Dietary arachidonic acid increases eicosanoid production in the presence of equal amounts of dietary eicosapentaenoic acid.
Previously, we demonstrated that dietary n-3 PUFA (1.5%, w/w) effectively inhibited the production of eicosanoids derived from tissue arachidonic acid (AA) (Whelan et al., 1991). More recently, we also reported that dietary AA (1.0%, w/w) significantly augmented platelet and macrophage eicosanoid production in vitro (Whelan et al., 1993). This present study was designed to investigate the antithetic relationship of dietary AA and EPA on eicosanoid production in vivo. Forty-nine CD-1 male mice were randomly divided into four dietary groups. Identical diets were supplemented with ethyl esters (1.5%, w/w) of the following fatty acids: oleic acid (OA), AA, EPA or AA + EPA (A + E). After four weeks on diet, peritoneal cells were stimulated in vivo with opsonized zymosan and analyzed for eicosanoid production (PGE2, 6-keto-PGF1a, TXB2, LTE4, LTB4, LTE5 and LTB5). The pooled eicosanoid production in the AA group was 41% and 300% higher compared to the OA (control) and EPA groups, respectively. Pooled eicosanoid production in the EPA group was 47% that of the OA group. When equivalent amounts of AA and EPA (AA + EPA) were included in the diet, the pooled eicosanoid production was 29% and 274% higher compared to the OA and EPA groups, respectively. These data demonstrate that dietary AA (1) enhances eicosanoid production in vivo and (2) abrogates virtually all of the effects observed with dietary EPA when both are included in the diet. The clinical implications of dietary AA as modulated by increased eicosanoid production could be significant, particularly when n-3 PUFA are used to reduce eicosanoid-mediated events.


A herbal formula, SYKT, reverses doxorubicin‑induced myelosuppression and cardiotoxicity by inhibiting ROS‑mediated apoptosis.
Doxorubicin (DOX) is an antineoplastic drug widely used for the treatment of various types of cancer; however, it can induce severe side effects, such as myelosuppression and cardiotoxicity. Sanyang Xuedai (SYKT) is a natural medicine originating from an ancient prescription of the Dai nationality in Southwest China. With eight Chinese herbal medicines, including sanguis draconis, radix et rhizoma notoginseng, radix et rhizoma glycyrrhizae and radix angelicae sinensis as the primary ingredients, SYKT has been reported to possess numerous biological functions. The present study investigated whether SYKT can confer protection against DOX‑induced myelosuppression and cardiotoxicity, and explored the potential mechanism involved. Mice were treated with DOX, SYKT or a combination of the two; hematopoietic functions were assessed by measuring the number of peripheral blood cells, cluster of differentiation CD34+/CD44+ bone marrow cells and apoptotic cells. Myocardial enzymes, including aspartate aminotransferase, lactate dehydrogenase, creatine kinase (CK) and its isoform CK‑MB, were assessed using a biochemical analyzer. The apoptotic rate of cardiomyocytes was assessed using flow cytometry. Histopathological analysis was conducted using hematoxylin‑eosin staining. Intracellular reactive oxygen species (ROS) production was evaluated using a dichlorofluorescein intensity assay. The mice treated with DOX exhibited a reduced survival rate, reduced peripheral blood and CD34+/CD44+ cell counts, elevated myocardial enzymes and apoptotic indices in bone marrow cells and cardiomyocytes, all of which were effectively prevented by SYKT co‑administration. Furthermore, bone marrow cells and myocytes from mice treated with DOX demonstrated increased dichlorofluorescein intensity, which was attenuated by SYKT. Notably, SYKT did not interfere with the effects of DOX on tumor volume or the induction of tumor cell apoptosis in tumor‑bearing mice. The present study indicated that SYKT may counteract DOX‑induced myelosuppression and cardiotoxicity through inhibiting ROS‑mediated apoptosis. These findings suggested that SYKT may have potential as a means to counteract the potentially fatal hematopoietic and cardiac complications associated with DOX treatment.


