Causes of calf mortality in Kabete area of Kenya.
A total of 345 calf carcases of mainly dairy breeds from the farms around Kabete area were examined at the post-mortem facility in the Department of Veterinary Pathology and Microbiology, University of Nairobi, over a 10-year period (1980-1989). About 46.8% of the total deaths took place within the first 2 months, 31.8% of them in the first month and 13.3% in the first 2 weeks. In 23 cases (6.7%) no specific cause of death was determined. The major causes of death were diseases of the alimentary tract (31.3%)--mainly gastroenteritis (76/108) due to colibacillosis, salmonellosis, coccidiosis and helminthiasis, and bloat (20/108). The other major causes of death were diseases of the respiratory tract (16.8%)--mainly pneumonia (42/58), and tick-borne diseases (13.3%)--mainly east coast fever (ECF) (37/46). The alimentary and respiratory diseases were most common in the 1-30 d age group. The other causes of death occurred in the following frequencies: musculoskeletal system (7.0%), septicaemia (6.7%), malnutrition (6.1%), cardiovascular system (3.7%), nervous system (3.2%), liver (2.6%) and poisoning (2.6%).


[Atrial fibrillation in Germany: A prospective cost of illness study].
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and associated with a high risk of stroke, heart failure and hospitalization. This study examines the indication-specific costs of illness of AF patients in Germany. The study was conducted nationwide with 54 general practitioners and internists, as well as 12 practicing cardiologists. The observational period per patient was one year. Costs were calculated from the perspective of the German statutory health insurance. The study collected the annual direct indication-specific costs and additional patient relevant outcomes. Indication-specific services of 361 patients (age: 75, male: 55%) documented by general practitioners and internists cause average costs of 582 € per patient. The highest cost are caused by hospitalization (289 €), followed by outpatient treatment costs (151 €) and costs of anticoagulation with 52 € per patient. Additional consulting of a cardiologist (115 patients) causes average costs of 81 €. Assuming that a patient with AF is treated once a year by a resident cardiologist, the average annual cost amounted to 664 €. The results of this prospectively cost of illness analysis for AF patients under real life conditions in Germany indicate a high socio-economic burden of AF.


Automatic segmentation of lung parenchyma in the presence of diseases based on curvature of ribs.
Segmentation of lungs using high-resolution computer tomographic images in the setting of diffuse lung diseases is a major challenge in medical image analysis. Threshold-based techniques tend to leave out lung regions that have increased attenuation, such as in the presence of interstitial lung disease. In contrast, streak artifacts can cause the lung segmentation to "leak" into the chest wall. The purpose of this work was to perform segmentation of the lungs using a technique that selects an optimal threshold for a given patient by comparing the curvature of the lung boundary to that of the ribs. Our automated technique goes beyond fixed threshold-based approaches to include lung boundary curvature features. One would expect the curvature of the ribs and the curvature of the lung boundary around the ribs to be very close. Initially, the ribs are segmented by applying a threshold algorithm followed by morphologic operations. The lung segmentation scheme uses a multithreshold iterative approach. The threshold value is verified until the curvature of the ribs and the curvature of the lung boundary are closely matched. The curve of the ribs is represented using polynomial interpolation, and the lung boundary is matched in such a way that there is minimal deviation from this representation. Performance of this technique was compared with conventional (fixed threshold) lung segmentation techniques on 25 subjects using a volumetric overlap fraction measure. The performance of the rib segmentation technique was significantly different from conventional techniques with an average higher mean volumetric overlap fraction of about 5%. The technique described here allows for accurate quantification of volumetric computed tomography and more advanced segmentation of abnormal areas.


Engineering optimal vaccination strategies: effects of physical properties of the delivery system on functions.
With rapid developments in medical science and technology, vaccination has become the key to solving public health problems. Various diseases can be prevented by vaccination, which mimic a disease by using a small part of the causal organism-also called an antigen-to stimulate the specific immune response to defend the host against the disease. The interaction between antigens and antigen-presenting cells (APCs) affects the efficacy of a vaccine. Adjuvants are crucial components of vaccines, optimizing the process of antigen phagocytosis by the APCs to some extent. However, many vaccinations fail during application in clinical trials owing to drawbacks of some antigens and adjuvants, such as immunogenicity and high degradability. Owing to rapid developments in the payload, targeted delivery and controllable release of drug delivery systems, they may have the potential to improve vaccines. In our review, we discuss multiple delivery systems and their role in vaccines and discuss how the major physical properties of delivery systems ultimately affect the success of vaccines, such as size, morphology, surface charge and elasticity.


R-based Tool for a Pairwise Structure-activity Relationship Analysis.
The Structure-Activity Relationship analysis is a complex process that can be enhanced by computational techniques. This article describes a simple tool for SAR analysis that has a graphic user interface and a flexible approach towards the input of molecular data. The application allows calculating molecular similarity represented by Tanimoto index & Euclid distance, as well as, determining activity cliffs by means of Structure-Activity Landscape Index. The calculation is performed in a pairwise manner either for the reference compound and other compounds or for all possible pairs in the data set. The results of SAR analysis are visualized using two types of plot. The application capability is demonstrated by the analysis of a set of COX2 inhibitors with respect to Isoxicam. This tool is available online: it includes manual and input file examples.


A Fast Calibration and Compensation Method for Magnetometers in Strap-Down Spinning Projectiles.
Attitude measurement is an essential technology in projectile trajectory correction. Magnetometers have been used for projectile attitude measurement systems as they are small in size, lightweight, and low cost. However, magnetometers are seriously disturbed by the artillery magnetic field during launch. Moreover, the error parameters of the magnetometers, which are calibrated in advance, usually change after extended storage. The changed parameters have negative effects on attitude estimation of the projectile. To improve the accuracy of attitude estimation, the magnetometers should be calibrated again before launch or during flight. This paper presents a fast calibration method specific for a spinning projectile. At the launch site, the tri-axial magnetometer is calibrated, the parameters of magnetometer are quickly obtained by optimal ellipsoid fitting based on a least squares criterion. Then, the calibration parameters are used to compensate for magnetometer outputs during flight. The numerical simulation results show that the proposed calibration method can effectively determine zero bias, scale factors, and alignment angle errors. Finally, a semi-physical experimental system was designed to further verify the performance of the calibration method. The results show that pitch angle error reduces from 3.52° to 0.58° after calibration. The roll angle error is reduced from 2.59° to 0.65°. Simulations and experimental results indicate that the accuracy of magnetometer in strap-down spinning projectile has been greatly enhanced, and the attitude estimation errors are reduced after calibration.


The luminal N-terminus of yeast Nvj1 is an inner nuclear membrane anchor.
The endoplasmic reticulum (ER) in Saccharomyces cerevisiae is largely divided between perinuclear and cortical compartments. Yeast Nvj1 localizes exclusively to small patches on the perinuclear ER where it interacts with Vac8 in the vacuole membrane to form nucleus-vacuole (NV) junctions. Three regions of Nvj1 mediate the biogenesis of NV junctions. A membrane-spanning domain targets the protein to the ER. The C-terminus binds Vac8 in the vacuole membrane, which induces the clustering of both proteins into NV junctions. The luminal N-terminus is required for strict perinuclear localization. Three-dimensional cryo-electron tomography reveals that Nvj1 clamps the separation between the two nuclear membranes to half the width of bulk nuclear envelope. The N-terminus contains a hydrophobic sequence bracketed by basic residues that resembles outer mitochondrial membrane signal-anchors. The hydrophobic sequence can be scrambled or reversed without affecting function. Mutations that reduce the hydrophobicity of the core sequence or affect the distribution of basic residues cause mislocalization to the cortical ER. We conclude that the N-terminus of Nvj1 is a retention sequence that bridges the perinuclear lumen and inserts into the inner nuclear membrane.


Allergen immunotherapy in asthma: current status and future perspectives.
Allergen immunotherapy targets Th2 cells activated by specific allergens, which constitutes the basis of allergic disease. Therefore, this approach has therapeutic potential for a variety of allergic diseases, including asthma, and may modify their natural course. Immunotherapy results in systemic immunological changes to allergens, thereby providing clinical benefits in allergic asthma. For example, immunotherapy attenuates T-cell-mediated airway inflammation by down-modulating Th2 and inducing Th1 differentiation. In addition, immunotherapy induces regulatory T cells, which produce IL-10. Meta-analysis has demonstrated that allergen immunotherapy improves clinical symptoms and non-specific airway hyperresponsiveness in asthma, and decreases drug requirements. Clinical studies have supported the usefulness if immunotherapy in mild to moderate asthma cases, particularly in patients with concomitant rhinitis. Several promising novel approaches have emerged as future immunotherapeutic strategies for the treatment of asthma. Current pharmacotherapy, including inhalational corticosteroids, provides powerful anti-symptomatic benefits in asthma; however, pharmacotherapy cannot cure or modify the natural course of asthma. As immunotherapy targets the background immunological state in asthma, it is expected to lead to long-term amelioration or cure. It is hoped that the positioning of allergen immunotherapy as a treatment option will allow the comprehensive management of symptoms in allergic individuals, and the modification of disease course.


The Effect of Lactiplantibacillus plantarum BX62 Alone or in Combination with Chitosan on the Qualitative Characteristics of Fresh-Cut Apples during Cold Storage.
In order to explore whether beneficial lactic acid bacteria (LAB) could prolong the shelf life and improve the quality of fresh-cut apples, Lactiplantibacillus plantarum BX62, which was isolated from traditional fermented yak yogurt, and chitosan (CT), were applied to fresh-cut apples, subsequently stored at 4 °C. On days 0, 2, 4, 6, and 8, apple slices were taken for physicochemical, microbiological analysis, and sensory evaluation. The results showed that apple slices coated with L. plantarum BX62 (8 log CFU/mL) presented lower weight loss and browning rate, higher DPPH scavenging capacity, and achieved more effective inhibition of polyphenol oxidase (PPO) and peroxidase (POD) activities compared to the control samples. The application of CT alone or in combination with L. plantarum BX62 resulted in a significant reduction in aerobic mesophilic bacteria (AMB), aerobic psychrophilic bacterial (APB), yeast and molds (YAMs) counts (2.31 log CFU/g for AMB, 2.55 for APB, and 1.58 for YAMs). In addition, L. plantarum BX62 coated apples showed acceptable sensory properties in terms of color, flavor, taste, texture, and overall visual quality during 8 d of storage. On this basis, L. plantarum BX62 could be used as an excellent bio-preservative to extend the shelf life and improve the quality of fresh-cut apples.


