[Effect and tolerance of Phanurane in the treatment of essential hypertension. (Double blind study) (author's transl)].
A double-blind study of Phanurane and placebo was conducted on 61 patients with mild essential hypertension. Each patient received 2 gelules daily (2 X 50 mg of canrenone) during a 2 month period. Statistical analysis has shown that patients on Phanurane experienced a significant decrease in systolic and diastolic blood pressure compared with patients on placebo. Clinical tolerance of canrenone was excellent. Uric acid and triglyceride levels remained normal.


Short-term and residential exposure to air pollution: Associations with inflammatory biomarker levels in adults living in northern France.
Air pollution has an impact on health, and low-grade inflammation might be one of the underlying mechanisms. The objective of the present study of adults from northern France was to assess the associations between short-term and residential exposure to air pollution and levels of various inflammatory biomarkers. The cross-sectional Enquête Littoral Souffle Air Biologie Environnement (ELISABET) study was conducted from 2011 to 2013 in the Lille and Dunkirk urban areas of northern France. Here, we evaluated the associations between PM10, NO2 and O3 exposure (on the day of the blood sample collection and on the day before, and the mean annual residential level) and levels of the inflammatory biomarkers high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17A, IL-22, and tumor necrosis factor α. We assessed 3074 participants for the association with hsCRP and a subsample of 982 non-smokers from Lille for the association with plasma cytokine levels. A 10 μg/m3 increment in PM10 and NO2 levels on the day of sample collection and on the day before was associated with a higher hsCRP concentration (3.43% [0.68; 6.25] and 1.75% [-1.96; 5.61], respectively, whereas a 10 μg/m3 increment in O3 was associated with lower hsCRP concentration (-1.2% [-3.95; 1.64]). The associations between mean annual exposure and the hsCRP level were not significant. Likewise, the associations between exposure and plasma cytokine levels were not statistically significant. Short-term exposure to air pollution was associated with higher serum hsCRP levels in adult residents of two urban areas in northern France. Our results suggest that along with other factors, low-grade inflammation might explain the harmful effects of air pollution on health.


Combined Anteversion Threshold to Avoid Anterior Dislocation in Primary Total Hip Arthroplasty Performed Through the Direct Anterior Approach.
Component malposition in total hip arthroplasty (THA) can lead to dislocation, early implant failure, and revision surgery. As the surgical approach might affect the targeted combined anteversion (CA) of THA components, the present study aimed to evaluate the optimal CA threshold to avoid anterior dislocation in primary THA performed through a direct anterior approach (DAA). A total of 1,176 THAs in 1,147 consecutive patients (men: 593, women: 554) who had an average age of 63 years (range, 24 to 91) and a mean body mass index of 29 (range, 15 to 48) were identified. Medical records were reviewed for dislocation, whereas postoperative radiographs were assessed to measure the acetabular inclination and CA using a previously validated radiographic method. An anterior dislocation occurred in 19 patients at an average of 40 days postoperatively. The average CA in patients who did and did not have a dislocation was 66 ± 8° and 45 ± 11°, respectively (P < .001). In 5 of 19 of the patients, a THA was performed for secondary osteoarthritis and 17 of 19 had a 28-mm femoral head. A CA ≥ 60° yielded a sensitivity of 93% and specificity of 90% for predicting an anterior dislocation in the present cohort. A CA ≥ 60° was associated with a significantly higher risk of anterior dislocation (odds ratio = 75.6; P < .001) compared to patients who had a CA<60 points. The optimal CA to avoid anterior dislocations in THA performed through the DAA should be less than 60°. Cross-sectional study, Level III.


Techno-economic analysis of wastewater sludge gasification: a decentralized urban perspective.
The successful management of wastewater sludge for small-scale, urban wastewater treatment plants, (WWTPs), faces several financial and environmental challenges. Common management strategies stabilize sludge for land disposal by microbial processes or heat. Such approaches require large footprint processing facilities or high energy costs. A new approach considers converting sludge to fuel which can be used to produce electricity on-site. This work evaluated several thermochemical conversion (TCC) technologies from the perspective of small urban WWTPs. Among TCC technologies, air-blown gasification was found to be the most suitable approach. A gasification-based generating system was designed and simulated in ASPEN Plus® to determine net electrical and thermal outputs. A technical analysis determined that such a system can be built using currently available technologies. Air-blown gasification was found to convert sludge to electricity with an efficiency greater than 17%, about triple the efficiency of electricity generation using anaerobic digester gas. This level of electricity production can offset up to 1/3 of the electrical demands of a typical WWTP. Finally, an economic analysis concluded that a gasification-based power system can be economically feasible for WWTPs with raw sewage flows above 0.093m(3)/s (2.1 million gallons per day), providing a profit of up to $3.5 million over an alternative, thermal drying and landfill disposal.


Specific antibodies are responsible for the low dose suppression of the immune response to thymus-independent antigens.
Animals primed to the thymus-independent antigen native dextran B512 could not respond to the FITC hapten after immunization with native FITC-dextran. The degree of suppression of the anti-FITC response paralleled the increase of the anti-alpha1-6 PFC after priming with different doses of dextran. Suppression could be passively transferred with serum from dextran primed animals. Young animals that are very low-or non-responders to the alpha1-6 epitope of dextran B512, failed to suppress the anti FITC PFC response after priming with native dextran. We conclude that antibodies against the dextran carrier were responsible for the suppressed response to the FITC epitope in FITC-dextran immunized animals that had been primed with low doses of the dextran carrier.


Ethionamide induced blue vision (cyanopsia): Case report.
Ethionamide is part of a group of drugs used in the treatment of drug resistant TB. With the advent of increasing drug resistance in pulmonary TB cases, use of Ethionamide, a second line anti tubercular drug is increasing. Vision changes are rare with ethionamide. Cyanopsia i.e., bluish tinted vision of surroundings with ethionamide is not known in literature. Here, we report a case of DRTB patient who developed cyanopsia soon after introducing ethionamide. Although reversible, ethionamide may sometimes need withdrawal because of significant distress caused to patient.


Outcomes of Breast Reduction Surgery Using the BREAST-Q: A Prospective Study and Comparison with Normative Data.
This study aimed to assess breast-related satisfaction and well-being in women with breast hypertrophy before and after breast reduction surgery, and to compare these scores with Australian general population norms, using the BREAST-Q Reduction module. A prospective cohort study was conducted between March of 2010 and February of 2016. Participants self-completed the BREAST-Q preoperatively and 12 months postoperatively. Normative BREAST-Q data were generated from women aged 18 years and older for comparison. Statistical analysis was performed and values of p < 0.05 were considered significant. The BREAST-Q was completed by 132 participants preoperatively and 12 months postoperatively. Statistically significant improvements were found following surgery in Satisfaction with Breasts, Psychosocial Well-being, Sexual Well-being, and Physical Well-being. In comparison with normative data, patients with breast hypertrophy had significantly lower scores preoperatively, with scores significantly increasing postoperatively to levels representative of the general population. Satisfaction with outcome was not significantly different between patients who were eligible by traditional insurance requirements (Schnur sliding scale/500-g minimum rule) and those who were not. The presence of surgical complications did not affect change in BREAST-Q scores or postoperative satisfaction with outcome. Differences were observed in mean BREAST-Q scores when comparing generated Australian norms to published U.S. norms. Breast reduction surgery significantly improves the satisfaction and quality of life in women with breast hypertrophy to a level that is at least equivalent to that of the normative population. Surgery is of benefit to all women, including those who do not meet traditional insurance requirements. Therapeutic, IV.


Comparison of different approaches to predict metabolic drug-drug interactions.
Three approaches were compared to predict the actual magnitude of drug interaction (the mean fold-change in the area under the curve (AUC)) of reversible or irreversible (mechanism-based) cytochrome P450 (CYP) inhibitors. These were: (1) the pragmatic use of the '[I]/K(i)' approach; (2) the 'Mechanistic-Static Model' (MSM), which is a more complex extension of the '[I]/K(i)' approach that incorporates f(m,CYP), intestinal availability for CYP3A substrates, and mechanism-based inhibition (MBI); and (3) the 'Mechanistic-Dynamic Model' (MDM) which considers the time-variant change in the concentration of the inhibitor by using physiologically-based pharmacokinetic (PBPK) models (as implemented within the Simcyp(R) Population-Based ADME Simulator). The three approaches ([I]/K(i), MSM, and MDM) predicted a 'correct' drug-drug interaction (DDI) result (interaction: Greater than or equal to twofold; no interaction: Less than twofold) in 74, 87, and 80% of the 100 trials evaluated, respectively. Importantly, for trials with a greater than or equal to twofold change in AUC in the presence of the inhibitor (59 trials), the [I]/K(i), MSM, and MDM approaches predicted the mean AUC change within twofold of actual in 17, 53, and 64% of the trials, respectively. Overall, the MDM approach showed an improvement in the prediction of DDI magnitude compared to the other methods evaluated and was useful in its ability to predict variability in DDI magnitude and pharmacokinetic parameters. Moreover, the MDM model allowed the automated prediction of the inhibition of parallel metabolic pathways and simulations of different dosing regimens.