Multiple time-frequency curve extraction Matlab code and its application to automatic bearing fault diagnosis under time-varying speed conditions.
Vibration signal analysis is an important technique for bearing fault diagnosis. For bearings operating under constant rotational speed, faults can be diagnosed in the frequency domain since each type of fault has a specific Fault Characteristic Frequency (FCF), which is proportional to the shaft rotational speed. However, bearings often operate under time-varying speed conditions. Additionally, the measurement of the time-varying rotational speed requires instruments, such as tachometers, which leads to extra cost and installation. With the development of time-frequency analysis, the time-varying FCFs manifest as curves in the Time-Frequency Representation (TFR). It has been shown that extracting multiple time-frequency curves from the TFR and then identifying the Instantaneous Fault Characteristic Frequency (IFCF) and Instantaneous Shaft Rotational Frequency (ISRF), bearing faults can be automatically diagnosed under time-varying speed conditions without using tachometers. However, the existing method used to identify the IFCF and the ISRF may lead to inaccurate results. In this study, the complete MATLAB© codes and a more reliable approach to use Multiple Time-Frequency Curve Extraction (MTFCE) for automatic bearing fault diagnosis under time-varying speed conditions are presented. •A Multiple time-frequency curve extraction (MTFCE) Matlab code is presented to extract multiple curves from the TFR.•Custom Matlab code for automatic bearing fault diagnosis under time-varying speed conditions without using tachometer data via the MTFCE is given and explained.•A new parameter, the allowable variance of the curve-to-curve ratio, is proposed to identify the IFCF and ISRF more reliably.


A mobile robots experimental environment with event-based wireless communication.
An experimental platform to communicate between a set of mobile robots through a wireless network has been developed. The mobile robots get their position through a camera which performs as sensor. The video images are processed in a PC and a Waspmote card sends the corresponding position to each robot using the ZigBee standard. A distributed control algorithm based on event-triggered communications has been designed and implemented to bring the robots into the desired formation. Each robot communicates to its neighbors only at event times. Furthermore, a simulation tool has been developed to design and perform experiments with the system. An example of usage is presented.


Relationship between the molecular size of poly I-poly C and its biological activity.
Seven polyinosinic-polycytidylic acid (poly I-poly C) preparations, ranging from 4.2 S to 21.2 S, prepared from various sizes of polyinosinate and polycytidylate, were examined for toxicity and interferon-inducing activity in mice. The increase in size of poly I-poly C was accompanied by increases both in the maximal amount of interferon produced and in the length of persistence of a high level of interferon in plasma. Toxicity of poly I-poly C was proportional to the molecular size within the range of 8 S to 16 S. The amount of interferon induced by 1/5 LD50 of poly I-poly C depended on the size of the inducer, being increasingly lower with progressively smaller sizes. Next, activities of poly I-poly C in culture cells were examined. The resistance-inducing activity of poly I-poly C in primary chick embryo cells (CEC) increased with the size of the inducer (4.2 S to 11.6 S), whereas the activity in L cells was not so markedly dependent upon its molecular size as in CEC. In the presence of calf serum during induction of resistance the activity was lowered. The activities of preparations with small molecular sizes were affected by calf serum more markedly than those of large molecular sizes. The interferon-inducing activity in RK13 was not appreciably influenced by the size of poly I-poly C, especially in the presence of DEAE-dextran, while the activity in L cells was markedly dependent upon the size of the inducer. These results suggest that the influence of the molecular size of poly I-poly C upon the resistance-inducing and interferon-inducing activities varies among different kinds of cells, and alters in the presence of serum or DEAE-dextran.