Macroscale Robust Superlubricity on Metallic NbB2.
Robust superlubricity (RSL), defined by concurrent superlow friction and wear, holds great promise for reducing material and energy loss in vast industrial and technological operations. Despite recent advances, challenges remain in finding materials that exhibit RSL on macrolength and time scales and possess vigorous electrical conduction ability. Here, the discovery of RSL is reported on hydrated NbB2 films that exhibit vanishingly small coefficient of friction (0.001-0.006) and superlow wear rate (≈10-17 m3 N-1 m-1 ) on large length scales reaching millimeter range and prolonged time scales lasting through extensive loading durations. Moreover, the measured low resistivity (≈10-6 Ω m) of the synthesized NbB2 film indicates ample capability for electrical conduction, extending macroscale RSL to hitherto largely untapped metallic materials. Pertinent microscopic mechanisms are elucidated by deciphering the intricate load-driven chemical reactions that generate and sustain the observed superlubricating state and assessing the strong stress responses under diverse strains that produce the superior durability.


Hepatic Artery Pseudoaneurysm: Delayed Presentation after a Blunt Trauma.
Ruptured hepatic artery pseudoaneurysm is a rare condition that is life-threatening if not diagnosed and treated rapidly. We present a case of a spontaneously ruptured hepatic artery pseudoaneurysm that occurred after a blunt trauma, and provide a review of the current literature on this topic. This case study demonstrates a spontaneously ruptured hepatic artery pseudoaneurysm which emerged following a blunt trauma and it also presents current literature studies on the topic. A man at the age of 34 years with blunt trauma dating back to 1.5 month was admitted to the emergency department of a hospital with hematemesis and epigastric tenderness. He also had a duodenal ulcer, blood in the gastric lumen and a large pseudoaneurysm that developed from the left hepatic artery. Soon after the diagnosis, the patient worsened and underwent distal gastrectomy and cholecystectomy that included removing the bleeding aneurysm. Ruptured hepatic artery pseudoaneurysm stands as a deadly condition which has to be diagnosed and managed as soon as possible. Physicians need to take aneurysms of abdominal arteries into consideration after routine diagnostic practises as long as the cause of gastrointestinal haemorrhage is unidentified.


Diisopropyl 1-(4-meth-oxy-phen-yl)-2,6-dimethyl-4-(3-nitro-phen-yl)-1,4-dihydro-pyridine-3,5-dicarboxyl-ate.
In the title compound, C(28)H(32)N(2)O(7), the 1,4-dihydro-pyridine ring adopts a flattened boat conformation. The two benzene rings are approximately perpendicular to the dihydro-pyridine ring, forming dihedral angles of 84.29 (9) and 82.96 (9)° with the mean plane of the 1,4-dihydro-pyridine unit, whereas the ester groups are only slightly twisted relative to this plane, with dihedral angles of 10.6 (1) and 9.0 (1)°.


Modelling Shows the Negative Impact of Age Dependent Pharmacokinetics on the Efficacy of Oxytetracycline in Young Steers.
The effect of age dependent pharmacokinetics (PK) on the clinical efficacy of oxytetracycline (OTC) against Bovine Respiratory Disease (BRD) in beef cattle was studied, using a Physiologically Based Pharmacokinetic (PBPK) model. The model includes a bodyweight dependent renal clearance. To mimic/reproduce the long terminal half-live a bone forming tissue compartment was considered. Data for the development, calibration and validation of the model were obtained from public literature. To integrate the PK with the pharmacodynamics (PD) of OTC, Monte Carlo simulations were performed using this PBPK model to predict time-concentration curves for two commonly used dosing regimens of short-acting and long-acting injectable OTC formulations in virtual populations of 5,000 steer calves of 100 kg and 400 kg. These curves were then used to calculate the value of the PKPD index for OTC, which is the ratio of the area under the concentration-time curve for 24 h (AUC24h) over the minimum inhibitory concentration (MIC) of the target pathogen (AUC24h/MIC). The MIC values were for Mannheimia haemolytica, the dose-limiting pathogen for BRD. This integration of PBPK and PD for OTC used for the treatment of BRD in calves indicated that the Probability of Target Attainment (PTA) was sufficient for efficacy in calves of 400 kg, but insufficient for calves of 100 kg, when using a long acting dosing regimen of 20 mg/kg BW, twice, with a 48-h interval. The use of a dosing regimen of 10 mg/kg BW/day for 4 days predicted sufficient PTAs in both age groups.


Evidence for the involvement of internal calcium stores during serotonin-induced meiosis reinitation in oocytes of the bivalve mollusc Ruditapes philippinarum.
In contrast to the situation found in the bivalves Barnea candida and Spisula solidissima, prophase-arrested oocytes of Ruditapes philippinarum cannot be fertilized when removed from the ovary. They must first undergo germinal vesicle breakdown under the influence of the neurohormone serotonin (5-HT), which drives them to a second block occurring in metaphase of the first maturation division. In the studies described in this paper, we investigate the possibility that calcium is involved as a second messenger in controlling this first step in the reinitiation of meiosis. Our data show that, in addition to 5-HT, ionophore, thapsigargin, and the weak bases ammonia and procaine can also induce prophase-arrested oocytes of Ruditapes to resume meiosis. 5-HT, thapsigargin, and ammonia all trigger a surge of intracellular Ca2+ and are effective even in the absence of external Ca2+. That such Ca2+ transients, which are enhanced in the presence of external Ca2+, actually play a key role in the process of meiosis reinitation is shown by the fact that loading the oocytes with BAPTA/AM or treating them with D-600 blocks maturation. In contrast, excess KCl, which has been shown to trigger meiosis reinitiation of prophase-arrested oocytes of Barnea and Spisula and to activate metaphase I-arrested oocytes of Ruditapes, does not produce any significant intracellular Ca2+ transient nor does it reinitiate meiosis, when added to Ruditapes prophase-arrested oocytes. These data suggest that such voltage-operated Ca2+ channels may only appear during the course of maturation and that both intracellular and extracellular Ca2+ are involved in triggering 5-HT-dependent release from the prophase block in this species.


Relative effect of surgery and radiotherapy on the internal jugular vein following functional neck dissection.
We examined the internal jugular veins in three groups of patients who had undergone (1) a functional neck dissection and radiotherapy, (2) a functional neck dissection alone, or (3) radiotherapy alone, using a noninvasive color Doppler ultrasound scan. The internal jugular veins were ultrasonically bilaterally normal in 18% of patients who had undergone a functional neck dissection and radiotherapy, in 88% of patients who had undergone a functional neck dissection alone, and in 57% of patients who had undergone radiotherapy alone. The combination of a functional neck dissection and radiotherapy significantly affected the internal jugular vein when compared with a functional neck dissection alone.


Hepatopulmonary syndrome: clinical perspectives.
Hepatopulmonary syndrome consists of a triad of chronic liver disease, pulmonary gas exchange abnormalities and pulmonary vascular dilatation in the absence of detectable cardiopulmonary disease. Patients usually present with symptoms of liver disease and the clinical recognition of this condition is a challenge. Newer non-invasive tests facilitate the diagnosis. Therapeutic strategies for this condition are still dismal. Liver transplantation is a possible curative option for a subgroup of patients with hepatopulmonary syndrome.


Incremental growth charts for condylar growth between 6 and 16 years of age.
This study provides sex specific reference data for the incremental growth of the mandibular condyle. The results pertain to a mixed-longitudinal sample of 113 males and 108 females followed annually between 6 and 16 years of age (total of 1647 observations). Growth of condylion was evaluated using naturally stable mandibular reference structures. The mean growth curves were estimated by multilevel models using iterative least squares procedures; between subject variation was estimated based on the sample's percentile distributions. Mean yearly velocities of condylar growth for males ranged between 2.1 and 3.1 mm/year. Growth rates decreased during childhood, increased during adolescence, and attained a maximum of 3.1 mm/year at approximately 14.3 years of age. Females showed a more constant rate of condylar growth during childhood (2.0-2.7 mm/year), a smaller adolescent peak (2.3 mm/year) at approximately 12.2 years and rapid deceleration after the peak. These reference data offer orthodontists an objective means of evaluating growth potential and treatment outcome in individual patients. Charts are provided for evaluating condylar growth of individual patients.


Responses of leukocytes to chemokines in whole blood and their antagonism by novel CC-chemokine receptor 3 antagonists.
CC-chemokine receptor 3 (CCR3)-stimulating chemokines are likely to have important in vivo roles in the regulation of eosinophil, basophil, and potentially helper T cell type 2 and mast cell recruitment. We have developed techniques to investigate the actions of eotaxin and other chemokines on multiple leukocyte populations in whole blood, without cell purification steps that might alter leukocyte responsiveness. We have shown that the potency of eotaxin in whole blood is limited by Duffy antigen binding, which may modulate the actions of this chemokine in vivo. We have also investigated the efficacy and potency of a new panel of small molecule antagonists of CCR3 on responses of eosinophils, neutrophils, basophils, and monocytes to chemokines, using whole blood assays of shape change, chemokine receptor internalization, and CD11b upregulation. These small molecule antagonists cause selective and potent inhibition of CCR3 on eosinophils and basophils, are bioavailable in blood, and are prototypic antagonists potentially of benefit in the treatment of human allergic disease. Such whole blood methods may also be employed in the investigation of other small molecule chemokine receptor antagonists.


New terpenoid constituents from Eunicea pinta.
The secondary metabolite composition of the gorgonian octocoral Eunicea pinta from San Andrés Island, Colombia, is described for the first time. This investigation has resulted in the isolation of eight new gamma-cembranolide-type diterpenes, namely, compounds 3-10, and a new saponin, 13, possessing a pregnene-derived aglycon. In addition, two previously known alpha-methylene-gamma-lactone cembranolides, euniolide (1) and succinolide (2), were also isolated. Their structures were determined on the basis of the results of spectroscopic analysis, X-ray diffraction analysis, and chemical conversions. The discovery of cembranolides 3-10 has prompted us to conclude that the structures proposed earlier for several uprolide-type cembranolides need revision and that a minor stereochemical correction is also in order for succinolide. Cytotoxicity of compounds 3, 4, and 13 toward various cancer cell lines and results of an antimycobacterial screening for 2, 4, and 13 also are described.