Comparison of machine learning approaches for radioisotope identification using NaI(TI) gamma-ray spectrum.
This research aims at comparing the performance of different machine learning algorithms used for NaI(TI) gamma-ray detector based radioisotope identification. Six machine learning algorithms were implemented, including support vector machine (SVM), k-nearest neighbor (KNN), logistic regression (LR), naive Bayes (NB), decision tree (DT), and multilayer perceptron (MLP). The hyper-parameters of each model were elaborately optimized. The effects of data size, statistical fluctuation, and spectrum drift were considered. Results show that for smaller data size (5 types of radioisotopes and 6000 spectra), the support vector machine and the logistic regression classifier exhibit higher identification accuracy with less training/predicting time. Whereas for larger data size (14 types of radioisotopes corresponding to the standard IEC 62327-2017), the multilayer perceptron showed highest accuracy but required the longest time for model training. The naive Bayes classifier and the decision tree were prone to make mistakes when fluctuations and distortions were added to the spectra. The k-nearest neighbor classifier, though showing high accuracy for most data sets, consumed the longest time while making prediction.


Effect of growth of Candida spp. in the presence of various glucocorticoids on the adherence to human buccal epithelial cells.
In vitro culturing of three different yeast species with a number of glucocorticoids altered their adherence ability in two ways: Incubation with dexamethasone and triamcinolone acetonide promoted the adherence in general (the increase in adherence ranged between 17% and 44%), whilst growth in the presence of cortisone acetate or hydrocortisone blocked the adherence (inhibition ranged from 16% to 32%). No statistical difference in the adherence capabilities of different growth phases of C. albicans noted, and the effects of glucocorticoids persisted irrespective of the phase of growth used. An attempt to explain the differences in adherence of the Candida spp. investigated, in the presence of various steroids, on the basis of variation in their structural configurations and/or steroid-receptor interaction is given.


Isolation of Projection-Specific and Behavior-Relevant Amygdala Circuit for RNA Sequencing.
One of the most sought-after topics in neuroscience is to understand how the environment regulates the activity and function of neural circuitry and subsequently influences relevant behaviors. In response to alterations in the environment, the neural circuits undergo adaptive changes ranging from gene expression changes to altered cellular function. Performing sequencing of the transcriptome involved in these behavior-related circuits will provide clues to accurately dissect the detailed mechanisms of related behavior. Here, we describe methods for marking and collecting the ventral hippocampus-projecting basolateral amygdala neurons, which have been repeatedly implicated in regulation of anxiety-like behavior, and subsequently constructing a library ready for sequencing. Specifically, the reported approaches include adeno-associated virus injection, acute brain slice isolation, cell suspension preparation, cell extraction, and cDNA library construction. By utilizing the techniques described here, researchers can comprehensively investigate the transcriptional levels of neural clusters embedded in particular circuits and discover potential pathogenic and therapeutic targets for behavior-relevant disorders. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Tagging of behavior-related neural circuits Basic Protocol 2: Isolation and capture of fluorescent-positive cells Basic Protocol 3: Foundation of sequencing library.


Semaphorin signaling in bone.
Semaphorin molecules regulate cell adhesion and motility in a wide variety of cell types and are therefore involved in numerous processes including axon guidance, angiogenesis, cardiogenesis, tumor growth, and immune response. Increasing evidence points to a role of transmembrane, membrane-associated and soluble semaphorins during bone development as well as in the control of normal bone homeostasis. Within bone, semaphorins are implicated in the communication between different cell types by relaying signals in an autocrine or paracrine way. Semaphorins are not only involved in bone resorption but also in bone formation. Therefore, targeting semaphorin-induced signaling in bone may constitute an interesting new therapeutic strategy in osteoporosis. However, all the pioneering research on semaphorins is performed in mice and it remains to be established to what extent semaphorin signaling pathways are conserved between mice and men. In addition, knowledge of semaphorin signaling in bone mostly arises from loss/gain of function studies of one single semaphorin and/or receptor. However, different semaphorin molecules are co-expressed in bone and their signaling pathways are likely to interact in a complex and coherent way that needs proper understanding before targeting semaphorin signaling can be therapeutically exploited.


Evidence for amino acid induced cholestasis in very-low-birth-weight infants with increasing enteral protein intake.
In the present investigation 32 very-low-birth-weight (VLBW) infants fed at three different levels of protein intake (2.92 g/kg/d from human milk, 3.22 and 4.06 g/kg/d from formula) were studied at the mean age of 21 days. Serum total alpha-amino nitrogen concentration correlated directly to total bile acid concentration. The serum and urine alpha-amino nitrogen and the serum bile acid concentration correlated with protein intake. The increase in protein intake was accompanied by a concomitant decrease in the intraluminal bile acid concentration in the AGA infants. The results offer indirect evidence of decreased bile flow in VLBW-infants on excessive oral protein intake. The cholestatic effect could be mediated by an increase in the plasma amino acid concentration.


The effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy: a randomized, double-blinded, controlled study.
We aimed to investigate the effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy. Eighty 18-70 years old, American Society of Anesthesiologists level I-III patients scheduled for hepatectomy with a J-shaped subcostal incision were enrolled and randomized to receive either intermittent bolus paravertebral ropivacaine (0.5% loading, 0.2% infusion) or 0.9% saline infusion at 1:1 ratio (25 ml loading before surgery, 0.125 ml/kg/h bolus for postoperative 48 h). The primary outcome was set as postoperative 48 h cumulative intravenous morphine consumption recorded by a patient-controlled analgesic pump. Thirty-eight patients in each group completed the study. The cumulative morphine consumptions were lower in the paravertebral block than control group at postoperative 24 (difference -10.5 mg, 95%CI -16 mg to -6 mg, P < 0.001) and 48 (difference -12 mg, 95%CI -19.5 mg to -5 mg, P = 0.001) hours. The pain numerical rating scales at rest were lower in the paravertebral block than control group at postoperative 4 h (difference -2, 95%CI -3 to -1, P < 0.001). The active pain numerical rating scales were lower in the paravertebral block than control group at postoperative 12 h (difference -1, 95%CI -2 to 0, P = 0.005). Three months postoperatively, the paravertebral block group had lower rates of hypoesthesia (OR 0.28, 95%CI 0.11 to 0.75, P = 0.009) and numbness (OR 0.26, 95%CI 0.07 to 0.88, P = 0.024) than the control group. Intermittent bolus paravertebral block provided an opioid-sparing effect and enhanced recovery both in hospital and after discharge in patients undergoing hepatectomy. clinicaltrials.gov (NCT04304274), date: 11/03/2020.


Comparison of two alternative wound closure methods for tumor arthroplasty of the hip: A frequency matched cohort study.
To examine the effect of an alternative wound closure method after tumor arthroplasty of the hip compared to routine wound closure with skin staples. Single center, frequency matched cohort study. We reviewed all patients who underwent tumor resection and endoprosthetic reconstruction of the proximal femur for pathologic fracture due to metastatic bone disease or malignant hematologic bone disease at our center between 2010 and 2014. All patients treated with occlusive wound closure (OWC), a combination of intradermal suture, Steri-Strips™, and an occlusive skin adhesive, during this period ( n = 35), were compared to an equally sized frequency matched group of patients having undergone routine wound closure with conventional skin staples. Patients with OWC were significantly faster to achieve dry wound status and consequently had significantly shorter administration of antibiotics and hospital stay. Compared to the patients with conventional wound closure with staples, their wounds were already dry after a mean 3.4 days (vs. 6.7 days [95%CI: 3-3.8 vs. 5.5-7.9], p < 0.0001), they received antibiotics for a mean 4.2 days (vs. 6.8 days [95%CI: 3.7-4.8 vs. 5.5-8.0], p < 0.0003) and their mean hospital stay was 6.3 days (vs. 8.0 days [95%CI: 5.5-7 vs. 6.8-9.3], p < 0.015). Prolonged wound discharge (PWD) for 7 days or more was observed in 34% of patients ( n = 12) in the conventional group, whereas this complication was completely absent ( n = 0) in the investigational group. For every three patients treated with OWC, one complication of PWD over 7 days is avoided (number needed to treat = 3). Compared to conventional staples, OWC appears to significantly reduce wound complications, use of antibiotics, and hospital stay in patients undergoing tumor arthroplasty procedures of the hip. As such, it may also contribute to a reduction of the substantially increased risk for prosthetic joint infection in this patient population.


Impact of Direct Transcatheter Aortic Valve Replacement Without Balloon Aortic Valvuloplasty on Procedural and Clinical Outcomes: Insights From the FRANCE TAVI Registry.
This study sought to describe the current practices and compare outcomes according to the use of balloon aortic valvuloplasty (BAV) or not during transcatheter aortic valve replacement (TAVR). Since its development, aortic valve pre-dilatation has been an essential step of TAVR procedures. However, the feasibility of TAVR without systematic BAV has been described. TAVR performed in 48 centers across France between January 2013 and December 2015 were prospectively included in the FRANCE TAVI (Registry of Aortic Valve Bioprostheses Established by Catheter) registry. We compared outcomes according to BAV during the TAVR procedure. A total of 5,784 patients have been included in our analysis, corresponding to 2,579 (44.6%) with BAV avoidance and 3,205 (55.4%) patients with BAV performed. We observed a progressive decline in the use of BAV over time (78% of procedures in 2013 and 49% in the last trimester of 2015). Avoidance of BAV was associated with similar device implantation success (97.3% vs. 97.6%; p = 0.40). TAVR procedures without BAV were quicker (fluoroscopy 17.2 ± 9.1 vs. 18.5 ± 8.8 min; p < 0.01) and used lower amounts of contrast (131.5 ± 61.6 vs. 141.6 ± 61.5; p < 0.01) and radiation (608.9 ± 576.3 vs. 667.0 ± 631.3; p < 0.01). The rates of moderate to severe aortic regurgitation were lower with avoidance of BAV (8.3% vs. 12.2%; p < 0.01) and tamponade rates (1.5% vs. 2.3%; p = 0.04). We confirmed that TAVR without BAV is frequently performed in France with good procedural results. This procedure is associated with procedural simplification and lower rates of residual aortic regurgitation.