Does the current fungicide risk assessment provide sufficient protection for key drivers in aquatic ecosystem functioning?
The level of protection provided by the present environmental risk assessment (ERA) of fungicides in the European Union for fungi is unknown. Therefore, we assessed the structural and functional implications of five fungicides with different modes of action (azoxystrobin, carbendazim, cyprodinil, quinoxyfen, and tebuconazole) individually and in mixture on communities of aquatic hyphomycetes. This is a polyphyletic group of fungi containing key drivers in the breakdown of leaf litter, governing both microbial leaf decomposition and the palatability of leaves for leaf-shredding macroinvertebrates. All fungicides impaired leaf palatability to the leaf-shredder Gammarus fossarum and caused structural changes in fungal communities. In addition, all compounds except for quinoxyfen altered microbial leaf decomposition. Our results suggest that the European Union's first-tier ERA provides sufficient protection for the tested fungicides, with the exception of tebuconazole and the mixture, while higher-tier ERA does not provide an adequate level of protection for fungicides in general. Therefore, our results show the need to incorporate aquatic fungi as well as their functions into ERA testing schemes to safeguard the integrity of aquatic ecosystems.


Applying Logistic Regression to Detect Differential Item Functioning in Multidimensional Data.
Conventional differential item functioning (DIF) approaches such as logistic regression (LR) often assume unidimensionality of a scale and match participants in the reference and focal groups based on total scores. However, many educational and psychological assessments are multidimensional by design, and a matching variable using total scores that does not reflect the test structure may not be good practice in multidimensional items for DIF detection. We propose the use of all subscores of a scale in LR and compare its performance with alternative matching methods, including the use of total score and individual subscores. We focused on uniform DIF situation in which 250, 500, or 1,000 participants in each group answered 21 items reflecting two dimensions, and the 21st item was the studied item. Five factors were manipulated in the study: (a) the test structure, (b) numbers of cross-loaded items, (c) group differences in latent abilities, (d) the magnitude of DIF, and (e) group sample size. The results showed that, when the studied item measured a single domain, the conventional LR incorporating total scores as a matching variable yielded inflated false positive rates (FPRs) when two groups differed in one latent ability. The situation worsened when one group had a higher ability in one domain and lower ability in another. The LR using a single subscore as the matching variable performed well in terms of FPRs and true positive rates (TPRs) when two groups did not differ in either one latent ability or differed in one latent ability. However, this approach yielded inflated FPRs when two groups differed in two latent abilities. The proposed LR using two subscores yielded well-controlled FPRs across all conditions and yielded the highest TPRs. When the studied item measured two domains, the use of either the total score or two subscores worked well in the control of FPRs and yielded similar TPRs across conditions, whereas the use of a single subscore resulted in inflated FPRs when two groups differed in one or two latent abilities. In conclusion, we recommend the use of multiple subscores to match subjects in DIF detection for multidimensional data.


A tail of two voltages: Proteomic comparison of the three electric organs of the electric eel.
The electric eel (Electrophorus electricus) is unusual among electric fishes because it has three pairs of electric organs that serve multiple biological functions: For navigation and communication, it emits continuous pulses of weak electric discharge (<1 V), but for predation and defense, it intermittently emits lethal strong electric discharges (10 to 600 V). We hypothesized that these two electrogenic outputs have different energetic demands reflected by differences in their proteome and phosphoproteome. We report the use of isotope-assisted quantitative mass spectrometry to test this hypothesis. We observed novel phosphorylation sites in sodium transporters and identified a potassium channel with unique differences in protein concentration among the electric organs. In addition, we found transcription factors and protein kinases that show differential abundance in the strong versus weak electric organs. Our findings support the hypothesis that proteomic differences among electric organs underlie differences in energetic needs, reflecting a trade-off between generating weak voltages continuously and strong voltages intermittently.