Synthesis and antiviral bioactivity of chiral thioureas containing leucine and phosphonate moieties.
A series of novel chiral thioureas 3a-n bearing leucine and phosphonate moieties were synthesized in excellent yields. The structures of the compounds were completely characterized by elemental analysis, IR, 1H-, 13C-, 31P- and 19F-NMR spectral data. A half-leaf method was used to determine the in vivo protective and curative efficacies of the title products against tobacco mosaic virus (TMV). The compounds 3l and 3n displayed good in vivo protection and curative effects against TMV with inhibitory rates of 60.1, 62.8% (protection) and 56.7, 53.6% (curative) at 0.5 mg/mL, respectively. To the best of our knowledge, this is the first report on the antiviral activity of chiral thioureas containing leucine and phosphonate moieties.


The challenges of modelling antibody repertoire dynamics in HIV infection.
Antibody affinity maturation by somatic hypermutation of B-cell immunoglobulin variable region genes has been studied for decades in various model systems using well-defined antigens. While much is known about the molecular details of the process, our understanding of the selective forces that generate affinity maturation are less well developed, particularly in the case of a co-evolving pathogen such as HIV. Despite this gap in understanding, high-throughput antibody sequence data are increasingly being collected to investigate the evolutionary trajectories of antibody lineages in HIV-infected individuals. Here, we review what is known in controlled experimental systems about the mechanisms underlying antibody selection and compare this to the observed temporal patterns of antibody evolution in HIV infection. We describe how our current understanding of antibody selection mechanisms leaves questions about antibody dynamics in HIV infection unanswered. Without a mechanistic understanding of antibody selection in the context of a co-evolving viral population, modelling and analysis of antibody sequences in HIV-infected individuals will be limited in their interpretation and predictive ability.


Exposure assessment of carbon nanotubes at pilot factory focusing on quantitative determination of catalytic metals.
The application of multiwall carbon nanotubes (MWCNTs) currently extends to various fields. However, it has been reported that exposure to CNT causes hazardous effects on animals and cells. The purpose of this study was to quantify the exposure to MWCNT in MWCNT/polymer composites for exposure assessment. We focused on catalytic metals included in the MWCNT and the diameter of dust released during the working processes. Although the Co in MWCNTs is not a common catalyst, it was used as a tracer in this study. A field survey was conducted in a MWCNT/polymer composite pilot factory. Airborne MWCNTs were monitored using black carbon monitors (BCMs) and optical particle sizers (OPSs) and collected on a filter. The MWCNT powder, all polymer resins used during the working processes, and the filter were analyzed in our lab using inductively coupled plasma mass spectrometry (ICP-MS) and electron microscopic observation. The mean concentration of airborne MWCNT contained in the collected dust was 0.92 μg/m3 a few meters away from the extruder during the working processes (using elemental analysis). The maximum concentration measured using BCMs was shown to be seven times higher than the base concentration during the pelletizing process of polycarbonate (PC) and MWCNT composites. However, free, isolated, and unbound agglomerated MWCNTs were not detected using scanning electron microscopic (SEM) observation. The result obtained by elemental analysis indicated it was possible to quantify MWCNT in composites. The mean concentration at this factory was lower than the recommended exposure limit. However, additional studies during the pelletizing process are required in the future.


[Diffusion-weighted echo-planar sequences for the evaluation of the upper abdomen: technique optimization].
To optimize the technique for the evaluation of molecular diffusion in the abdomen. Fifteen healthy volunteers, 6 males and 9 females, ranging in age between 24 and 31 years underwent an MRI evaluation of the upper abdomen, using a superconductive 1.5T magnet (maximum gradient strength, 25 mT/m; minimum rise time 600 ms), equipped with phased array abdominal multicoil. Diffusion study was performed with a single-shot Inversion Recovery Spin-Echo Echo-planar sequence (IR-SE-EPI) with the following parameters: TR = infinite; TE=101 ms; matrix 128 yen 128; receiver bandwidth 2080 Hz/pixel; slices: n.20; slice thickness: 8 mm; acquisition time: 5.41 s. For diffusion weighting the following b values were employed: b=30 mm/s2, b=300 mm/s2 e b=500 mm/s2. Both qualitative and quantitative (calculation of linear regression analysis and of apparent diffusion coefficient) image analysis was performed. Image quality was graded as diagnostic in all the cases. Image quality decreased with the increase of b values: at low b values, the anatomy of upper abdominal organs was easily recognized, whereas, at high b values, the same organs could not be adequately assessed unless the images were compared with those obtained with low b values. Magnetic susceptibility artifacts were observed in all the cases; no significant chemical-shift artifacts were observed as the fat saturation pre-pulse was employed. Quantitative analysis demonstrated an apparent diffusion coefficient of 1.58 s/mm2 for the liver, 1.61 s/mm2 for the spleen and 5,14 s/mm2 for the gallbladder. A statistically significant difference (p<0.001) was observed between parenchymatous organs (liver and spleen) and gallbladder, presenting as a stationary fluid. Diffusion-weighted MR sequences may be implemented for abdominal studies, but the optimization of same parameters is slightly different compared with neuroradiologic applications. The potential applications are interesting above all as regards the characterization of focal liver lesions. Further developments are awaited in both sequence optimization (greater stability and lower sensitivity to magnetic susceptibility artifacts) and data analysis, with more complex algorithms able to better quantify the real diffusion coefficient.


Genome-wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications.
Recent advances in molecular genetics have enabled assessments of the associations among genetic variants (e.g., single-nucleotide polymorphisms) and susceptibility for complex diseases, including psychiatric disorders. Specifically, genome-wide association studies (GWAS), meta-analyses of the GWAS summary statistics, and mega-analyses (which use raw data, not summary statistics) of GWAS have provided revolutionary results and have identified numerous susceptibility genes or single-nucleotide polymorphisms. By using several tens of thousands of subjects, >40 genes have been identified as being associated with susceptibility for bipolar disorder so far. The purpose of this systematic review was to summarize the recent findings of bipolar disorder GWAS and discuss their clinical implications.


A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells.
We have shown previously (J. A. Houghton et al., Proc. Natl. Acad. Sci. USA, 94: 8144-8149, 1997) that thymineless death in thymidylate synthase-deficient (TS-) colon carcinoma cells is mediated via Fas/FasL interactions after deoxythymidine (dThd) deprivation, and that Fas-dependent sensitivity of human colon carcinoma cell lines may be dependent upon the level of Fas expressed. The objective of this study was to elucidate whether a Fas-dependent component exists in 5-fluorouracil (FUra)/leucovorin (LV)-induced cytotoxicity of colon carcinoma cells, and whether this may be potentiated by IFN-gamma-induced elevation in Fas expression, using the HT29 cell line as a model. The cytotoxic activity of FUra/LV was inhibited by dThd in HT29 cells and also, in part, by NOK-1+NOK-2 MoAbs that prevent Fas/FasL interactions. FUra/LV-induced cytotoxicity was significantly potentiated by IFN-gamma, reversed by exposure to NOK-1+NOK-2 antibodies, and correlated with a 4-fold induction of Fas expression in the presence of IFN-gamma and significant elevation in expression of FasL. Using five additional human colon carcinoma cell lines, FUra/LV-induced cytotoxicity was dThd-dependent in GC3/c1, VRC5/c1, and Caco2 but not in HCT8 or HCT116 cells. Like HT29 cells, this cytotoxicity was potentiated by IFN-gamma in GC3/c1 and VRC5/c1 but not in Caco2, which fails to express Fas, nor in HCT8 and HCT116, in which no dThd-dependent FUra-induced cytotoxicity was demonstrated. Data suggest that a Fas-dependent component, potentiated by IFN-gamma, exists in FUra/LV-induced cytotoxicity but requires FUra/LV-induced DNA damage for IFN-gamma-induced potentiation to occur.


Diabetes increases the risk of acute hepatic failure.
It is unclear whether patients with diabetes are at an increased risk of developing acute liver failure (ALF). We performed a large cohort study to examine the occurrence of ALF by using the databases of the Department of Veterans Affairs. We identified all patients with a hospital discharge diagnosis of diabetes (ICD-9 codes: 250 [1-9][0-4]) from 1985 to 1990 and randomly assigned patients without diabetes for comparison (3:1 ratio). We excluded patients with concomitant liver disease as far back as 1980. After excluding the first year of follow-up, the remaining patients were observed through 2000 for the occurrence of ALF (ICD-9 570). The cumulative risk and the relative risk of ALF were determined by Kaplan-Meier and Cox Proportional Hazard survival analysis, respectively. We included 173,643 patients with diabetes and 650,620 patients without diabetes. Patients with diabetes were significantly older (62 vs. 54 years) and were less likely to be white (28% vs. 24%). The cumulative risk of ALF was significantly higher among patients with diabetes (incidence rate, 2.31 per 10,000 vs. 1.44 per 10,000 person-years; P < 0.0001). In the Cox proportional hazard model, diabetes was associated with a relative risk of 1.44 (95% CI, 1.26-1.63; P < 0.0001) for ALF while controlling for comorbidity index, age, sex, ethnicity, and period of service. This risk remained significantly increased after excluding patients with liver disease or viral hepatitis recorded during follow-up or those with ALF recorded after the introduction of troglitazone (relative risk = 1.40; P < 0.0001). Diabetes increases the risk of ALF. The increase in ALF is independent of recognized underlying chronic liver disease or viral hepatitis.


Reduction in susceptibility to Brugia malayi of F2 progeny of Aedes togoi treated with ethyl methanesulfonate.
The susceptibility to Brugia malayi infection was tested in F2 female progeny derived from male and female Aedes togoi treated with ethyl methanesulfonate (EMS). Three-day-old males and females were treated with 0.025, 0.050, and 0.075, 0.10, 0.15, or 0.20% EMS by allowing them to feed for 5 days on sugar cubes containing EMS and then mated at random. Percentage of susceptibility and mean number of infective larvae (L3) in F2 females were analyzed over a 2-wk period. Reductions in susceptibility were significant in the F2 populations arising from the 3 highest EMS concentrations. F2 infections were reduced by 80%, indicating that EMS-induced mutations affect loci associated with filarial nematode susceptibility.