Dorsal Preservation Rhinoplasty: Measures to Prevent Suboptimal Outcomes.
Preservation rhinoplasty is making a resurgence as a reliable method of performing primary rhinoplasty. Dorsal preservation is an important part of the approach to preserve favorable nasal contours when performing rhinoplasty. Keys to success require proper patient selection and careful execution. There are potential sequelae, such saddle nose deformity, recurrence of the dorsal convexity, cerebrospinal fluid leak, and radix step-off. This article discusses methods and adjustments in technique to help minimize these potential problems when performing dorsal preservation.


SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication.
Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.


Comparison of the nucleotide sequences of cucumber mosaic virus and brome mosaic virus.
Cucumber mosaic virus (CMV) and brome mosaic virus (BMV) are isometric plant viruses. Although biologically distinct, they share many common chemical properties. An analysis of the partial genomic RNA sequence available for these two viruses reveals that they are evolutionarily related. Different segments of the genome exhibit different evolutionary rates. The coat proteins, which serve as carriers of genetic material, possess little or no homology. In contrast, the 3a proteins show over 35% homology. The non-coding regions of the genome also exhibit extensive but variable homology suggesting the functional importance of the nucleic acid.


High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation.
Capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF) provides 15-s temporal resolution of amino acid levels in microdialysate, which, for the first time, allows almost real time measurement of changes during episodes of behavior. We trained Sprague-Dawley rats to self-administer either 10% ethanol-containing gelatin or non-alcoholic gelatin in a typical operant chamber. After rats reached stable daily levels of responding, microdialysis probes were inserted into nucleus accumbens and samples were collected before, during and after operant sessions with on-line analysis via CE-LIF. During the first 15 min of the operant session, there was a significant increase in taurine that correlated with the amount of ethanol consumed (R(2)=0.81) but no change in rats responding for plain gel. There were large, consistent increases in glycine in both the ethanol and plain gel groups which correlated with the amount of gel consumed. A smaller increase was observed in rats with free non-operant access to plain gel compared to the increase seen with the same amount of gel consumed under operant conditions. When rats were given a time out after each delivery of gel in the operant protocol, the greatest increase of glycine was obtained with the longest time out period. Thus, increases in glycine in nucleus accumbens appear to be related to anticipation of reinforcement.


Device Thrombogenicity Emulation: An In Silico Predictor of In Vitro and In Vivo Ventricular Assist Device Thrombogenicity.
Ventricular assist devices (VAD), a mainstay of therapy for advanced and end-stage heart failure, remain plagued by device thrombogenicity. Combining advanced in silico and in vitro methods, Device Thrombogenicity Emulation (DTE) is a device design approach for enhancing VAD thromboresistance. Here we tested DTE efficacy in experimental VAD designs. DTE incorporates iterative design modifications with advanced CFD to compute the propensity of large populations of platelets to activate by flow-induced stresses (statistically representing the VAD 'Thrombogenic Footprint'). The DTE approach was applied to a VAD (MINDTE) design with a favorable thromboresistance profile and compared against a design (MAXDTE) that generated an intentionally poor thromboresistance profile. DTE predictions were confirmed by testing physical prototypes in vitro by measuring VAD thrombogenicity using the modified prothrombinase assay. Chronic in vivo studies in VAD implanted calves, revealed MINDTE calf surviving well with low platelet activation, whereas the MAXDTE animal sustained thromboembolic strokes. DTE predictions were confirmed, correlating with in vitro and in vivo thrombogenicity, supporting utility in guiding device development, potentially reducing the need for animal studies.


Intraosseous lipoma: a clinical study of 12 patients.
We studied 12 patients (13 bones) with intraosseous lipoma to elucidate the clinical features of this disease. The patients ranged in age from 14 to 54 years. Eleven patients were men and 1 was a woman. The involved bones were the calcaneus in 6 patients (7 bones), humerus in 3, ischium in 2, and sacrum in 1. Three bones were in Milgram's stage I, 8 were in stage II, and 2 were in stage III. On plain radiographs, all bones showed a well-circumscribed radiolucent area. Nine bones showed calcification or ossification. Computed tomography or magnetic resonance imaging showed low density or high signal intensity, respectively, identical to the findings in normal adipose tissue. The tumor was curetted in 3 patients (3 bones), in whom local recurrence was not seen thereafter. In the remaining 9 patients (10 bones), we observed the natural course; in 1 of these patients, incisional biopsy was performed. During the follow-up period, only 1 patient showed slight enlargement of the lesion, while the findings in the others remained unchanged. Three patients had pain, which disappeared after the surgery or during the course of the observation. Partly because intraosseous lipoma tends to undergo spontaneous involution, and partly because diagnosis is easy from the radiological findings, surgery does not seem to be necessary in most patients.


Simultaneous imaging of temporal changes of NF-κB activity and viable tumor cells in Huh7/NF-κB-tk-luc2/rfp tumor-bearing mice.
Few studies have reported that the effect of sorafenib on advanced human hepatocellular carcinoma (HCC) is taking place via the inhibition of NF-κB signal transduction. Here we constructed a human HCC Huh7 stable clone with NF-κB-responsive element to drive dual reporter genes, herpes simplex virus thymidine kinase (tk) and firefly luciferase (luc2), and co-transfected with a third red fluorescent protein (rfp) gene, renamed as Huh7/NF-κB-tk-luc2/rfp cells, and combined with bioluminescent imaging (BLI) and red fluorescent protein imaging (RFPI) to monitor the effect of sorafenib on NF-κB activation and tumor inhibition. The results show that sorafenib could suppress the NF-κB-DNA binding activity, and the expression of downstream effector proteins. Notably, the relative photon fluxes obtained from RFPI and BLI, which represent the viable tumor cells and cells with NF-κB activation, decreased after sorafenib treatment by 50 to 65%, and 87.5 to >90%, respectively, suggesting that NF-κB activation is suppressed in viable HCC cells by sorafenib. Simultaneous molecular imaging of the temporal change of NF-κB activity and of viable cells in the same Huh7/NF-κB-tk-luc2/rfp tumors of the animal may reflect the real status of NF-κB activity and the viable tumor cells at the time of imaging.


Emotional symptoms in inattentive primary school children: a population-based study.
The present study investigates teacher and parent reports of inattention and emotional symptoms in 6,229 primary school children. The assessment included the Emotional Symptoms subscale and the Impact scale from the Strengths and Difficulties Questionnaire and the inattention items from the Swanson, Nolan, and Pelham IV Questionnaire. Children defined as inattentive showed a high risk of being defined as high scorers on the Emotional Symptoms subscale. A high score on both the Inattention and Emotional Symptoms subscales was associated with a high impact score. Teachers but not parents reported a higher risk of such co-occurrence of symptoms in girls than in boys. Inattentive children should be screened for emotional problems by use of the multi-informants method.


Tetrameric detergent-soluble acetylcholinesterase from human caudate nucleus: subunit composition and number of active sites.
Purified tetrameric detergent-soluble acetylcholinesterase (DS-AChE) from human caudate nucleus was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the absence as well as in presence of a reducing agent. Staining for protein revealed a main band at 66,000 daltons (light monomer) with additional bands at 78,000 daltons (heavy monomer) as well as 130,000 and 150,000 daltons (light and heavy dimers). The same four polypeptides were also detected by Western blotting and by autoradiography of [3H]diisopropylphosphoryl enzyme. Labeling of the enzyme with 3-trifluoromethyl-3-(m-[125I]-iodophenyl)diazirine showed that the heavy monomer contained the hydrophobic anchor of the enzyme, whereas the light monomer was practically not labeled. The hydrophobic anchor was susceptible to proteolytic degradation by proteinase K. The functional molarity of DS-AChE was determined by two independent methods. Four active sites for the tetrameric enzyme were estimated. The turnover number per site was 1.7 X 10(7) mol of acetylthiocholine iodide hydrolyzed X h-1.


Development of a novel detection method for changes in lung conditions during radiotherapy using a temporal subtraction technique.
We aimed to develop a novel method of detecting changes in lung conditions during radiotherapy using temporal subtraction technique. Twenty patients who underwent radiotherapy were retrospectively assessed by calculating optimal direct similarity error (ODSE) between initial and mid-treatment registered images. Patients were grouped according to region in tumor size and atelectasis for lung of < 20 or ≥ 20 cm3, which analyzed two field regions (1024 × 768 pixels, 512 × 512 pixels). Correlations between ODSE and changes in lung conditions were analyzed based on effect of radiation dose; receiver operating characteristic (ROC) analysis was performed to evaluate whether changes can be detected during treatment period. The ODSE of 1024 × 768 pixels was changed to 1.00 (0.28-3.48) for lung lesion size of < 20 cm3 and 1.86 (0.55-6.58) for the ≥ 20 cm3 lung lesion size. ODSE of 512 × 512 pixels was 1.03 (0.40-2.12) for the region in tumor size and atelectasis of < 20 cm3 and 1.90 (0.39-27.8) for the ≥ 20 cm3 lung lesion size. The region under the curve values from ROC analysis were 0.796 (1024 × 768 pixels) and 0.983 (512 × 512 pixels). A novel method can visually and numerically help to detect changes in lung condition at early treatment stages. Using this method, difference between plan and actual positional relationship for target and risk organs that cannot be predicted at the time of planning can be avoided, ensuring high safety and accuracy in lung radiotherapy.