Novel Convenient Approach to 6-, 7-, and 8-Numbered Nitrogen Heterocycles Incorporating Endocyclic Sulfonamide Fragment.
A new effective method for the construction of nitrogen heterocycles incorporating endocyclic pharmacophore sulfonamide fragment, based on the use of easy accessible N-(chlorosulfonyl)imidoyl chloride, CCl3C(Cl)=NSO2Cl (1), has been developed. Thus, a reaction of 1 as bielectrophilic 1,3-C-N-S reagent with benzylamines that act as 1,4-N-C-C-C binucleophiles, affords respective 1,2,4-benzothiadiazepine-1,1-dioxides. On the other hand, 1 reacts with alkenyl amines with the formation of respective N-alkenyl amidines undergoing Lewis acids initiated intramolecular cyclization to afford derivatives of 1,2,4-thiadiazines and 1,2,4-thiadiazocines bearing a halomethyl group able for further functionalization. The first examples of electrophilic heterocyclization of the chlorosulfonyl group onto an alkenyl or alkynyl group have been revealed.


Successful treatment of intrauterine cytomegalovirus infection with an intraventricular cyst in a dichorionic diamniotic twin gestation using cytomegalovirus immunoglobulin.
Congenital cytomegalovirus (CMV) infection is the leading cause of severe congenital abnormalities. CMV immunoglobulin (CMVIG) may lower risk for symptomatic disease in congenital CMV infection. In a twin pregnancy, only one fetus shows CMV infection, raising a dilemma about intervention since the uninfected fetus would be exposed to treatment unnecessarily. CMVIG (2 × 200 U/kg) was given due to high viral load and development of an intraventricular cyst. The cyst growth plateaued, no other brain damage developed, and at 8 months, the infant was symptom-free. CMVIG appears appropriate to treat intrauterine CMV infection in this setting.


The concept of the epileptogenic zone: a modern look at Penfield and Jasper's views on the role of interictal spikes.
In modern times, the determination of the epileptogenic zone demands a sophisticated combination of neurophysiological and neuroimaging tools. Historically however, the concept of the epileptogenic zone was based on and has evolved from the recording of interictal spikes, both in the scalp electroencephalogram (EEG) and, particularly, in the acute electrocorticogram (ECoG). Because the role of interictal spikes is still not always clear in the decision-making process of epilepsy surgery, the relevance of these spikes in the definition of the epileptogenic zone is reviewed here, starting with the pioneering work of the Montreal school.


Machine-learning-based radiomics identifies atrial fibrillation on the epicardial fat in contrast-enhanced and non-enhanced chest CT.
The purpose is to establish and validate a machine-learning-derived radiomics approach to determine the existence of atrial fibrillation (AF) by analyzing epicardial adipose tissue (EAT) in CT images. Patients with AF based on electrocardiographic tracing who underwent contrast-enhanced (n = 200) or non-enhanced (n = 300) chest CT scans were analyzed retrospectively. After EAT segmentation and radiomics feature extraction, the segmented EAT yielded 1691 radiomics features. The most contributive features to AF were selected by the Boruta algorithm and machine-learning-based random forest algorithm, and combined to construct a radiomics signature (EAT-score). Multivariate logistic regression was used to build clinical factor and nested models. In the test cohort of contrast-enhanced scanning (n = 60/200), the AUC of EAT-score for identifying patients with AF was 0.92 (95%CI: 0.84-1.00), higher than 0.71 (0.58-0.85) of the clinical factor model (total cholesterol and body mass index) (DeLong's p = 0.01), and higher than 0.73 (0.61-0.86) of the EAT volume model (p = 0.01). In the test cohort of non-enhanced scanning (n = 100/300), the AUC of EAT-score was 0.85 (0.77-0.92), higher than that of the CT attenuation model (p < 0.001). The two nested models (EAT-score+volume and EAT-score+volume+clinical factors) for contrast-enhanced scan and one (EAT-score+CT attenuation) for non-enhanced scan showed similar AUCs with that of EAT-score (all p > 0.05). EAT-score generated by machine-learning-based radiomics achieved high performance in identifying patients with AF. A radiomics analysis based on machine learning allows for the identification of AF on the EAT in contrast-enhanced and non-enhanced chest CT.


