, and the one exception had neither intA, intB nor intC at one position. The loss of the intC element from the virulent strain 1311 resulted in loss of thermostable protease activity, a virulence factor in D. nodosus. A model for virulence is proposed whereby integration of the intA and intC genetic elements modulates virulence by altering the expression of glpA, pnpA, tRNA-serGCU and tRNA-serGGA.