Taurine biosynthetic enzymes and taurine transporter: molecular identification and regulations.
Many biological effects of taurine rely upon its cellular concentration, which is primarily controlled by taurine biosynthetic enzymes cysteine dioxygenase (CDO) and cysteine sulfinate decarboxylase (CSD) and taurine transporter (TauT). The cloning of CDO, CSD and TauT in various species provided first-hand information on these proteins, as well as molecular tools to investigate their regulations. CDO upregulation in hepatocytes in response to high sulfur amino acids appears clearly as the most spectacular among the regulations of the biosynthetic enzymes. Downregulation of TauT activity by activation of PKC appears particularly well documented. A unique serine residue could be identified as a phosphorylation site that leads to an inactive form of TauT. The previously revealed downregulation of TauT expression by taurine and hypertonicity-induced upregulation of TauT expression were shown to result from a modified transcription rate of TauT gene, but the precise molecular mechanisms are not yet formally established. Other regulations of taurine transporter expression were more recently reported, which involve glucose, tumor suppressor protein p53, tumor necrosis factor-alpha, and nitric oxide. This review reports the experimental models and data that support these various regulations but also points out the aspects that remain poorly understood or unknown concerning their molecular basis and physiological significance.


Assessment of immunity.
An approach to the assessment of the immune system primarily from the vantage point of the general physician is presented, indicating the clinical situations where analysis is most likely to yield informative results. Preliminary screening by the primary physician is discussed, followed by a brief description of measures which are employed in referral centers. A definitive diagnosis should be possible in nearly all cases. With the rapid advances in recombinant DNA technology and bone marrow transplantation, a cure can be expected for most patients, particularly if the diagnosis is made early.


Subcellular localization and putative role of VPS13A/chorein in dopaminergic neuronal cells.
Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene encoding chorein. Although a deficiency in chorein function leads to apoptosis of striatal neurons in ChAc model mouse, its detailed subcellular localization and physiological role remain unclear. In this study, we produced two anti-chorein polyclonal antibodies and examined the intracellular localization of endogenous chorein in neuronal cells. Immunocytochemically, chorein was observed in the termini of extended neurites and partially colocalized with synaptotagmin I in differentiated PC12 cells. Subcellular localization analysis by sucrose density gradient fractionation showed that chorein and synaptotagmin I were located in dense-core vesicles (DCVs), which contain dopamine. In addition, PC12 cells stably expressing carboxyterminal fragment of chorein increased K(+)-induced dopamine release. Taken together, these results suggest that chorein is involved in exocytosis of DCV.


A nosocomial Pseudomonas aeruginosa ST3495 isolated from a wild Burmese python (Python bivittatus) with suppurative pneumonia and bacteremia in Hainan, China.
Pseudomonas aeruginosa is a common infectious agent associated with respiratory diseases in boas and pythons, however, the histopathology, resistance and virulence are yet described for this species. In this study, we investigated a dying Burmese python rescued from tropical rainforest in Hainan. Clinical signs were open-mouthed breathing, abnormal shedding and anorexia. Abundant yellow mucopurulent secretions were observed in highly ectatic segmental bronchi by postmortem. Histopathological lesions included systemic pneumonia, enteritis, nephritis and carditis. P. aeruginosa was the only species isolated from heart blood, kidney, trachea and lung. The phenotype analysis demonstrated that the isolates had strong biofilm, and were sensitive to amikacin, spectinomycin, ciprofloxacin, norfloxacin and polymyxin B, moreover, the LD50 of the most virulent isolate was 2.22×105 cfu/mL in a zebrafish model. Molecular epidemiological analysis revealed that the isolates belonged to sequence type 3495, the common gene patterns were toxA + exoSYT + phzIM + plcHN in virulence and catB + blaTEM + ant (3'')-I+ tetA in resistance. This study highlights that P. aeruginosa should be worth more attention in wildlife conservation and raise the public awareness for the cross infection and cross spread between animals and human.


The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production.
Previous data suggested that constitutive expression of the transcription factor Bright (B cell regulator of immunoglobulin heavy chain transcription), normally tightly regulated during B cell differentiation, was associated with autoantibody production. Here we show that constitutive Bright expression results in skewing of mature B lineage subpopulations toward marginal zone cells at the expense of the follicular subpopulation. C57Bl/6 transgenic mice constitutively expressing Bright in B lineage cells generated autoantibodies that were not the result of global increases in immunoglobulin or of breaches in key tolerance checkpoints typically defective in other autoimmune mouse models. Rather, autoimmunity correlated with increased numbers of marginal zone B cells and alterations in the phenotype and gene expression profiles of lymphocytes within the follicular B cell compartment. These data suggest a novel role for Bright in the normal development of mature B cell subsets and in autoantibody production.


Antipyrine elimination test as a guideline for selecting patients for transhepatic biliary drainage.
Antipyrine elimination halflife (AP t1/2) was studied in 18 patients with obstructive jaundice along with routine liver function tests 24-48 h before the expected time of percutaneous transhepatic biliary drainage (PTBD). To see if it is possible to predict the outcome of PTBD, various predrainage parameters were correlated with the postdrainage bilirubin clearance after 1 week of drainage. Predrainage AP t1/2 correlated best with bilirubin clearance (r = 0.775, P less than 0.01) compared with predrainage serum bilirubin, alkaline phosphatase and serum proteins/albumin. Eight patients had AP t1/2 less than 15 h, while 10 had AP t1/2 greater than 15 h. Patients with AP t1/2 less than 15 h had significantly faster recovery after PTBD than patients with AP t1/2 greater than 15 h. If PTBD can be restricted to those with AP t1/2 less than 15 h, the advantages of preliminary PTBD can be achieved with minimum complications. Thus, estimation of AP t1/2 may aid in the selection of patients with obstructive jaundice who are likely to benefit by preliminary biliary decompression.


Differential treatment of nerve root compression pain caused by lumbar disc herniation applying nucleoplasty.
Nucleoplasty is a minimally invasive intervention use to perform disc decompression in cases of nerve root compression caused by disc herniation. It is important to find rational guidelines for choosing between nucleoplasty and microsurgery. To analyze factors that may impact the results of nucleoplasty, and to validate the rational guidelines between minimally invasive treatment and open surgery. Prospective, non-randomized, cohort study with a minimal follow-up period of 18 months. Patients were given a neurological examination, visual analogue scale and Oswestry disability questionnaire, obligatory MRI, optional RCT, and discography, only before nucleoplasty. Patients have been divided into the following groups: Group 1 - patients with a disc protrusion treated with nucleoplasty (n = 46), which has been divided into Subgroup 1A, those with a disc protrusion size ≤ 5 mm (n = 24), and Subgroup 1B, those with a disc protrusion size 6 - 9 mm (n = 22); Group 2 - patients with a disc extrusion treated with nucleoplasty (n = 27); Group 3 - patients with a disc extrusion or sequester treated with microdiscectomy (n = 65). Clinically significant outcomes were a 50% relief of pain intensity and a 40% decrease of Oswestry Disability Index (ODI). A decrease of pain intensity and disability was found in all groups of patients, P < 0.0001; SP (statistical power) = 99 - 100%. Subgroups 1A and 1B showed no clinically significant differences in outcome, P = 0.99; SP = 5.3. Clinically significant results: Group 1 - 78%; 95% CI (confidence interval) [66; 90%], Group 2 - 44%; 95% CI [25; 65%], Group 3 - 93%; 95% CI [85; 98%]. Total annulus disruption increases the rate of unsatisfactory results of nucleoplasty, OR (odds ratio) = 4.5; 95% CI [1.57; 12.87] (logistic regression model, P = 0.0034). Nucleoplasty performed in cases of uncontained disc herniation (disc extrusion) have a significantly higher rate of unsatisfactory results versus microdiscectomy, OR = 19.06; 95% CI [2.29; 68.73] (logistic regression model, P < 0.0001). This study was limited by the small number of patients in each group. The size of the disc protrusion does not significantly affect the outcome of nucleoplasty. The rational guideline for choosing between the 2 types of surgery is the integrity of the annulus.


[CorBene: a new model for collaborative care of patients with congestive heart failure].
Congestive heart failure (CHF) is one of the most common medical disorders. The prognosis tends to be unfavorable and the quality of care needs further improvement. The aim of the CorBene project is to improve the health-related quality of life and the prognosis in patients in all stages of CHF and to reduce the hospitalization rate. For this purpose a modern collaborative treatment program involving all relevant health care professionals was developed. The key feature is the close collaboration between family physicians, practicing cardiologists, hospitals and rehabilitation facilities. The CorBene model was launched in Cologne and then spread to North-Rhine/Westphalia and to Saarland. Currently, there is the possibility to offer it in all German states. Preliminary analyses confirm an optimal, guideline-based therapy of CHF.


Disentangling Genetic Risks for Metabolic Syndrome.
A quarter of the world's population is estimated to meet the criteria for metabolic syndrome (MetS), a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type 2 diabetes, leading to increased risk of premature death and significant health costs. In this study we investigate whether the genetics associated with MetS components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations of fasting glucose, HDL cholesterol, systolic blood pressure, triglycerides, and waist circumference was used, which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on MetS to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more MetS components, indicating that MetS is a complex, heterogeneous disorder. Associated loci harbor genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the MetS factor GWAS predicts 5.9% of the variance in MetS. These results provide mechanistic insights into the genetics of MetS and suggestions for drug targets, especially fenofibrate, which has the promise of tackling multiple MetS components.


Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations.
Disorders caused by defects in the mitochondrial translation system are clinically and genetically heterogeneous. The elongation phase of mitochondrial protein synthesis requires, among many other components, three nuclear-encoded elongation factors: EFTu (TUFM; 602389), EFTs (TSFM; 604723), and EFG1 (GFM1; 606639). Mutations have been identified in the genes encoding all three elongation factors, and they result in combined respiratory chain deficiencies and severe phenotypes with an early fatal outcome. So far, only eleven patients have been reported with mutations in GFM1. Here we describe an additional three patients with novel GFM1 mutations. Our results confirm the tissue-specific effect of GFM1 mutations, since we found only slightly decreased respiratory chain enzyme activities in muscle and fibroblasts, but a severe deficiency in the liver. Hence, a thorough biochemical evaluation is important to guide genetic investigation in patients suspected for a mitochondrial disorder.


Pattern formation in the monocot embryo as revealed by NAM and CUC3 orthologues from Zea mays L.
All aerial parts of a higher plant originate from the shoot apical meristem (SAM), which is initiated during embryogenesis as a part of the basic body plan. In contrast to dicot species, the SAM in Zea mays is not established at an apico-central, but at a lateral position of the transition stage embryo. Genetic and molecular studies in dicots have revealed that members of the NAC gene family of plant-specific transcription factors such as NO APICAL MERISTEM (NAM) from Petunia or the CUP-SHAPED COTYLEDON (CUC) genes from Arabidopsis contribute essential functions to the establishment of the SAM and cotyledon separation. As an approach to the understanding of meristem formation in a monocot species, members of the maize NAC family highly related to the NAM/CUC genes were isolated and characterized. Our phylogenetic analysis indicates that two distinct NAM and CUC3 precursors already existed prior to the separation of mono- and dicot species. The allocation of the two maize paralogues, ZmNAM1 and ZmNAM2 together with PhNAM, AtCUC2 and AmCUP in one sub-branch and the corresponding expression patterns support their contribution to SAM establishment. In contrast, the ZmCUC3 orthologue is associated with boundary specification at the SAM periphery, where it visualizes which fraction of cells in the SAM is committed to a new leaf primordium. Other maize NAC gene family members are clearly positioned outside of this NAM/CUC3 branch and also exhibit highly cell type-specific expression patterns.


Lung transplantation in patients with coal workers' pneumoconiosis.
Patients with coal workers' pneumoconiosis (CWP) can develop chronic respiratory failure and require lung transplantation. A retrospective review was performed of the 712 referrals and 143 patients undergoing unilateral or bilateral lung transplantation at the University of Kentucky Medical Center between January 1999 and July 2009. Twenty-one of the 712 referrals (3%) had a diagnosis of CWP with eight patients eventually undergoing lung transplant (six single, two bilateral). The mean age of the cohort was 53 ± 5 (mean ± SD) yr (range 45-59). There was no increased risk of perioperative or postoperative complications. Six patients (75%) remain alive after a mean follow-up of 1013 ± 857 d with the two deaths attributable to sepsis 683 and 145 d after transplant, respectively. There were no pulmonary complications because of the native lung in patients after a single lung transplant, with otherwise good clinical outcomes seen after lung transplantation.


Epidemiology of infantile hydrocephalus in Sweden. I. Birth prevalence and general data.
The livebirth prevalence of infantile simple hydrocephalus (IH) was investigated in a Swedish population-based survey. The study comprised all liveborn infants with IH apparent before the age of one year and born in the study area between 1967-82. A total of 202 infants fulfilled these criteria; of these, 141 (70%) were born at term and 61 (30%) were preterm. The mean prevalence was 0.53 per 1,000, with a slightly increasing trend from 0.48 in 1967-70 to 0.63 in 1979-82. The increase was entirely referable to the preterm group, in which the prevalence rose from 0.13 per 1,000 in 1967-70 to 0.30 in 1979-82. There was no tendency to an increase in the term group. In 12 of 23 children born very preterm the origin of the IH was a diagnosed cerebral haemorrhage. This is compatible with the increased risk of the latter condition that has been found in very preterm newborns. The mortality among children with IH was highest before the age of one year (15%), after which it was 1.2% per year.


Post-streptococcal glomerulonephritis in African children.
Streptococcal infection remains almost the sole cause of the clinical syndrome of acute glomerulonephritis in African children. Evidence for this is in elevated levels of antistreptolysin "O" (ASO) titre in 93% of 28 patients and growth of Group Abeta haemolytic streptococci from the skin and throat in 32%. Spread of infection from the skin, where lesions were present in all patients, to the throat would account for positive cultures at both sites and the frequent and vigorous antistreptolysin "O" responses. Clinical recovery occurred in most within seven days and in all within 60 days of admission. IgG and IgA, but not IgM, were increased in patients; C4 was normal in the majority and low in seven out of 24 (29%), C3 was diminished in 26 out of 28 (93%) and the mean level of C3 PA was lower than in controls. Total haemolytic complement paralleled C3 values; C3 breakdown products were not detected in any patient. Renal biopsies in seven out of 28 patients showed typical histological changes of diffuse exudative proliferative glomerulonephritis on light microscopy and fibrinogen and C3 on immunofluorescent staining. These findings suggest that events leading to glomerular damage in acute post-streptococcal nephritis in African children involve activation of both classical and alternative pathways of complement proteins and also confirm the well recognized and predictable nature of the disease, irrespective of geographical distribution.


Epigenetic Biomarkers of Lead Exposure and Cardiovascular Disease: Prospective Evidence in the Strong Heart Study.
Background Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead exposure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. Methods and Results Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989-1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17-1.72]) compared with women (HR, 1.04 [95% CI, 0.89-1.22]). Conclusions Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflecting the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure.


Time for a change in blood lead reference value for Chinese children.
In China, the first and also the latest version of national childhood lead exposure control guidelines was issued by the National Health Commission in 2006, when the reference value of high blood lead exposure was set at 100 μg/L and lead poisoning was set at 200 μg/L. Lead exposure levels have been decreasing in China over the last few decades, with almost all blood lead concentrations in children under 7 years of age being under 100 μg/L in non-industrial areas. However, lead concentrations lower than 100 μg/L in blood in children are associated with neurodevelopmental deficits. Thus, if the reference value remains at a high level, a large percent of children with exposure levels that are high but lower than the current reference value will be diagnosed as 'safe' and be ignored. Thus, we appeal that the reference value should be lowered according to local actual exposure level. A more stringent reference value would give care givers, doctors, communities, and officials more opportunities to take action earlier.


Evaluation of left ventricular rotation and twist using speckle tracking imaging in patients with atrial septal defect.
Speckle tracking imaging (STI) was employed to investigate the effect of right ventricular (RV) volume and pressure overload on left ventricular (LV) rotation and twist in 35 patients with atrial septal defect (ASD), 18 of which with pulmonary hypertension, and 21 healthy subjects serving as controls. The peak rotations of 6 segments at the basal and apical short-axises and the average peak rotation and interval time of the 6 segments in the opposite direction during early systolic phase were measured respectively. LV twist versus time profile was drawn and the peak twist and time to peak twist were calculated. LV ejection fraction (EF) was measured by Biplane Simpson. Compared to ASD patients without pulmonary hypertension and healthy subjects, the peak rotations of posterior, inferior and postsept walls at the basal level were lower (P<0.05), and the average counterclockwise peak rotation of 6 segments at the basal level during early systolic phase was higher (P<0.05), and the average interval time was delayed (P<0.05). LV peak twist was also lower (P<0.05), and had a significant negative correlation with pulmonary arterial systolic pressure (r=-0.57, P=0.001). No significant differences were found in LVEF among the three groups. It was suggested that although RV volume overload due to ASD has no significant effects on LV rotation and twist, LV peak twist is lower in ASD patients with pulmonary hypertension. Thus LV twist may serve as a new indicator of the presence of pulmonary hypertension in ASD patients.


Robotic radiosurgery versus micro-multileaf collimator: a dosimetric comparison for large or critically located arteriovenous malformations.
Stereotactic irradiation of large or critically located arteriovenous malformations (AVMs) is a special challenge for clinicians and radiation physicists. To date, no comprehensive comparison of two linac-based radiosurgery systems used for hypofractionated radiotherapy of large AVMs was published. The aim of the study was to compare dose distributions between CyberKnife (CK) system and linac with a micro-multileaf collimator (L-mMLC) in high-grade or critically located cerebral AVMs. Two sets of plans made for 15 different patients with at least 95% target coverage were selected for comparisons. Conformity (CI), homogeneity (HI) and gradient score (GSI) indices, conformity index proposed by Lomax (CIL), conformation number (CN), quality of coverage (Q), volumes of brain receiving 12,10,8,6,4, and 2 Gy, minimum and maximum doses for critical structures in both treatment planning systems (TPS) were compared. Finally, the number of monitor units needed to deliver the prescribed dose was compared. The mean minimum doses in the target volume were 93.3% (CK) and 90.7% (L-mMLC),p=n.s, maximum: 119.7 and 110%, respectively (p=0.004). The mean CI was 1.46 and 1.86, HI: 1.2, and 1.11, CIL 0.7, and 0.6, CN: 0.68 and 0.58 for CK and mMLC, respectively (p<0.05). The values of GSI and Q were not significantly different. The volumes of the brain receiving low doses (4 Gy and 2 Gy) were significantly lower in the CK system. The number of monitor units necessary to deliver the prescribed dose was significantly greater in case of the CK system. Better conformity can favor the CK system for treatment of large AVMs at the cost of higher maximum doses and worse homogeneity. L-mMLC is superior when shorter treatment time is required. Neither system can assure satisfying dose gradients outside large targets surrounded by numerous critical structures.