SecretePipe: a screening pipeline for secreted proteins with competence to identify potential membrane-bound shed markers.
The identification of secreted protein markers has been receiving great attention as part of the trend toward noninvasive biomarker discovery. In addition, certain cell membrane proteins are known to be released into the extracellular milieu via ectodomain shedding. As membrane proteins play an essential role in signaling pathways and because most of the cancer biomarkers approved by the FDA today are membrane shed proteins, a tool that can correctly predict these class shed proteins is valuable. In this study, an in-house predictor, ShedP, was developed to predict the ectodomain shedding events of membrane proteins. ShedP is the first computational method to our knowledge to allow shed membrane protein prediction. By integrating ShedP with other state-of-the-art predictors, a screening pipeline, SecretePipe, has been created that is able to identify secreted nonmembrane proteins on the basis of signal peptides and to identify released membrane proteins on the basis of ectodomain shedding. The predictive results using secretome data sets revealed that SecretePipe outperformed other state-of-the-art secreted protein predictors. When evaluated against released membrane proteins, SecretePipe performed better than other predictors in identifying membrane-bound released proteins due to the presence of ShedP. SecretePipe showed a great potential in assisting the identification of membrane-bound shed markers in biomarker discovery.


Effect of the preovulatory gonadotropin surge on matrix metalloproteinase (MMP)-14, MMP-2, and tissue inhibitor of metalloproteinases-2 expression within bovine periovulatory follicular and luteal tissue.
The matrix metalloproteinases (MMPs) have been implicated in the ovulatory process, but the specific roles of individual MMPs are unclear. This study examined the effect of the preovulatory gonadotropin surge on localization and regulation of MMP-2, MMP-14, and tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA and MMP-2 and TIMP-2 activity in bovine preovulatory follicles and new corpora lutea (CL). Ovaries containing ovulatory follicles or new CL were collected at approximately 0, 6, 12, 18, 24, and 48 h (CL) after a GnRH-induced gonadotropin surge. Messenger RNA for TIMP-2 and MMP-14 increased within 6 and 24 h of the gonadotropin surge, respectively, whereas MMP-2 mRNA was constitutively expressed. Activity for MMP-2 in follicular fluid and follicle homogenates was not changed, but follicular fluid TIMP-2 activity increased in response to the gonadotropin surge. Messenger RNA for MMP-2 was localized to the thecal layer of bovine preovulatory follicles, whereas MMP-14 mRNA was localized primarily to the thecal layer and adjacent ovarian stroma. Expression of MMP-14 was also observed in the granulosal layer after the gonadotropin surge. In contrast, TIMP-2 mRNA was localized predominantly to the granulosal layer with intense expression in the antral portion of the granulosal layer in response to the gonadotropin surge. These data support the hypothesis that increased expression of MMP-14 and TIMP-2 may help regulate follicle rupture and/or the ovulatory follicle-CL transition in cattle.


Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics.
To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism. This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids. After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 25 mg daily) and 500 ± 278 ng in those men treated with transdermal testosterone. These values were higher than Day 1 values but not different from each other (p = 0.23, T-test). All three doses of enclomiphene increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups. Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.


GO-Functionalized Large Magnetic Iron Oxide Nanoparticles with Enhanced Colloidal Stability and Hyperthermia Performance.
Because of their high magnetization and suitable biocompatibility, iron-oxide nanoparticles (IONPs) have been widely employed in various biomedical applications, including magnetic hyperthermia for cancer treatment. In many cases, the colloidal stability requirement will limit the usage of ferromagnetic particles that are usually associated with good magnetic response. To address this challenge, a stable carrier for better colloidal stability regardless of the size or shape of the IONPs while at the same time providing enhanced magnetic hyperthermia heating performance is required. In this work, IONPs of different sizes (4, 8, 20, 45, and 250 nm) were engineered to reside in the graphene oxide (GO) sheet carrier, which were stable in aqueous solution even in the presence of a strong magnetic field. Out of various IONPs sizes, highest specific absorption rate (SAR) value of 5020 W g-1 was obtained with 45 nm GO-IONPs nanocomposites at a frequency and alternating magnetic field of 400 kHz and 32.5 kA m-1, respectively. The calculated intrinsic loss power (ILP) was 12.21 nH m2 kg-1, which is one of the highest ILP values reported for synthesized IONPs to the best of our knowledge. To enhance the excellent colloidal stability in biological environment, the GO-IONPs nanocomposites can be further grafted with polyethylene glycol (PEG) because agglomeration of pristine GO sheets occurs because of adsorption of cations. High ILP values could be well maintained even after PEG coating. The PEGylated 45 nm GO-IONP showed excellent antitumor efficacy in 4T1-tumor model mice by inhibiting tumor progression within a safe dosage range. Overall, the novel nanocomposite in this work-PEG-GO-IONP-possesses high hyperthermia performance, excellent colloidal stability in biological environment, and availability of functional groups in GO and can be utilized for tagging in various biomedical applications.