A release from developmental bias accelerates morphological diversification in butterfly eyespots.
Development can bias the independent evolution of traits sharing ontogenetic pathways, making certain evolutionary changes less likely. The eyespots commonly found on butterfly wings each have concentric rings of differing colors, and these serially repeated pattern elements have been a focus for evo-devo research. In the butterfly family Nymphalidae, eyespots have been shown to function in startling or deflecting predators and to be involved in sexual selection. Previous work on a model species of Mycalesina butterfly, Bicyclus anynana, has provided insights into the developmental control of the size and color composition of individual eyespots. Experimental evolution has also shown that the relative size of a pair of eyespots on the same wing surface is highly flexible, whereas they are resistant to diverging in color composition, presumably due to the underlying shared developmental process. This fixed color composition has been considered as a prime example of developmental bias with significant consequences for wing pattern evolution. Here, we test this proposal by surveying eyespots across the whole subtribe of Mycalesina butterflies and demonstrate that developmental bias shapes evolutionary diversification except in the genus Heteropsis which has gained independent control of eyespot color composition. Experimental manipulations of pupal wings reveal that the bias has been released through a novel regional response of the wing tissue to a conserved patterning signal. Our study demonstrates that development can bias the evolutionary independence of traits, but it also shows how bias can be released through developmental innovations, thus, allowing rapid morphological change, facilitating evolutionary diversification.


Inhibition of protein synthesis and amino acid transport by crystal violet in Trypanosoma cruzi.
[35S]methionine incorporation into proteins of either T. cruzi epimastigotes or trypomastigotes was drastically inhibited by low concentrations of crystal violet in a dose-dependent manner. This inhibition was not due to ATP depletion since cellular ATP levels did not change significantly after incubation of epimastigotes with 50 microM crystal violet for similar periods of time, and was unaffected by changes in the extracellular free calcium concentration. Although crystal violet was able to inhibit protein synthesis in a cell-free system from T. cruzi epimastigotes, half maximal inhibition was at 1 mM, a concentration three orders of magnitude higher than those that inhibited protein synthesis in intact cells. On the other hand, crystal violet was able to inhibit total [35S]methionine uptake at similar concentrations to those that inhibited protein synthesis while addition of increasing concentrations of cold methionine to the incubation medium protected the cells against crystal violet inhibition. Crystal violet also inhibited total [3H]proline uptake thus indicating that it has a general inhibitory effect upon the transport of amino acids, and not specifically upon methionine. These results indicate that inhibition of protein synthesis by crystal violet is probably due to inhibition of amino acid uptake.


Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology.
The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. The articles in this CCR Focus provide insights into molecular mechanisms of resistance to targeted therapy. Recent discoveries of the molecular pathways that mediate intrinsic resistance to targeted therapy have led to the identification of predictive biomarkers that allow for better patient selection for front line treatment. Equally important, the identification of mechanisms of acquired resistance following front line therapy has led to the discovery of novel agents that overcome these resistance mechanisms. Improving the efficacy of targeted therapies in the future will require expanding our understanding of resistance mechanisms, the development of new generations of rationally designed targeted agents, and translating this information to the clinic to select patients for appropriate therapy. (Clin Cancer Res 2009;15(24):7471-8).


Progress on the Elucidation of the Antinociceptive Effect of Ginseng and Ginsenosides in Chronic Pain.
Ginseng (Panax ginseng C.A. Meyer) is a traditional Oriental herbal drug widely used in East Asia. Its main active ingredients are ginsenosides whose constituents are known to have various pharmacological activities such as anticancer, antinociception, and neuroprotection. The analgesic effects of ginsenosides, such as Rg1, Rg2, and Rb1, as well as compound K, are well known and the analgesic mechanism of action in inflammatory pain models is thought to be the down regulation of pro-inflammatory cytokine expression (TNF-α IL-1β, and IL-6). Several studies have also demonstrated that ginsenosides regulate neuropathic pain through the modulation of estrogen receptors. Recently, an increasing number of pathways have emerged in relation to the antinociceptive effect of ginseng and ginsenosides. Therefore, this review presents our current understanding of the effectiveness of ginseng in chronic pain and how its active constituents regulate nociceptive responses and their mechanisms of action.


Targeted Therapy After Brain Radiotherapy for BRAF-Mutated Melanoma With Extensive Ependymal Disease With Prolonged Survival: Case Report and Review of the Literature.
Melanoma brain metastasis with ependymal spread/metastases is uncommon. These cases are frequently classified together with leptomeningeal disease. However, the commonalities and differences in the underlying pathophysiology and clinical outcomes between these two types of spread are not clear. Very few reports on long term outcome and durable central nervous system (CNS) disease control have been reported in the literature. Here, we report a case of a 45 year-old Caucasian lady with BRAF-V600E mutant metastatic melanoma to the brain who had whole brain radiotherapy followed by two Gamma knife radiosurgery treatments for localized disease progression. She then developed extensive ependymal disease progression with no evidence of leptomeningeal spread. She was treated with a repeat course of whole brain radiotherapy and maintained on BRAF and MEK inhibitors with durable CNS disease control for more than a year. This study reviews the management of BRAF-V600E mutant melanoma with ependymal involvement. Management using radiation therapy with maintenance targeted therapy seems to be a reasonable approach to this challenging disease.


Altered Default Mode Network and Salience Network Functional Connectivity in Patients with Generalized Anxiety Disorders: An ICA-Based Resting-State fMRI Study.
This study aimed to explore the role of the default mode network (DMN) and salience network (SN) in the assessment of pathophysiology of generalized anxiety disorder (GAD) through analyzing the characteristics of internal function connectivity (FC) and to investigate the relationship of FC with Hamilton anxiety (HAMA) scale scores in untreated GAD patients during a resting-state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI and HAMA scale scoring were performed in 51 GAD patients (31 GAD patients with liver stagnation transforming into fire type and 20 GAD patients with stagnation of liver-Qi syndrome type) and 20 healthy controls. Spearman correlation analysis was performed to assess the association between HAMA scores and abnormal brain FC. Compared with healthy controls, the FC of the right medial prefrontal gyrus of the DMN and the right superior temporal gyrus of the SN increased significantly in the GAD patients (P < 0.001). However, the FC of the left middle frontal gyrus and bilateral medial superior frontal gyrus of the SN reduced significantly in the GAD patients with stagnation of liver-Qi syndrome type as compared with healthy controls and GAD patients with liver stagnation transforming into fire type (P < 0.001). There was no relationship between abnormal brain FC and HAMA scores. In conclusion, the FC of the DMN and SN may be abnormal in the GAD patients at the resting state. The aberrant FC of some crucial brain regions of these networks may contribute to the pathophysiology of GAD.


Central action of tachykinins on activity of expiratory pumping muscles.
The central effects of tachykinins (substance P, neurokinin A, and neurokinin B) on the distribution of the motor activity to rib cage and abdominal expiratory muscles were studied in anesthetized tracheotomized spontaneously breathing dogs and cats. Intracisternal application of substance P (11 dogs) in doses of 10(-5) to 10(-4) M caused diaphragm electrical activity to change insignificantly from 19.3 +/- 1.9 to 24.8 +/- 3.2 units (P greater than 0.05), produced a moderate increase of triangularis sterni activity from 12.6 +/- 2.2 to 19.2 +/- 2.2 units (P less than 0.05), and stimulated a large increase of transversus abdominis activity from 9.4 +/- 2.7 to 28.5 +/- 2.6 units (P less than 0.01). Comparable effects were seen with similar doses of neurokinin A (8 dogs) and neurokinin B (3 dogs) administered intracisternally. Local application of substance P to the ventral medullary surface (5 dogs and 4 cats) also caused expiratory muscle activity to increase more than diaphragm activity, and in addition transversus abdominis activity increased to a larger extent than triangularis sterni activity. Furthermore, administration of the substance P antagonist [D-Pro2,D-Trp7,9]-SP to the ventral medullary surface decreased respiratory motor output, with expiratory muscles activity being attenuated to a greater extent than diaphragm activity. Application of neurotensin and N-methyl-D-asparate to the ventral surface of the medulla produced responses similar to those observed as a result of central administration of tachykinin peptides. The results suggest that 1) mammalian tachykinins are involved in the regulation of thoracic and abdominal expiratory muscle activity, 2) these muscles manifest substantial differences in their electrical responses to excitatory neuropeptides acting centrally, and 3) inputs from modulatory neurons located in this vicinity of the ventral medullary surface seem to be distributed unevenly to different expiratory premotor and/or motoneurons.


Fluorescent nanosensors for intracellular chemical analysis: decyl methacrylate liquid polymer matrix and ion-exchange-based potassium PEBBLE sensors with real-time application to viable rat C6 glioma cells.
Fluorescent spherical nanosensors, or PEBBLEs (probes encapsulated by biologically localized embedding), in the 500 nm-1 microm size range have been developed using decyl methacrylate as a matrix. A general scheme for the polymerization and introduction of sensing components creates a matrix that allows for the utilization of the highly selective ionophores used in poly(vinyl chloride) and decyl methacrylate ion-selective electrodes. We have applied these optically silent ionophores to fluorescence-based sensing by using ion-exchange and highly selective pH chromoionophores. This allows the tailoring of selective submicrometer sensors for use in intracellular measurements of important analytes for which selective enough fluorescent probes do not exist. The protocol for sensor development has been worked out for potassium sensing. It is based on the BME-44 ionophore (2-dodecyl-2-methyl-1,3-propanediylbis[N-[5'nitro(benzo-15-crown-5)-4'-yl]carbamate]). The general scheme should work for any available ionophore used in PVC or decyl methacrylate ion-selective electrodes, with minor adjustments to account for differences in ionophore charge and analyte binding constant. The reversible and highly selective sensors developed have a subsecond response time and an adjustable dynamic range. Applications to live C6 glioma cells demonstrate their utility; the intracellular potassium activity is followed in real time upon extracellular administration of kainic acid.