Physics of active jamming during collective cellular motion in a monolayer.
Although collective cell motion plays an important role, for example during wound healing, embryogenesis, or cancer progression, the fundamental rules governing this motion are still not well understood, in particular at high cell density. We study here the motion of human bronchial epithelial cells within a monolayer, over long times. We observe that, as the monolayer ages, the cells slow down monotonously, while the velocity correlation length first increases as the cells slow down but eventually decreases at the slowest motions. By comparing experiments, analytic model, and detailed particle-based simulations, we shed light on this biological amorphous solidification process, demonstrating that the observed dynamics can be explained as a consequence of the combined maturation and strengthening of cell-cell and cell-substrate adhesions. Surprisingly, the increase of cell surface density due to proliferation is only secondary in this process. This analysis is confirmed with two other cell types. The very general relations between the mean cell velocity and velocity correlation lengths, which apply for aggregates of self-propelled particles, as well as motile cells, can possibly be used to discriminate between various parameter changes in vivo, from noninvasive microscopy data.


Age-related differences in social grooming among adult female Japanese monkeys ( Macaca fuscata).
The present study investigated the influence of dominance rank in combination with kinship on age-related differences in social grooming among adult females in a free-ranging group of Japanese monkeys ( Macaca fuscata). Eighty-three adult females were divided into six sub-groups according to age-class (younger: 5-9 years old; middle: 10-14 years old; older: 15-22 years old) and dominance rank (high and low rank). The ratio of the number of unrelated females that each female groomed to the total number of available unrelated females and grooming bouts which she gave to unrelated females decreased with increasing age for both high- and low-ranking females, whereas age did not appear to affect corresponding values for related females. On the other hand, compared with low-ranking females, high-ranking females of all age-classes received grooming more often from a larger number of unrelated females. Moreover, older females of low rank received grooming less often from a smaller number of unrelated females than younger females of low rank. These results indicate that with increasing age females are more likely to concentrate on related females when they have grooming interactions with other females. This tendency seems to be more apparent for low-ranking females. Moreover, the present findings also indicate that older high-ranking females could maintain their social attractiveness as high as younger high-ranking females.


Distinct HLA-DR epitopes and distinct families of HLA-Dr molecules defined by 15 monoclonal antibodies (mAb) either anti-DR or allo-anti-Iak cross-reacting with human DR molecule. I. Cross-inhibition studies of mAb cell surface fixation and differential binding of mAb to detergent-solubilized HLA molecules immobilized to a solid phase by a first mAb.
A series of HLA-DR-reactive mouse anti-human B cell or anti-Ia monoclonal antibodies (mAb) have been used to explore the serological complexity of human class II antigens at the determinant level, using two techniques: (a) cross antibody-binding competitor assays using 125I-labeled and-unlabeled mAb were performed to study the topological organization of the corresponding determinants to determine epitopic clusters recognized by this collection of mAb and (b) differential reactivity of mAb to detergent-solobilized solid-phase-immobilized HLA-DR molecules to determine epitopes expressed on identical DR isotypes. The fifteen mAb could be classified according to the first technique as falling into three different epitopic clusters. Using the second technique, we were able to define at least two independent molecular subsets, one co-expressing two of the three epitopic clusters and the second expressing only the third one. We could not formally identify molecular subsets expressing only one of the first two clusters, using the second technique. The precise serological mapping of the determinants recognized by various anti-class II mAb should prove very useful if such mAb were to be introduced in anti-class II-specific T cell clone blocking experiments. We anticipate that some of them should facilitate the correlation at the clonal level between the T cell repertoire and the epitopes or molecular subsets defined by these mAb. However, within mAb belonging apparently to a same cluster, some could mediate different biological effects.


Tutor Uncertainty in Dealing with Unprofessional Behaviours of Medical Students and Residents: a Mixed Methods Study.
Despite acknowledgement of medical students' expected professional behaviours and attitudes, there remains widespread reluctance to report students that behave inappropriately. Existing literature focuses on why faculty fail to fail, overlooking the tutors who deal with students day to day. We investigated how tutors address inappropriate behaviours and attitudes in students and residents. A mixed methods study was carried out consisting of a survey and two focus groups with tutors. Seventeen tutors from the University of Limerick School of Medicine, Ireland, took part in the survey (n = 22%) and eight tutors participated in two focus groups during the 2018-2019 academic year. Findings suggested that 59% of tutors would take a different approach to addressing unprofessional behaviours witnessed in medical students and residents. A total of 88% of tutors said they intervened on a professionalism issue with 52% saying 'once in a while'. In contrast to the survey, tutors in the focus groups expressed a lack of confidence in addressing some behaviours due to a lack of time, not seeing the outcome of process/remediation etc. Tutors indicated a strong preference for case-based training on assessing professional identity formation (PIF). We found tutors typically work closely with students on a day-to-day basis managing unprofessionalism issues. Tutors valued regular communication about policies and procedures about appropriate conduct as well as support, advice, and/or oversight from independent members of university staff. This research highlights the need for training designed for busy tutors as a distinct type of medical teacher. The online version contains supplementary material available at 10.1007/s40670-021-01429-1.


False positive non-synonymous polymorphisms of G-protein coupled receptor genes.
Polymorphisms of G-protein coupled receptor (GPCR) genes are associated with disease risk and modification, and the response to receptor-directed therapy. Genomic sequencing ( approximately 1700 automated runs) from as many as 120 chromosomes from 60 multiethnic individuals was performed to confirm non-synonymous coding polymorphisms reported in the dbSNP database from 25 randomly selected GPCR genes. These polymorphisms were in regions of the receptors responsible for structural integrity, ligand binding, G-protein coupling and phosphoregulation. However, most of these putative polymorphisms could not be confirmed (false positive rate of 68%). Based on these results, we suggest that the variability of the superfamily is not well defined, and we caution against exclusive reliance on databases for selection of candidate GPCR polymorphisms for disease association and pharmacogenetic studies.


TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2.
Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.


The maturity index: an ecological measure of environmental disturbance based on nematode species composition.
Nematode assemblages constitute a potential instrument for assessing the quality of submersed, temporarily submersed, and terrestrial soils and for the development of an ecological typology and biomonitoring system. Interpretation of physical or pollution-induced disturbances has hitherto mainly been based on changes in diversity, dominance patterns or percentage of dorylaimids (Adenophorea). The maturity index, based on the nematode fauna, is proposed as a gauge of the condition of the soil ecosystem. Values on a coloniser/persister scale are given for nematodes that occur in The Netherlands. The possibilities of the use of this index are demonstrated by a retrospective interpretation of some literature data. The use of nematodes in environmental studies is discussed.


CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.
Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with in vivo AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine (n = 12) or placebo (n = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the in vivo AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the Galantamine group (60% ± 14) after 3 months compared to baseline (p < 0.0023) or (p < 0.0004). This index remained high in the Galantamine group compared to baseline (54% ± 11) at 12 months follow-up, while it showed an increase in the Placebo group when they switched to active galantamine treatment (44% ± 14 vs. baseline, 61% ± 14 vs. 3 months, all p-values < 0.05). Furthermore, the in vivo brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months (r = 0.98, p < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.


Euterpe oleracea extract (açaí) exhibits cardioprotective effects after chemotherapy treatment in a breast cancer model.
Açaí, a Brazilian native fruit, has already been demonstrated to play a role in the progress of breast cancer and cardiotoxicity promoted by chemotherapy agents. Thus, the present study aimed to evaluate the combined use of açaí and the FAC-D chemotherapy protocol in a breast cancer model in vivo. Mammary carcinogenesis was induced in thirty female Wistar rats by subcutaneous injection of 25 mg/kg 7,12-dimethylbenzanthracene (DMBA) in the mammary gland. After sixty days, the rats were randomized into two groups: treated with 200 mg/kg of either açaí extract or vehicle, via gastric tube for 45 consecutive days. The FAC-D protocol was initiated after 90 days of induction by intraperitoneal injection for 3 cycles with a 7-day break each. After treatment, blood was collected for haematological and biochemical analyses, and tumours were collected for macroscopic and histological analyses. In the same way, heart, liver, and kidney samples were also collected for macroscopic and histological analyses. Breast cancer was found as a cystic mass with a fibrotic pattern in the mammary gland. The histological analysis showed an invasive carcinoma area in both groups; however, in the saline group, there was a higher presence of inflammatory clusters. No difference was observed regarding body weight, glycaemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urea in either group. However, açaí treatment decreased creatine kinase (CK), creatine kinase MB (CKMB), troponin I and C-reactive protein levels and increased the number of neutrophils and monocytes. Heart histopathology showed normal myocardium in the açaí treatment, while the saline group presented higher toxicity effects with loss of architecture of cardiac tissue. Furthermore, the açaí treatment presented greater collagen distribution, increased hydroxyproline concentration and lower H2AX immunostaining in the heart samples. Açaí decreased the number of inflammatory cells in the tumor environment and exhibited protection against chemotherapy drug cardiotoxicity with an increased immune response in animals. Thus, açaí can be considered a promising low-cost therapeutic treatment that can be used in association with chemotherapy agents to avoid heart damage.


Pregnancy after Breast Reconstruction.
Breast cancer is one of the most commonly diagnosed malignancies in women of childbearing age. One of the surgeries performed in the management of the disease is mastectomy , which might negatively affect body image and quality of life, and breast reconstruction is seen as a remedy to this problem. However, for the women who are interested in having children after treatment of breast cancer, the debate is whether they can have a successful pregnancy and delivery after breast reconstruction.