Non-fatal overdose among a cohort of active injection drug users recruited from a supervised injection facility.
Non-fatal overdose among injection drug users (IDU) is a source of significant morbidity. Since it has been suggested that supervised injecting facilities (SIF) may increase risk for overdose, we sought to evaluate patterns of non-fatal overdose among a cohort of SIF users. We examined recent non-fatal overdose experiences among participants enrolled in a prospective study of IDU recruited from within North America's first medically supervised safer injecting facility. Correlates of recent non-fatal overdoses were identified using generalized estimating equations (GEE). There were 1,090 individuals recruited during the study period of which 317 (29.08%) were female. At baseline, 638 (58.53%) reported a history of non-fatal overdose and 97 (8.90%) reported at least one non-fatal overdose in the last six months. This proportion remained approximately constant throughout the study period. In the multivariate GEE analysis, factors associated with recent non-fatal overdose included: sex-trade involvement (Adjusted Odds Ratio [AOR]: 1.45 [95% Confidence Interval [CI] 1.07-1.99], p = 0.02) and public drug use (AOR: 1.50 [95% CI 1.09-2.06]; p = 0.01). Using the SIF for >or= 75% of injections was not associated with recent non-fatal overdose in univariate (Odds Ratio: 1.05, p = 0.73) or multivariate analyses (AOR: 1.01, p = 0.96). The proportion of individuals reporting recent non-fatal overdose did not change over the study period. Our findings indicate that a sub-population of IDU might benefit from overdose prevention interventions. Our findings refute the suggestion that the SIF may increase the likelihood of overdose.


Ureteroarterial fistula with ruptured anastomotic pseudoaneurysm: successful management with vascular exclusion, extra-anatomic bypass and nephrectomy--a case report.
Ureteroarterial fistula is a rare but life-threatening condition most often arising as a consequence of combined vascular and urologic pathology. Only about 70 cases are reported in the English literature. Principles of repair include complete vascular isolation, extra-anatomic bypass, and urinary stream diversion away from major vascular conduits. The case presented herein is only the second reported instance of fistulization to an anastomotic pseudoaneurysm of an iliopopliteal bypass.


A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.
In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode.


Are neuropeptides important in arthritis? Studies on the importance of bombesin/GRP and substance P in a murine arthritis model.
Interference with the effects of neuropeptides may be of potential therapeutic value for the treatment of rheumatoid arthritis (RA). Two neuropeptides that can be discussed in this context are bombesin/gastrin-releasing peptide (BN/GRP) and substance P (SP). In order to obtain new information on the possible importance of these two peptides, the patterns of immunohistochemical expression of BN/GRP and SP and their related receptors in the mouse knee joint from healthy and arthritic mice were examined. Positive staining for GRP receptor and the SP preferred receptor (the neurokinin-1 receptor [NK-1 R]) was observed in articular chondrocytes. On the whole, there was a decrease in immunoreactions for both the GRP- and the NK-1 receptors in the articular chondrocytes in joints exhibiting severe arthritis. Staining for BN/GRP and GRP receptor was seen in the inflammatory infiltrates of the arthritic joints. New evidence for the occurrence of marked effects of BN/GRP concerning both the articular chondrocytes and the inflammatory process is obtained in this study. With these findings and previous observations of neuropeptide expression patterns and functions we discuss the possibility that interventions with the effects of BN/GRP, SP, and other neuropeptides might be worthwhile in RA.