Global informetric perspective studies on translational medical research.
Translational medical research literature has increased rapidly in the last few decades and played a more and more important role during the development of medicine science. The main aim of this study is to evaluate the global performance of translational medical research during the past few decades. Bibliometric, social network analysis, and visualization technologies were used for analyzing translational medical research performance from the aspects of subject categories, journals, countries, institutes, keywords, and MeSH terms. Meanwhile, the co-author, co-words and cluster analysis methods were also used to trace popular topics in translational medical research related work. Research output suggested a solid development in translational medical research, in terms of increasing scientific production and research collaboration. We identified the core journals, mainstream subject categories, leading countries, and institutions in translational medical research. There was an uneven distribution of publications at authorial, institutional, and national levels. The most commonly used keywords that appeared in the articles were "translational research", "translational medicine", "biomarkers", "stroke", "inflammation", "cancer", and "breast cancer". The subject categories of "Research & Experimental Medicine", "Medical Laboratory Technology", and "General & Internal Medicine" play a key role in translational medical research both in production and in its networks. Translational medical research and CTS, etc. are core journals of translational research. G7 countries are the leading nations for translational medical research. Some developing countries, such as P.R China, also play an important role in the communication of translational research. The USA and its institutions play a dominant role in the production, collaboration, citations and high quality articles. The research trends in translational medical research involve drug design and development, pathogenesis and treatment of disease, disease model research, evidence-based research, and stem and progenitor cells.


Human connectome module pattern detection using a new multi-graph MinMax cut model.
Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding the large-scale brain networks that underlie higher-level cognition in human. However, suitable computational network analysis tools are still lacking in human connectome research. To address this problem, we propose a novel multi-graph min-max cut model to detect the consistent network modules from the brain connectivity networks of all studied subjects. A new multi-graph MinMax cut model is introduced to solve this challenging computational neuroscience problem and the efficient optimization algorithm is derived. In the identified connectome module patterns, each network module shows similar connectivity patterns in all subjects, which potentially associate to specific brain functions shared by all subjects. We validate our method by analyzing the weighted fiber connectivity networks. The promising empirical results demonstrate the effectiveness of our method.


Insulin-like growth factor gene expression in human smooth muscle tumors.
A role for insulin-like growth factors (IGF) in autocrine or paracrine growth stimulation of tumor cells has been proposed for tumors of different origins. We have studied IGF gene expression in human uterus smooth muscle (myometrium) and in a panel of benign (leiomyoma) and malignant (leiomyosarcoma) smooth muscle tumors. Using RNA transfer blot analysis we could demonstrate that in smooth muscle tissue and tumors IGF genes are differentially expressed. The mRNA species detected had the same size as reported for IGF mRNAs from other tissues. However, the abundance of the IGF gene transcripts varied from tissue to tissue. The amounts of IGF mRNAs detected in smooth muscle tumors were compared to the levels found in normal smooth muscle. The IGF-I gene was expressed at high levels in normal myometrium and in leiomyomas but appears to be repressed in leiomyosarcomas. Also the IGF-I peptide was detected in myometrium and in leiomyomas, but in leiomyosarcomas the level was substantially lower. The IGF-II gene was expressed at low levels in normal myometrium and leiomyomas but is activated in leiomyosarcomas. With increasing malignancy from the two major IGF-II mRNA species, 6.0 and 4.8 kilobases, in particular the 6.0-kilobase mRNA is produced at higher levels. In conclusion, these data suggest that for IGF-I a role in tumor cell growth is not likely, but probably IGF-II is involved in malignant smooth muscle tumor growth progression.


Expression of growth hormone (GH)-releasing factor gene in GH-producing pituitary adenoma.
Pituitary cells synthesize various neuropeptides that influence pituitary hormone secretion. GH-releasing factor (GRF) may also be produced by normal or pituitary tumor cells. We examined GRF gene expression in pituitary tumors. Standard techniques for the analysis of GRF gene expression did not appear to be suitable. Highly sensitive reverse transcription coupled to polymerase chain reaction was used. Specimens of pituitary adenoma were obtained by transsphenoidal adenomectomy from six patients with acromegaly and three patients with no clinical evidence of pituitary hormone overproduction; non-functioning adenoma. Pituitary glands were collected at autopsy from three patients who died from nonendocrine disorders. A specific GRF gene transcript was detected in five out of six GH-producing pituitary adenomas, whereas this was not found in three separate specimens of nonfunctioning pituitary adenoma or anterior and posterior pituitary tissue. The data suggest that GRF is synthesized as an intrinsic product in human GH-producing pituitary adenoma.


Polyamine metabolism in experimental brain tumors of rat.
Biosynthesis and accumulation of the polyamines putrescine, spermidine, and spermine are closely associated with cellular growth processes. We examined polyamine levels and the activity of their first rate-limiting enzyme, ornithine decarboxylase (ODC), in stereotactically induced experimental gliomas of the rat brain 1 and 2 weeks after implantation. Regional ODC activity and polyamine levels were determined in the tumor and in the ipsi- and contralateral striatum, white matter, and cerebral cortex. In the tumor, both ODC activity and polyamine levels markedly increased with progressive tumor growth, as compared to those in the white matter of the opposite hemisphere. In the peritumoral brain tissue, ODC activity did not change, but there was a marked increase of putrescine and, to a lesser degree, of spermidine and spermine almost throughout the whole ipsilateral hemisphere. ODC activity, therefore, seems to be a reliable marker of neoplastic growth in the brain, which may be of use for new clinical concepts of the diagnosis and therapy of brain tumors. The more diffuse distribution of polyamines, however, may be associated with the formation and spreading of edema, which would explain some of the biological effects of tumors on distant brain tissue.


Sexual conflict drives male manipulation of female postmating responses in Drosophila melanogaster.
In many animals, females respond to mating with changes in physiology and behavior that are triggered by molecules transferred by males during mating. In Drosophila melanogaster, proteins in the seminal fluid are responsible for important female postmating responses, including temporal changes in egg production, elevated feeding rates and activity levels, reduced sexual receptivity, and activation of the immune system. It is unclear to what extent these changes are mutually beneficial to females and males or instead represent male manipulation. Here we use an experimental evolution approach in which females are randomly paired with a single male each generation, eliminating any opportunity for competition for mates or mate choice and thereby aligning the evolutionary interests of the sexes. After >150 generations of evolution, males from monogamous populations elicited a weaker postmating stimulation of egg production and activity than males from control populations that evolved with a polygamous mating system. Males from monogamous populations did not differ from males from polygamous populations in their ability to induce refractoriness to remating in females, but they were inferior to polygamous males in sperm competition. Mating-responsive genes in both the female abdomen and head showed a dampened response to mating with males from monogamous populations. Males from monogamous populations also exhibited lower expression of genes encoding seminal fluid proteins, which mediate the female response to mating. Together, these results demonstrate that the female postmating response, and the male molecules involved in eliciting this response, are shaped by ongoing sexual conflict.


Race, outpatient mental health service use, and survival after an AIDS diagnosis in the highly active antiretroviral therapy era.
We examined the relationships between survival after AIDS diagnosis and outpatient mental health service use among men with history of highly active antiretroviral therapy (HAART). Analysis involved 1913 black and 1684 white men with AIDS who received HIV care in 2003 in the Veterans Affairs health care system. Negative binomial regression was used to assess the association between service use and length of AIDS diagnosis. Patients with longer survival after AIDS had higher rates of outpatient visits for stress and adjustment disorders as well as for mood, anxiety, and sexual disorders. Blacks had more visits for stress and adjustment disorders (7.4 versus 5.1; p < 0.05). Multiple regression analysis showed that prolonged survival after AIDS (incident rate ratios [IRR] = 1.87; 95% confidence interval [CI] = 1.25-2.77), having CD4 cell count less than 200 cells/mm(3) (IRR = 1.91; 95% CI = 1.19-3.04), and mortality (IRR = 3.84; 95% CI = 1.29-11.43) were associated with greater number of visits for mood, anxiety, and sexual disorders. Injection drug users (IRR = 3.52; 95% CI = 1.94-6.38), men who have sex with men (IRR = 2.87; 95% CI = 1.62-5.06), and patients with AIDS-defining illness (IRR = 2.48; 95% CI = 1.47-4.17) had greater rates of visits for stress and adjustment disorders. Survival after AIDS is associated with mental health service use. As more HIV-infected persons survive longer, adequate risk assessment of mental health concerns that considers race and HIV risk factors should be undertaken to effectively address the impact of mental health on treatment outcomes and mortality.


Daily single-dose regimen and alternate-two-week triple-dose/day regimen of oral ofloxacin for the prophylaxis and control of exacerbations of chronic respiratory tract infections.
Two different oral ofloxacin regimens, a daily single-dose regimen with 200 mg (Regimen I) and an every-two-week multidose regimen with 3 x 200 mg/day (Regimen II) was compared as to the efficacy in controlling repeated acute exacerbations of chronic respiratory tract infections. Fifty-eight patients consisting of 19 patients each of bronchiectasis and pulmonary emphysema, 10 patients of chronic bronchitis, 5 patients of old pulmonary tuberculosis, 4 patients of diffuse panbronchiolitis and 1 patient of multiple pulmonary bullae were evaluated: 32 patients in Regimen I and 26 patients in Regimen II. The corrected mean incidence of exacerbations per case decreased from pre-study 2.47 to intra-study 0.59 in Regimen I, and from pre-study 2.66 to intra-study 0.95 in Regimen II, respectively, with a statistically significant difference (p < 0.05, respectively). Only one of 12 persistent isolates of Pseudomonas aeruginosa acquired a certain degree of resistance to ofloxacin. Adverse reactions were found in six of 66 patients. We conclude that long-term administration of an new-quinolone, especially a daily single-dose regimen with ofloxacin, is useful to control acute exacerbations of chronic respiratory tract infections.