Multiple skeletal muscle metastases from poorly differentiated gastric adenocarcinoma.
We report here a rare case of gastric carcinoma with multiple intramuscular metastases. A 71-year-old man presented with rapidly evolving swelling of his left thigh and severe pain. Three years earlier, he had undergone neoadjuvant chemotherapy followed by gastrectomy for advanced gastric cancer. A computed tomography scan showed unusual swellings in multiple skeletal muscles with no vessel or bone invasion. Importantly, the affected muscles did not contain distinct masses but were diffusely enlarged. Pathological examination of an open muscle biopsy showed a poorly differentiated adenocarcinoma, supporting a diagnosis of gastric cancer metastases in multiple skeletal muscles.


Conformational and hydrational properties during the L(beta)- to L(alpha)- and L(alpha)- to H(II)-phase transition in phosphatidylethanolamine.
Differential scanning calorimetry (DSC) measurements have been carried out simultaneously with small- and wide-angle X-ray scattering recordings on liposomal dispersions of stearoyl-oleoyl-phosphatidylethanolamine (PE) in a temperature range from 20 to 80 degrees C. The main transition temperature, T(m), was determined at 30.9 degrees C with an enthalpy of 28.5 kJ/mol and the lamellar-to-inverse hexagonal phase transition temperature, T(hex), at 61.6 degrees C with an enthalpy of 3.8 kJ/mol. Additionally highly resolved small angle X-ray diffraction experiments performed at equilibrium conditions allowed a reliable decomposition of the lattice spacings into hydrophobic and hydrophilic structure elements as well as the determination of the lipid interface area of the lamellar gel-phase (L(beta)), the fluid lamellar phase (L(alpha)) and of the inverse hexagonal phase (H(II)). The rearrangement of the lipid matrix and the coincident change of free water per lipid is illustrated for both transitions. Last, possible transition mechanisms are discussed on a molecular level.


Altered levels of fecal short-chain fatty acids are associated with subclinical inflammation and worse cognitive performance in patients with schizophrenia.
Schizophrenia is a multi-systemic disorder that is associated with lipid profile disturbances, altered glucose homeostasis and subclinical inflammation. It has been proposed that dysfunction of the gut-brain axis might underlie these alterations. Short-chain fatty acids (SCFAs) are considered to play a pivotal role in the gut-brain axis. In this study, we aimed to compare fecal levels of SCFAs in patients with schizophrenia and healthy controls (HCs), taking into consideration their relationship with common peripheral blood alterations observed in schizophrenia. The study included 100 stable outpatients with schizophrenia and 55 HCs. The levels of SCFAs (acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid) in fecal samples were measured. Also, lipid profile together with the levels of C-reactive protein, glucose and insulin were determined. The levels of isovaleric acid were significantly higher in patients with schizophrenia after co-varying for age, sex, and the adherence to the Mediterranean diet. Moreover, there were significant positive correlations of the levels of valeric acid, isovaleric acid and CRP in patients with schizophrenia. In this group of participants, higher levels of isovaleric acid were associated with significantly lower scores of delayed memory after adjustment for potential covariates and interactions with CRP levels. Our results indicate that individuals with schizophrenia show altered levels of isovaleric acid that might be associated with impairments of delayed memory. The association with cognitive impairments might be independent of interactions with immune-inflammatory processes. Longitudinal and experimental studies are needed to test causal mechanisms of observed correlations.


Guanine nucleotide binding properties of the mammalian RalA protein produced in Escherichia coli.
The simian ralA cDNA was inserted in a ptac expression vector, and high amounts of soluble ral protein were expressed in Escherichia coli. The purified p24ral contains 1 mol of bound nucleotide/mol of protein that can be exchanged against external nucleotide. The ral protein exchanges GDP with a t 1/2 of 90 min at 37 degrees C in the presence of Mg2+, and has a low GTPase activity (0.07 min-1 at 37 degrees C). We have also studied its affinity for various guanine nucleotides and analogs. NMR measurements show that the three-dimensional environment around the nucleotide is similar in p21ras and p24ral. In addition to these studies on the wild-type ral protein, we used in vitro mutagenesis to introduce substitutions corresponding to the Val12, Val12 + Thr59, and Leu61 substitutions of p21ras. These mutant ral proteins display altered nucleotide exchange kinetics and GTPase activities, however, the effects of the substitutions are less pronounced than in the ras proteins. p24ralVal12 + Thr59 autophosphorylates on the substituted Thr, as a side reaction of the GTP hydrolysis, but the rate is much lower than those of the Thr59 mutants of p21ras. These results show that ras and ral proteins have similar structures and biochemical properties. Significant differences are found, however, in the contribution of the Mg2+ ion to GDP binding, in the rate of the GTPase reaction and in the sensitivity of these two proteins to substitutions around the phosphate-binding site, suggesting that the various "small G-proteins" of the ras family perform different functions.


Role of the phytoestrogenic, pro-apoptotic and anti-oxidative properties of silymarin in inhibiting experimental benign prostatic hyperplasia in rats.
Androgen and estrogen play an important role in the pathogenesis of benign prostatic hyperplasia (BPH). Estrogen exerts its action through two distinct estrogen receptors (ERs) either ER-α or ER-β. The phytoestrogenic property of silymarin (SIL) has been previously characterized. Thus, this study examined the protective effect of SIL against testosterone-induced BPH in rats. In an initial dose-response study, SIL in a dose of 50mg/kg was the most effective in preventing the rise in prostate weight, prostate weight/body weight ratio and histopathologic changes induced by testosterone. Testosterone significantly decreased ER-β and increased ER-α and AR expressions as compared to the control group and these effects were significantly ameliorated by SIL. Furthermore, SIL significantly protected against testosterone-provoked decline in mRNA expression of P21(WAF1/Cip1) and Bax/Bcl-xl ratio as well as caspase-3 activity. SIL minimized the number of proliferating cell nuclear antigen (PCNA) positive cells as compared to testosterone-treated group. Moreover, SIL significantly blunted the inducible NF-κB expression and restored the oxidative status to within normal values in the prostatic tissues. Collectively these findings elucidate the effectiveness of SIL in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its phytoestrogenic, pro-apoptotic and anti-oxidative properties.


[Development and thinking of Chinese expert consensus on diagnosis of pleural effusion].
The consensus published in this issue was developed over a period of 1.5 years, and it was discussed and revised by the expertpanel from pleural and mediastinal diseases working group (preparatory) of Chinese Thoracic Society and external experts in several meetings. This article introduced the purpose, process and thinking in the writing of the consensus, hoping to provide a reference for readers to understand the content of this consensus and to make reasonable application in clinical practice.


Caffeine elicited withdrawal signs in morphine-dependent rhesus monkeys.
In the dose range of 4.0--32.0 mg/kg s.c., caffeine produced most of the signs which are commonly seen after the administration of naloxone (0.05 mg/kg s.c.) to morphine-dependent monkeys. The signs designated as lying on side or abdomen, avoiding contact, vocalizing, crawling or rolling, restlessness or pacing, tremors, retching, vomiting, coughing, vocalizing when abdomen palpated, rigid abdomen and salivation were noted. A randomized and blind experimental design, which included vehicle and positive (naloxone) controls was used. The significance of the differences between total scores for the whole syndrome was tested by the Mann-Whitney U-test. In preliminary studies in naive monkeys, caffeine was found to elicit some withdrawal signs but the results were equivocal. Na benzoate also elicited some withdrawal signs in morphine-dependent monkeys at 32.0 mg/kg s.c., but few signs were seen in naive monkeys. Caffeine was found to be approximately 10X more active than Na benzoate in inhibiting cAMP phosphodiesterase activity in a neuroblastoma cell whole homogenate assay. These results are consistent with the observations of Collier and Francis that morphine abstinence in rodents is associated with increased brain levels of cAMP.


Effect of triptolide on T-cell receptor beta variable gene mRNA expression in rats with collagen-induced arthritis.
Triptolide (TP) has been used in the treatment of rheumatoid arthritis (RA), but its mechanism of action is not understood. T-cell activation and associated release of cytokines appear to be major factors in the pathogenesis of RA. The overexpression of T-cell receptor (TCR) variable gene (V gene) fragments can cause the activation and infiltration of autoreactive T cells. This study examines the effects of TP on rats with collagen-induced arthritis (CIA). The levels of interleukin-10 (IL-10) in the serum were examined with ELISA. Compared to the CIA group, the levels of IL-10 were greater in the TP treatment group. Real-time quantitative polymerase chain reaction confirmed that the expression of TCR V beta (BV) 15 and TCR BV19 was increased in the CIA group, whereas in the TP treatment group, the expression was decreased. In this study, TP was found to enhance IL-10 levels and decrease the expression levels of TCR BV15 and TCR BV19. These changes might help explain the effectiveness of TP in the treatment of RA.


SARS-CoV-2-specific T cells are generated in less than half of allogeneic HSCT recipients failing to seroconvert after COVID-19 vaccination.
Little is known about the cellular immune response to SARS-CoV-2 vaccination in patients after HSCT and B-NHL with iatrogenic B-cell aplasia. In nonseroconverted HSCT patients, induction of specific T-cell responses was assessed. The majority of allogeneic HSCT patients not showing humoral responses to vaccination also fail to mount antigen-specific T-cell responses.