The diagnostic value of serum and urinary NT-proBNP for heart failure.
Serum B-type natriuretic peptide (BNP) and the amino-terminal cleavage product of the prohormone (NT-proBNP) have been shown to be valuable parameters for the diagnosis of heart failure (HF) in the general population. Urinary BNP and NT-proBNP have also been suggested for diagnosis of HF. The present study investigated the diagnostic value of both serum and urinary NT-proBNP in selected groups of controls and patients diagnosed with HF. Creatinine clearance and serum and urinary NT-proBNP were measured in 76 controls and in 47 patients diagnosed with HF (NYHA III and IV). Echocardiography was used to exclude cardiac dysfunction in the control population by the combined normality of left ventricular ejection fraction (LVEF), E/A ratio (echocardiographic early [E] and late, or atrial [A] phases of ventricular filling), deceleration time and LV mass index. All patients diagnosed with HF had LVEF <40%. NT-proBNP measurements in urine samples are subject to high variability. Receiver-operating characteristic area under the curve (AUC) for serum, urinary NT-proBNP and their products were 0.94, 0.72 and 0.93, respectively. Correction of urinary NT-proBNP for urinary creatinine content improved the AUC from 0.72 to 0.80. Negative predictive values for ruling out HF were 0.94, 0.67 and 0.89, respectively. Linear regression analysis revealed that creatinine clearance was more important in determining serum NT-proBNP concentrations than age. Serum NT-proBNP is the best parameter to rule out HF. The product of the serum and urinary concentrations has equal value. Urinary NT-proBNP alone performs rather poorly. Renal function influences NT-proBNP concentrations more than age in this selected population.


[Transient ischemic attack in amyloid angiopathy].
Two cases of cerebral amyloid angiopathy with transient ischemic attacks are reported. Both patients died of cerebral hemorrhage. Transient ischemic attacks seem to having been due to the cerebral angiopathy a disease in which small infarcts are frequently mentioned at post-mortem examination. However only 6 other cases of transient ischemic attacks with cerebral amyloid angiopathy have yet been reported.


Cell-Based Biohybrid Sensor Device for Chemical Source Direction Estimation.
This paper describes a method to estimate the direction from which the signal molecule reaches the sensor by using living cells. In this context, biohybrid sensors that utilize a sophisticated sensing system of cells can potentially offer high levels of chemical-detection sensitivity and selectivity. However, biohybrid-sensor-based chemical-source-direction estimation has not received research attention because the cellular response to chemicals has not been examined in the context of directional information. In our approach, we fabricated a device that can limit the interface between the cell-laden hydrogel and the chemical solution of interest to enhance the time difference over which the chemical solution reaches the cells. Chemical detection by cells that express specific receptors is reflected as the fluorescence of the calcium indicator within the cells. Our device has eight chambers that each house 3D cell-laden collagen hydrogels facing circularly outward. The device also works as a cover to prevent chemicals from permeating the hydrogel from above. In our study, by observing the time course of the fluorescence emission of each chamber, we were able to successfully estimate the chemical-source direction within an error range of 7-13°. Our results suggest that a combination of microstructure devices embedded with living cells can be used to exploit cell functionalities to yield chemical-source directional information.