Expression of HLA class I molecules and the transporter associated with antigen processing in hepatocellular carcinoma.
The expression of the HLA class I molecules on the cell surface was investigated in hepatocellular carcinoma (HCC) cell lines using complement-mediated cytotoxicity (CMC) and flow cytometric analysis. Although HLA-A antigens were detected by CMC in all cell lines tested, HLA-B and -C antigens were not detectable in six of seven HCC cell lines. These results were also confirmed by flow cytometric analysis focusing on HLA-Bw4 and Bw6 public antigens. Furthermore, complementary DNA (cDNA) from each cell line was tested for the expression of HLA-A, -B, -C and the transporter associated with antigen processing genes (TAP1 and TAP2). Two cell lines showed a reduced level of one or both of the TAP messenger RNAs (mRNAs), and one of these showed a reduction of HLA-B and -C gene expression as well, but the others had detectable mRNA levels. These results demonstrate that hepatocellular carcinoma cell lines tested in the current study lose or decrease the expression of HLA-B and -C alleles on the cell surface, even though mRNA encoding these alleles is present, suggesting that the loss of the HLA molecules might be caused by posttranscriptional events or failure to transport and load peptides necessary for HLA expression. The selective loss of HLA-B and -C, but not -A, molecules (which also excludes a beta 2-microglobulin defect) is intriguing, and may be attributable to the ability of some of the HLA-A molecules to load signal peptides not requiring TAP transport, or to natural selection of HLA-B or -C locus-specific immune surveillance.


Near-infrared Spectroscopy of Vastus Lateralis Muscle during Incremental Cycling Exercise in patients with Type 2 Diabetes.
It is clinically important to elucidate the precise mechanism of exercise intolerance in patients with type 2 diabetes (T2DM). The aim of this study was to examine whether there is a difference in the time course change of the oxygenation in the vastus lateralis (VL) muscle during submaximal incremental cycling exercise between patients with T2DM and age-matched healthy subjects. Nine elderly men with T2DM and 10 age-matched healthy men (CON) participated in this study. All participants performed an incremental cycling exercise.Total, deoxygenated and oxygenated hemoglobin/myoglobin in the VL muscle were assessed using near-infrared spectroscopy, and cardiorespiratory response was also evaluated during the exercise. There were no significant differences in the time course changes of deoxygenated hemoglobin/myoglobin between groups ( p > 0.05). However, the oxygenated hemoglobin/myoglobin in T2DM was significantly higher than that in CON at an intensity above ventilatory threshold during the incremental cycling exercise ( p< 0.05). This study suggests that patients with T2DM had early limitation of oxygen extraction and lower capacity of oxygenated myoglobin dissociation in the VL muscle. The fact that patients with T2DM showed different oxygen kinetics in a peripheral tissue from healthy subjects may partly explain the potential mechanisms of exercise intolerance in T2DM.


Interaction of emodin, aloe-emodin, and rhein with human serum albumin: a fluorescence spectroscopic study.
The interaction of the dihydroxyanthraquinones, emodin (1), aloe-emodin (2), and rhein (3) with human serum albumin (HSA) has been studied through fluorescence spectroscopy. Quenching studies and the association constant of the anthraquinoid compounds 1, 2, and 3 in the presence of HSA were estimated. The binding and quenching studies suggest that only emodin (1) may serve as a useful fluorescence probe for structure/function studies of different emodin binding proteins. No photoinduced binding was observed after irradiation of compounds 1, 2, and 3 in presence of human serum albumin.


Hypersensitive reactions to mosquito bites in congenital agammaglobulinemia.
A 6-year-old girl with congenital agammaglobulinemia exhibited severe delayed onset cutaneous reactions to mosquito bites with scar formation. The bites were not associated with immediate reactions accompanied by itching. The patient had non-detectable IgE levels (less than 0.2 IU/mL) in addition to absence of three other major classes of immunoglobulins, but showed normal T cell functions. Immunologic and histopathologic examination of the skin lesions revealed that this unusual reaction may be caused by a delayed type hypersensitivity response.


Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles.
An efficient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cyclization of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H activation. In a single-step approach, a variety of 2-substituted indoles were also generated via a Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes. The arylacetylenes proved to be more effective than the alkyl derivatives.


[Brain biopsies in HIV-infected patients].
Stereotactic brain biopsies of 25 HIV-seropositive patients (age range between 20 and 56 years, 23 males, 2 females) were retrospectively studied. Biopsy material was examined cytologically, histologically, immunohistochemically and electron microscopically. A definitive diagnosis could be established in 23 cases (92%). Diagnosis included non-Hodgkin's lymphoma (10 cases), toxoplasmosis (10 cases), progressive multifocal leukoencephalopathy (PML) (2 cases) and combined toxoplasmosis and lymphoma (1 case). Two biopsies were non-diagnostic. All lymphomas were B-cell lymphomas of high malignancy including one K1-lymphoma. In six cases, in which autopsy was performed, biopsy diagnosis could be confirmed. In one patient suffering from toxoplasmosis, autopsy demonstrated an additional cytomegalovirus infection. Conventional histology was not sufficiently decisive for toxoplasmosis, for some lymphomas and for PML. Stereotactic brain biopsy appears to be an effective method in the diagnosis of HIV-associated brain lesions.


Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.
Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a-/-/Mdr1b-/- or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a-/-/Mdr1b-/- mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.


The woody plant poplar has a functionally conserved salt overly sensitive pathway in response to salinity stress.
In Arabidopsis thaliana, the salt overly sensitive (SOS) pathway plays an essential role in maintaining ion homeostasis and conferring salt tolerance. Here we identified three SOS components in the woody plant Populus trichocarpa, designated as PtSOS1, PtSOS2 and PtSOS3. These putative SOS genes exhibited an overlapping but distinct expression pattern in poplar plants and the transcript levels of SOS1 and SOS2 were responsive to salinity stress. In poplar mesophyll protoplasts, PtSOS1 was specifically localized in the plasma membrane, whereas PtSOS2 was distributed throughout the cell, and PtSOS3 was predominantly targeted to the plasma membrane. Heterologous expression of PtSOS1, PtSOS2 and PtSOS3 could rescue salt-sensitive phenotypes of the corresponding Arabidopsis sos mutants, demonstrating that the Populus SOS proteins are functional homologues of their Arabidopsis counterpart. In addition, PtSOS3 interacted with, and recruited PtSOS2 to the plasma membrane in yeast and in planta. Reconstitution of poplar SOS pathway in yeast cells revealed that PtSOS2 and PtSOS3 acted coordinately to activate PtSOS1. Moreover, expression of the constitutively activated form of PtSOS2 partially complemented the sos3 mutant but not sos1, suggesting that PtSOS2 functions genetically downstream of SOS3 and upstream of SOS1. These results indicate a strong functional conservation of SOS pathway responsible for salt stress signaling from herbaceous to woody plants.


Inhibition of Photosystem II in Isolated Chloroplasts by Lead.
Inhibition of photosynthetic electron transport in isolated chloroplasts by lead salts has been demonstrated. Photosystem I activity, as measured by electron transfer from dichlorophenol indophenol to methylviologen, was not reduced by such treatment. However, photosystem II was inhibited by lead salts when electron flow was measured from water to methylviologen and Hill reaction or by chlorophyll fluorescence. Fluorescence induction curves indicated the primary site of inhibition was on the oxidizing side of photosystem II. That this site was between the primary electron donor of photosystem II and the site of water oxidation could be demonstrated by hydroxylamine restoration of normal fluorescence following lead inhibition.


The use of shear stress for targeted drug delivery.
Stenosed segments of arteries significantly alter the blood flow known from healthy vessels. In particular, the wall shear stress at critically stenosed arteries is at least an order of magnitude higher than in healthy situations. This alteration represents a change in physical force and might be used as a trigger signal for drug delivery. Mechano-sensitive drug delivery systems that preferentially release their payload under increased shear stress are discussed. Therefore, besides biological or chemical markers, physical triggers are a further principle approach for targeted drug delivery. We hypothesize that such a physical trigger is much more powerful to release drugs for vasodilation, plaque stabilization, or clot lysis at stenosed arteries than any known biological or chemical ones.


Can mitochondrial dysfunction be initiated by dissociative electron attachment to xenobiotics?
Resonance attachment of low-energy electrons to xenobiotic molecules, 2,4-dichlorophenoxyacetic acid (2,4-D), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE), was investigated under gas-phase conditions by means of complementary experimental techniques. Electron transmission spectroscopy (ETS) and dissociative electron attachment spectroscopy (DEAS), in the 0-6 eV and 0-15 eV energy range, respectively, were applied with the aim of modeling the behavior of these pesticide molecules under reductive conditions in vivo. Formation of long-lived parent molecular anions and fragment negative ions was observed at incident electron energies very close to zero, in agreement with the results of density functional theory calculations. The gas-phase DEA process, analogous to dissociative electron transfer in solution, was considered as a model for the initial step which occurs in the intermembrane space of mitochondria when a xenobiotic molecule captures an electron "leaked" from the respiratory chain. A possible involvement of the fragments produced by DEA to the pesticides under investigation into cellular processes is discussed. It is concluded that the free radicals and potential DNA adducts formed by DEA are expected to be dangerous for mitochondrial functionalities, while several of the products observed could act as messenger molecules, thus interfering with the normal cellular signaling pathways.


Aligned carbon nanotube based ultrasonic microtransducers for durability monitoring in civil engineering.
Structural health monitoring of porous materials such as concrete is becoming a major component in our resource-limited economy, as it conditions durable exploitation of existing facilities. Durability in porous materials depends on nanoscale features which need to be monitored in situ with nanometric resolution. To address this problem, we put forward an approach based on the development of a new nanosensor, namely a capacitive micrometric ultrasonic transducer whose vibrating membrane is made of aligned single-walled carbon nanotubes (SWNT). Such sensors are meant to be embedded in large numbers within a porous material in order to provide information on its durability by monitoring in situ neighboring individual micropores. In the present paper, we report on the feasibility of the key building block of the proposed sensor: we have fabricated well-aligned, ultra-thin, dense SWNT membranes that show above-nanometer amplitudes of vibration over a large range of frequencies spanning from 100 kHz to 5 MHz.


Labyrinthitis and Labyrinthitis Ossificans - A case report and review of the literature.
Labyrinthitis most commonly results from an infectious and less commonly from an inflammatory process of the inner ear, but it can be associated with temporal bone trauma, hemorrhage, or tumor. This inflammation (regardless of the etiology) disrupts the transmission of sensory information from the ear to the brain. Labyrinthitis ossificans is the pathological ossification of the membranous labyrinthine spaces in response to an insult to the inner ear involving membranous labyrinth or the endosteum of the otic capsule. Herein, we present a case of a 67-year-old female with progressive bilateral sensorineural hearing loss and positional vertigo.