A Polyamine Twist on Hedgehog Signaling.
The Hedgehog pathway plays important roles in embryonic development and oncogenesis, but how it affects metabolism is less clear. D'Amico et al. (2015) now demonstrate that the Hedgehog pathway regulates translation of ornithine decarboxylase, thereby enhancing polyamine biosynthesis and cell proliferation in neural precursor cells and in brain tumors.


RNase Protection Assay.
Unbound, single-stranded RNA can be digested by RNase (A or T1) to ribonucleotides, whereas double-stranded RNA is not digested by RNase. Based on this principle, the RNase Protection Assay (RPA) is used to validate chimeric RNAs. Importantly, this assay does not employ reverse transcription (RT), thus avoiding potential false-positive results which could occur during RT such as template-switching. We first generate RNA probes with 32phosphate (P) or biotin that are complementary to the predicted nucleotide sequence of the chimeric RNA, then hybridize them to RNA samples. The labeled RNA probes can bind specifically with the target chimeric RNA in order to form double-stranded RNA. This newly formed RNA is resistant to digestion by RNase and therefore can be identified by high-resolution, denaturing polyacrylamide gel electrophoresis.


Value of N-terminal pro brain natriuretic peptide in the elderly: data from the prospective Copenhagen Hospital Heart Failure study (CHHF).
We describe the value of Nt-proBNP in relation to cardiac normality and risk of major adverse cardiac events (MACE) in consecutive hospitalised patients below and above 75 years of age. During a 10 month period 2224 consecutive patients, admitted to all departments in a general city hospital, had a full cardiac examination and were prospectively followed for 1 year. We identified a normal group (without obvious heart disease) and a group with MACE (significant heart disease at admission or a cardiac event within the following 90 days). NT-proBNP measurements were done using an ELISA-a two-step sandwich assay with streptavidin coated microtitre plates. The age dependent 90th percentiles of Nt-proBNP in the normal group were approximately 3 times higher than values reported in previous community studies. Elderly patients had 3-fold higher absolute cut off values than did patients under the age of 75 years. One-hundred-and-sixteen patients had a MACE, and areas under the receiver operating curve (ROC) to predict a MACE were 0.83 (from 40 to 59 years), 0.82 (60 to 74) and 0.79 (from 75 years). In younger patients, the upper limit of Nt-proBNP in normal patients was similar to the value, which defined the top quintile of risk. In patients aged greater than 75 years the predictive cut point included more than 40% of the population. Nt-proBNP was useful at all ages but specificity was slightly lower in the elderly. Cut off values in hospitalised cardiac normal patients are approximately three times higher than community derived values.


Modeling the biogeochemistry of sulfur in beech (Fagus sylvatica L.) stands of the Vienna Woods.
In this article, we describe the setup and the application of a novel Sulfur Dynamics Model (SDM), with the aim to identify and quantify processes, which are crucial for the understanding of the biogeochemical sulfur (S) cycle of forest ecosystems. The simulator takes into account abiotic processes as well as biotic interactions between atmosphere, plant and soil. We applied the model to two Austrian beech stands where deposition of S and soil solution chemistry were monitored intensively over a two-year period. Under consideration of high historic loads and the more recent recession of atmospheric S deposition, we found a suitable model configuration where it was possible to assign both intra-annual fluctuations of the SO4-S in soil solution and long-time trends in the stream discharge to specific S transformation processes. We identified the interplay of microbial immobilization (the microbial conversion of solute sulfate to organic soil S) and mineralization as key driver of short-term fluctuations in the soil solution. In the long term, the delayed release of historically accumulated S is driven mainly by the slow mineralization of S rich plant biomass, recalcitrant to decomposition. Adsorption and desorption processes seem to play only a negligible role on our investigated stands. We conclude that our proposed model which is based on the current understanding of S biogeochemistry is sufficient to describe S dynamics on the investigated forest stands. The code file (SAS) for all model functions will be provided by the authors after request.


Unusual Nernst effect suggesting time-reversal violation in the striped cuprate superconductor La(2-x)Ba(x)CuO4.
The striped cuprate La(2-x)Ba(x)CuO(4) (x=1/8) undergoes several transitions below the charge-ordering temperature T(co)=54 K. From Nernst experiments, we find that, below T(co), there exists a large, anomalous Nernst signal e(N,even)(H,T) that is symmetric in field H, and remains finite as H→0. The time-reversal violating signal suggests that, below T(co), vortices of one sign are spontaneously created to relieve interlayer phase frustration.


Failure to alter neonatal transplantation tolerance by the injection of interleukin 2.
It has been postulated that the establishment of acquired, neonatal immunologic tolerance is due to a "deficit" in interleukin 2 (IL-2). To test this hypothesis, chickens were made immunologically tolerant to both major and minor histocompatibility antigens by transplantation of skin grafts onto newly hatched recipients. In this study, we injected various doses of IL-2 and concanavalin A simultaneously with transplantation and in some cases, several days posttransplantation, and we failed to enhance graft rejection. These results may have practical importance in respect to the clinical use of recombinant IL-2. Injection of IL-2 in and around surviving skin grafts also failed to alter skin graft survival.


The effect of increased nutrient availability on leaf turnover and aboveground productivity of two evergreen ericaceous shrubs.
Leaf turnover and aboveground productivity in relation to nutrient availability were studied in the evergreen shrubs Erica tetralix and Calluna vulgaris. In monospecific stands of these species four levels of nutrient (NPK) availability were created during three growing seasons. Percentage survival and life expectancy of Erica leaves decreased with increasing nutrient availability. For Calluna there was no effect. Winter mortality of Erica leaves was smaller than growing season mortality. These was no difference for Calluna. The timing of leaf mortality of both species was not affected by nutrient treatment. At the end of the experimental period current year leaf biomass, total biomass and current year second year and third year biomass of both species showed a significant increase with increasing nutrient availability. The relative increase was greater for Calluna, except for second and third year biomass. Stem production and stem mortality of both species increased with increasing nutrient availability. The increased stem mortality resulted also for Calluna in an increased leaf turnover (per unit ground area) with increasing nutrient availability. Nutrient cycling in ecosystems dominated by these species will increase with increasing nutrient availability, because of increased leaf and stem turnover and productivity. This phenotypic effect is similar to the effect of the shift in dominance between different species which occurs along natural gradients of nutrient availability.


Local circuit neurons of developing and mature macaque prefrontal cortex: Golgi and immunocytochemical characteristics.
A study has been made of the nonpyramidal, local circuit neurons in developing and mature macaque monkey prefrontal cortex with Golgi and immunocytochemical techniques. The area chosen for study is located between the cingulate gyrus and the ventral bank of the principal sulcus, and contains areas 9 and 46 as described by Walker (J. Comp. Neurol. 73:59-86, '40). In Golgi studies, the unique axonal features of impregnated neurons made possible the identification of thirteen separate classes of local circuit neurons. Five of these cell types, in their general characteristics, resembled classes identified in human prefrontal cortex, as well as in other cortical areas of macaque monkeys and other species. Measurements of the scale of axon arbors and dendritic fields of the Golgi-stained local circuit neurons also suggested particular spatial relationships of certain classes to the scale of intrinsic lattice connections made by the axons of pyramidal neurons in the same region. Similarities in morphology between cells described in human prefrontal cortex and neuron varieties described in this study indicate that this region of monkey prefrontal cortex may serve as a useful model for neuron populations in human prefrontal cortex. Sufficient morphological detail was present in immunocytochemical studies to suggest one or more identifying biochemical characteristics for seven of the thirteen classes of local circuit neurons. The calcium binding proteins, parvalbumin, calbindin D-28K, and calretinin, were found in chandelier and wide arbor neurons, neurogliaform cells, and double bouquet neurons, respectively. In addition, cholecystokinin immunoreactivity was present in medium arbor neurons and in narrow arbor cells connecting layers 2 and 4. Somatostatin 28(1-12) immunoreactivity was detected in beaded axon neurons in layers 5 and 6. This biochemical characterization of local circuit neurons, although incomplete, confirms the separate identity of at least some of the varieties distinguished by Golgi morphology, and allows a start to be made on studies examining changes in their functional state. The general inhibitory nature of these interneurons suggests that they are likely to play a crucial role in determining patterns of neural activation in the prefrontal cortex.


miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells.
Hypoxia-inducible factors (HIF) are heterodimeric transcription factors that allow cells to adapt and survive during hypoxia. Regulation of HIF1A and HIF2A mRNA is well characterized, whereas HIF3A mRNA regulation and function are less clear. Using RNA-Seq analysis of primary human umbilical vein endothelial cells, we found two isoforms of HIF3A were expressed, HIF3A2 and HIF3A3. Comparing HIF3A expression profiles to HIF1A mRNA during 48 hours of hypoxia revealed that HIF1A message peaked at 4 hours, whereas HIF3A expression increased while HIF1A was decreasing. Given that HIF1A mRNA is regulated by miR-429, we tested miR-429 effects on both HIF3A isoforms and found that they too were regulated by miR-429. Analysis of a HIF-3 target, DNA-damage-inducible transcript 4, a key survival gene, indicated that DDIT4 mRNA is induced by HIF-3 and negatively regulated by miR-429 through miR-429's actions on HIF3A message. This provides a compelling model for how hypoxia-induced miR-429 regulates the switch between HIF-1 adaptive responses to HIF-3 survival responses by rapidly decreasing HIF1A levels while simultaneously slowing the progression of HIF3A expression until the miR-429 levels drop below normoxic levels. Since HIF-1 drives HIF3A and miR-429 expression, this establishes a regulatory network in which miR-429 plays a pivotal role.