Molecular Evolution of Apolipoprotein Multigene Family and the Original Functional Properties of Serum Apolipoprotein (LAL2) in Lampetra japonica.
Apolipoprotein (APO) genes represent a large family of genes encoding various binding proteins associated with plasma lipid transport. Due to the long divergence history, it remains to be confirmed whether these genes evolved from a common ancestor through gene duplication and original function, and how this evolution occurred. In this study, based on the phylogenetic tree, sequence alignment, motifs, and evolutionary analysis of gene synteny and collinearity, APOA, APOC, and APOE in higher vertebrates may have a common ancestor, lamprey serum apolipoprotein LAL1 or LAL2, which traces back to 360 million years ago. Moreover, the results of immunofluorescence, immunohistochemistry, and flow cytometry show that LAL2 is primarily distributed in the liver, kidney, and blood leukocytes of lampreys, and specifically localized in the cytoplasm of liver cells and leukocytes, as well as secreted into sera. Surface plasmon resonance technology demonstrates that LAL2 colocalizes to breast adenocarcinoma cells (MCF-7) or chronic myeloid leukemia cells (K562) associated with lamprey immune protein (LIP) and further enhances the killing effect of LIP on tumor cells. In addition, using quantitative real-time PCR (Q-PCR) and western blot methods, we found that the relative mRNA and protein expression of lal2 in lamprey leukocytes and sera increased significantly at different times after stimulating with Staphylococcus aureus, Vibrio anguillarum, and Polyinosinic-polycytidylic acid (Poly I:C). Moreover, LAL2 was found to recognize and bind to gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli) and play an important role in the antibacterial process. All in all, our data reveals a long, complex evolutionary history for apolipoprotein genes under different selection pressures, confirms the immune effect of LAL2 in lamprey sera against pathogens, and lays the foundation for further research regarding biological functions of lamprey immune systems.


Calf vein thrombosis outcomes comparing patients with and without cancer.
Distal or calf deep vein thrombosis (DVT) are said to have low rates of propagation, embolization, and recurrence. The objective of this study was to determine outcomes among cancer patients with calf DVT compared to those without cancer. Consecutive patients with ultrasound confirmed acute calf DVT (3/1/2013-8/10/2019) were assessed for venous thromboembolism (VTE) recurrence and bleeding outcomes compared by cancer status. There were 830 patients with isolated calf DVT; 243 with cancer and 587 without cancer. Cancer patients were older (65.9 ± 11.4 vs. 62.0 ± 15.9 years; p = 0.006), with less frequent recent hospitalization (31.7% vs. 48.0%; p < 0.001), surgery (30.0% vs. 38.0%; p = 0.03), or trauma (3.7% vs. 19.9%; p < 0.001). The four most common cancers included hematologic malignancies (20.6%), lung (11.5%), gastrointestinal (10.3%), and ovarian/GYN (9.1%). Nearly half of patients had metastatic disease (43.8%) and 57% were receiving chemotherapy. VTE recurrence rates were similar for patients with (7.1%) and without cancer (4.0%; p = 0.105). Major bleeding (6.3% vs. 2.3%; p = 0.007) were greater for cancer patients while clinical relevant non major bleeding rates did not differ (7.1% vs. 4.6%; p = 0.159). In this retrospective analysis, cancer patients with calf DVT have similar rates of VTE recurrence but higher major bleeding outcomes compared to patients without cancer.


S-layer protein production by Corynebacterium strains is dependent on the carbon source.
Three strains of Corynebacterium producing various amounts of PS2 S-layer protein were studied. For all strains, more PS2 was produced if the bacteria were grown in minimal medium supplemented with lactate than if they were grown in minimal medium supplemented with glucose. The consumption of substrate and PS2 production was studied in cultures with mixed carbon sources. It was found that the inhibitory effect of glucose consumption was stronger than the stimulatory effect of lactate in one strain, but not in the other two strains. The regulation of gene expression involved in S-layer formation may involve metabolic pathways, which probably differ between strains. S-layer organization was also studied by freeze-fracture electron microscopy. It was found that low levels of PS2 production correlated with the partial covering of the cell surface by a crystalline array. Finally, it was found that PS2 production was mainly regulated by changes in gene expression and that secretion was probably not a limiting step in PS2 accumulation.


Bilateral Erector Spinae Blocks Decrease Perioperative Opioid Use After Pediatric Cardiac Surgery.
The present study examined the feasibility and efficacy of continuous bilateral erector spinae blocks for post-sternotomy pain in pediatric cardiac surgery. Prospective cohort study; patients were retrospectively matched 1:2 to control patients. Conditional logistic regression was used to compare dichotomous outcomes, and generalized linear models were used for continuous measures, both accounting for clusters. Quaternary children's hospital, university setting. The study comprised 10 children ages five-to-17 years undergoing elective cardiac surgery requiring cardiopulmonary bypass. Ultrasound-guided bilateral erector spinae blocks at the conclusion of the cardiac surgical procedure, with postoperative infusion of ropivacaine until chest tube removal. Postoperative management otherwise followed standardized guidelines. Patient characteristics were similar in the two groups. The median time to completion of the bilateral blocks was 16.0 minutes (interquartile range [IQR] 14.8-19.3), and no major adverse events were identified. Pain scores were low in both groups. Postoperative opioid use at 48 hours, rendered as oral morphine equivalents, was significantly reduced in the patients receiving the blocks. Cluster-adjusted squared-root-transformed means ± standard error were 0.89 ± 0.06 mg/kg for patients receiving the blocks versus 1.05 ± 0.06 mg/kg for control patients (p = 0.04; raw medians 0.81 [IQR 0.41-1.04] v 1.10 [IQR 0.78-1.35] mg/kg, respectively). There were no differences in recovery metrics, length of stay, or complications. Bilateral erector spinae blocks were associated with a reduction in opioid use in the first 48 hours after pediatric cardiac surgery compared with a matched cohort from the enhanced recovery program. Larger studies are needed to determine whether this can result in an improvement in recovery and patient satisfaction.


Multimeric structure enables the acceleration of KaiB-KaiC complex formation induced by ADP/ATP exchange inhibition.
Circadian clocks tick a rhythm with a nearly 24-hour period in a variety of organisms. In the clock proteins of cyanobacteria, KaiA, KaiB, and KaiC, known as a minimum circadian clock, the slow KaiB-KaiC complex formation is essential in determining the clock period. This complex formation, occurring when the C1 domain of KaiC hexamer binds ADP molecules produced by the ATPase activity of C1, is considered to be promoted by accumulating ADP molecules in C1 through inhibiting the ADP/ATP exchange (ADP release) rather than activating the ATP hydrolysis (ADP production). Significantly, this ADP/ATP exchange inhibition accelerates the complex formation together with its promotion, implying a potential role in the period robustness under environmental perturbations. However, the molecular mechanism of this simultaneous promotion and acceleration remains elusive because inhibition of a backward process generally slows down the whole process. In this article, to investigate the mechanism, we build several reaction models of the complex formation with the pre-binding process concerning the ATPase activity. In these models, six KaiB monomers cooperatively and rapidly bind to C1 when C1 binds ADP molecules more than a given threshold while stabilizing the binding-competent conformation of C1. Through comparison among the models proposed here, we then extract three requirements for the simultaneous promotion and acceleration: the stabilization of the binding-competent C1 by KaiB binding, slow ADP/ATP exchange in the binding-competent C1, and relatively fast ADP/ATP exchange occurring in the binding-incompetent C1 in the presence of KaiB. The last two requirements oblige KaiC to form a multimer. Moreover, as a natural consequence, the present models can also explain why the binding of KaiB to C1 reduces the ATPase activity of C1.


Developing an epoetin alfa medication protocol to improve patient care and foster collaboration.
This article describes the process undertaken by the nursing staff, management staff, and education department of a community hospital-based outpatient dialysis unit to address the numerous issues related to the management of anemia in their dialysis population. Through good observations and assessments made by the nursing staff, major problems related to anemia management were identified. As a result, staff members developed a medication protocol and a tracking tool to better manage the anemia associated with chronic renal failure. Evaluation of this protocol and tracking tool demonstrated improvement in two clinical patient outcomes and two unit management outcomes.


Clinical Phenotypes of Heart Failure With Preserved Ejection Fraction to Select Preclinical Animal Models.
At least one-half of the growing heart failure population consists of heart failure with preserved ejection fraction (HFpEF). The limited therapeutic options, the complexity of the syndrome, and many related comorbidities emphasize the need for adequate experimental animal models to study the etiology of HFpEF, as well as its comorbidities and pathophysiological changes. The strengths and weaknesses of available animal models have been reviewed extensively with the general consensus that a "1-size-fits-all" model does not exist, because no uniform HFpEF patient exists. In fact, HFpEF patients have been categorized into HFpEF phenogroups based on comorbidities and symptoms. In this review, we therefore study which animal model is best suited to study the different phenogroups-to improve model selection and refinement of animal research. Based on the published data, we extrapolated human HFpEF phenogroups into 3 animal phenogroups (containing small and large animals) based on reports and definitions of the authors: animal models with high (cardiac) age (phenogroup aging); animal models focusing on hypertension and kidney dysfunction (phenogroup hypertension/kidney failure); and models with hypertension, obesity, and type 2 diabetes mellitus (phenogroup cardiometabolic syndrome). We subsequently evaluated characteristics of HFpEF, such as left ventricular diastolic dysfunction parameters, systemic inflammation, cardiac fibrosis, and sex-specificity in the different models. Finally, we scored these parameters concluded how to best apply these models. Based on our findings, we propose an easy-to-use classification for future animal research based on clinical phenogroups of interest.


The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β.
TGF-β's multipotent cellular effects and their relations are critical for TGF-β's pathophysiological functions. However, these effects may appear to be paradoxical in understanding TGF-β's functions. Apoptosis and epithelial-mesenchymal transition (EMT) are two fundamental events that are deeply linked to various physiological and disease-related processes. These two major cellular fates are subtly regulated and can be potently stimulated by TGF-β, which profoundly contribute to the biological roles of TGF-β. Moreover, these two events are also indirectly and directly correlated with TGF-β-mediated growth inhibition and are relevant to the current understanding of the roles of TGF-β in tumorigenesis and cancer progression. Although TGF-β-induced apoptosis and EMT can be singly independent cellular events, they can also be mutually exclusive but interrelated concomitant events in various cases. Thus, the modulation of apoptosis and EMT is essential for the seemingly paradoxical functions of TGF-β. However, the concomitant effect of TGF-β on apoptosis and EMT, the balance and regulated alterations of them are still been ignored or underestimated. This review focuses on the TGF-β-induced concomitant apoptosis and EMT. We aim to provide an insight in understanding their significance, balance, and modulation in TGF-β-mediated biological functions.


Alfaxalone induction dose following administration of medetomidine and butorphanol in the dog.
To determine in dogs the effects of medetomidine and butorphanol, alone and in combination, on the induction dose of alfaxalone and to describe the induction and intubation conditions. Prospective, randomized, blinded clinical trial. Eighty-five client-owned dogs (ASA 1 or 2). Subjects were block randomized to treatment group according to temperament. The treatment groups were: medetomidine 4 microg kg(-1) (M), butorphanol 0.1 mg kg(-1) (B), or a combination of both (MB), all administered intramuscularly. After 30 minutes, a sedation score was assigned, and alfaxalone 0.5 mg kg(-1) was administered intravenously over 60 seconds by an observer who was unaware of treatment group. Tracheal intubation conditions were assessed and, if tracheal intubation was not possible after 20 seconds, further boluses of 0.2 mg kg(-1) were given every 20 seconds until intubation was achieved. Induction dose and adverse events (sneezing, twitching, paddling, excitement, apnoea and cyanosis) were recorded; induction quality and intubation conditions were scored and recorded. The mean dose of alfaxalone required for induction was similar for groups M and B: 1.2 +/- 0.4 mg kg(-1). The mean dose requirement for group MB (0.8 +/- 0.3 mg kg(-1)) was lower than groups M and B (p < 0.0001). Induction dose was not influenced by temperament or level of sedation. Induction and intubation scores did not differ between treatment groups. Adverse events were noted in 16 dogs; there was no association with treatment group, temperament or level of sedation. Medetomidine and butorphanol administered in combination reduce the anaesthetic induction dose of alfaxalone compared to either agent alone. This difference should be taken into account when using this combination of drugs in a clinical setting.


Pharmacodynamics of bisphosphonates in arthritis.
Inflammatory arthritis is a group of autoimmune diseases characterized by chronic inflammation of the joints. Rheumatoid arthritis, the most common form of arthritis, is associated with local joint destruction and systemic bone loss. Osteoclasts, the only cells of the body able to resorbe bone, are key players in these two types of bone loss. Bisphosphonates are analogs of pyrophosphate that inhibit osteoclast action and bone resorption. They are indicated in pathology associated with excess resorption. Besides their effect on bone they also exhibit extra-osseous properties, acting on tumor cells, inflammation and angiogenesis. As a result, they have been trialed in the context of arthritis. It is now clear that they do not have any significant direct effect on disease activity or pain. If their indication in the prevention of glucocorticoid-induced osteoporosis is clear, any beneficial effects on bone erosions are still controversial but interesting preliminary results warrant further investigations.


Changes in oxytocin immunoreactivity and mRNA expression in the sheep brain during pregnancy, parturition and lactation and in response to oestrogen and progesterone.
The effects of pregnancy, parturition and lactation and exogenous treatments with oestradiol and progesterone on oxytocin (OXY) immunoreactivity and gene expression in the sheep brain were investigated. Immunocytochemistry was used to demonstrate that increased OXY-immunoreactivity occurred in cells of the paraventricular (PVN) and supraoptic nuclei (SON), the bed nucleus of the stria terminalis (BNST), the anterior commissural nuclei (ACN) and the periventricular part of the medial preoptic area (PvMP). Oxytocin immunoreactive terminals were also seen in the accessory olfactory nucleus, the glomerular and peri-glomerular layers of the olfactory bulb, the lateral septum, the zona incerta and the pars compacta of the substantia nigra. Compared to ovariectomized and late pregnant animals, the intensity of immunoreactivity was increased in all of these oxytocinergic elements at parturition, during lactation and following exogenous treatment with oestradiol. The OXY-immunoreactivity was also more intense in late pregnant animals compared to ovariectomized ones. Quantitative in situ hybridization histochemistry showed that cells in the PVN, SON, BNST and PvMP all showed significantly increased expression of OXY mRNA in animals at parturition and during lactation compared to late pregnant or ovariectomized animals. Expression levels in late pregnant animals were also significantly higher than in ovariectomized ones. Progesterone treatment significantly increased OXY mRNA in the PVN, SON, BNST and PvMP whereas oestradiol treatment was only effective in the PVN, BNST and PvMP. Combined treatment with these steroids did not significantly increase OXY mRNA levels in comparison with their administration alone. These results show that OXY-immunoreactivity and mRNA expression are at their highest in the sheep brain when maternal behaviour is induced. The increased synthesis/storage of the peptide at parturition may be due to changes in circulating concentrations of both progesterone and oestradiol during late pregnancy.


CCT6A, a novel prognostic biomarker for Ewing sarcoma.
Ewing sarcoma (ES), the second most prevalent bone malignant tumor has no widely known prognostic biomarker. Earlier studies have suggested that chaperonin containing TCP1 complex 6A (CCT6A), which encodes a molecular protein chaperone, is involved in the pathogenesis of many cancers. However, there are no known reports providing clear evidence of its role in ES pathogenesis. We performed a bioinformatic analysis of 32 ES specimens from the GSE17618 dataset concentrating on the differences in gene expression, OS, event-free survival (EFS) in the different subgroups. Immunohistochemical studies were also performed to identify the expression levels of selected genes in ES and immediate paracancerous tissues. After 3 screenings, CCT6A was identified to be highly correlated with ES prognosis. Our survival analysis revealed a low overall survival (OS) for high CCT6A expression (P-value = .024). Our Cox regression analysis identified CCT6A expression, lEFS, and age were strongly associated with prognosis of ES. Our multivariate Cox regression analysis shows that CCT6A (P-value = .015), age (P-value = .026), and EFS (P-value = .002) were independent poor prognostic biomarkers. Our immunohistochemical analysis showed that the expression levels of CCT6A were significantly higher in ES tissues compared to the paracancerous tissues. From the results of our study, we identified the expression levels of CCT6A to be strongly associated with prognosis of ES. Thus, the expression levels of the CCT6A gene could serve as a biomarker for the prediction of ES prognosis.


Reversible fluorescence quenching by micelle selective benzophenone-induced interactions between brij micelles and polyacrylic acids: implications for chemical sensors.
The fluorescence response of pyrene has been studied in the presence of nonionic brij micelles and poly(acrylic acid) (PAA) with benzophenone (BP) as a neutral hydrophobic quencher. Pyrene emission is quenched ("off" state) in the presence of BP in brij 35 (polyoxyethylene-23-lauryl ether) and brij 56 (polyoxyethylene-10-cetyl ether) micelles. Quenched pyrene emission is selectively recovered ("on" state) for brij 35 micelles with the addition of PAA (starting conc 2.0 x 10(-5) M). Due to the interaction of PAA and brij 35 micelles and the relatively easier accessibility of PAA polymer chains near the bulky polyoxyethylene chain of brij 35 micelles, the chances of BP partition inside the hydrophobic polymer coil are more compared to brij 56 micelles. The PAA sensing ability of the "brij 35:pyrene:BP" system is dependent on the molecular weight (M) of the polymer. Fluorescence recovery has been observed with PAA (M approximately 150000) and complete recovery has been recorded with high M of PAA (M approximately 450000); however, no fluorescence change is observed in the presence of low M of PAA (M approximately 2000). In solution, such selective reversible fluorescence quenching has the potential for a new class of highly sensitive chemical sensor systems.


Synchronous Pseudomonas Infection in Nose and Maxillery Sinus After Septorhinoplasty.
A 50-year-old patient who underwent secondary rhinoplasty 1 year after the operation presented with signs of localized infection on the postoperative twentieth day. An abscess due to Pseudomonas aeruginosa was detected in the nose and maxillary sinus. The infection regressed after surgical debridement combined with intravenous antibiotic therapy.Pseudomonas infection has been reported in only six patients after septorhinoplasty. Rhinoplasty was combined with other aesthetic procedures in three patients. The mean time of onset of complaints was 33.25 days. The most common complaint was pain. The mean time to complete regression of complaints after treatment was 44.5 days.Pseudomonas infection risk is especially increased in patients with combined surgical procedures and complicated revision rhinoplasty surgery. Careful examination of the patient, early and aggressive therapy, and surgical debridement are essential. The treatment of infection is incision and drainage of the affected areas. Antibiotic therapy followed by sensitivity-specific regimens should be administered."


Does the Overall Survival of the Resectable Periampullary Carcinomas Correlate with High Expression of p53 and ki67?
Introduction: Periampullary carcinomas represent a group of tumors that develop in a complex area, implying different anatomical structures. The most common histological type of periampullary carcinomas is the adenocarcinoma. The pancreatic type of periampullary adenocarcinomas has the worst prognosis. Immunohistochemical markers, such as ki-67 and p53, can be used in predicting survival. Material and method: we selected the patients with periampullary adenocarcinomas, intestinal or biliopancreatic type, with resectable tumors, and we performed immunohistochemical stains for ki-67 and p53 markers. The overall survival was analyzed according to the expression of immunohistochemical markers, TNM staging, tumor grade and perineural invasion. Results: Sixty-seven patients were included in the study. The median overall survival for the whole cohort was 12 months, with a 2-year survival rate of 25%. High rate of tumor proliferation (ki67 more than 80%) was significantly associated with shorter overall survival (median survival 3 months compared with 17 months for the group with ki67 index less than 80%). A high expression of p53 protein has been associated with low overall survival. The low survival was associated with poorly differentiated tumor grade and lymph node status. Conclusion: Both immunohistochemical expression of ki67 and p53 can be used as prognostic and predictive factors for overall survival of patients with resectable periampullary adenocarcinomas.