The impact of radiotherapy costs on clinical outcomes in breast cancer.
In cost-effective healthcare systems, the cost of services should parallel patient complexity or quality of care. The purpose of this study was to determine whether the cost of radiotherapy correlates with patient-related outcomes among a large cohort of breast cancer patients treated with adjuvant breast radiation. 23,127 women with non-metastatic breast cancer undergoing radiotherapy after breast conservation surgery were identified from the Surveillance, Epidemiology, and End Results database from 2000 to 2009. Medicare reimbursements were used as a proxy for cost of radiotherapy, and Medicare claims were examined to identify local toxicities, and breast cancer-related endpoints. The impact of cost on these outcomes was studied with multivariable Fine-Gray models to account for competing risks. The median cost (and interquartile range) of a course of breast radiation was $8100 ($6700-9700). Increased radiation costs were not associated with the occurrence of treatment-related toxicities (all p-values>0.05), ipsilateral breast recurrence (p=0.55), or breast cancer-related mortality (p=0.55). Higher costs for adjuvant radiation in breast cancer were not associated with a decreased risk of patient-related outcomes suggesting inefficiency in Medicare reimbursements. Future efforts should focus on prospective evaluation of alternative payment models for radiotherapy.


Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment.
The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer's disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow-4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis.


Nanorattles or yolk-shell nanoparticles--what are they, how are they made, and what are they good for?
The development of nanotechnology has led to the design of cutting-edge nanomaterials with increasing levels of complexity. Although "traditional" solid, uniform nanoparticles are still the most frequently reported structures, new generations of nanoparticles have been constantly emerging over the last several decades. The outcome of this nano-art extends beyond nanomaterials with alternative compositions and/or morphologies. The current state-of-the-art allows for the design of nanostructures composed of different building blocks that exhibit diverse properties. Furthermore, those properties can be a reflection of either individual features, which are characteristic of a particular building block alone, and/or synergistic effects resulting from interactions between building blocks. Therefore, the unique structures as well as the outstanding properties of nanorattles have attracted increasing attention for possible biomedical and industrial applications. Although these nanoparticles resemble core-shell particles, they have a distinctive feature, which is a presence of a void that provides a homogenous environment for the encapsulated core. In this Review, we give a comprehensive insight into the fabrication of nanorattles. A special emphasis is put on the choice of building blocks as well as the choice of preparation method, because those two aspects further influence properties and thus possible future applications, which will also be discussed.


BnP1, a novel P-I metalloproteinase from Bothrops neuwiedi venom: biological effects benchmarking relatively to jararhagin, a P-III SVMP.
Snake venom metalloproteinases (SVMPs) have been extensively studied and their effects associated with the local bleeding observed in human accidents by viper snakes. Representatives of P-I and P-III classes of SVMPs similarly hydrolyze extracellular matrix proteins or coagulation factors while only P-III SVMPs induce significant hemorrhage in experimental models. In this work, the effects of P-I and P-III SVMPs on plasma proteins and cultures of muscle and endothelial cells were compared in order to enlighten the mechanisms involved in venom-induced hemorrhage. To reach this comparison, BnP1 was isolated from B. neuwiedi venom and used as a weakly hemorrhagic P-I SVMPs and jararhagin was used as a model of potently hemorrhagic P-III SVMP. BnP1 was isolated by size exclusion and anion-exchange chromatographies, showing apparent molecular mass of approximately 24kDa and sequence similarity with other members of SVMPs, which allowed its classification as a group P-I SVMP. The comparison of local effects induced by SVMPs showed that BnP1 was devoid of significant myotoxic and hemorrhagic activities and jararhagin presented only hemorrhagic activity. BnP1 and jararhagin were able to hydrolyze fibrinogen and fibrin, although the latter displayed higher activity in both systems. Using HUVEC primary cultures, we observed that BnP1 induced cell detachment and a decrease in the number of viable endothelial cells in levels comparable to those observed by treatment with jararhagin. Moreover, both BnP1 and jararhagin induced apoptosis in HUVECs while only a small increase in LDH supernatant levels was observed after treatment with jararhagin, suggesting that the major mechanism involved in endothelial cell death is apoptosis. Jararhagin and BnP1 induced little effects on C2C12 muscle cell cultures, characterized by a partial detachment 24h after treatment and a mild necrotic effect as evidenced by a small increase in the supernatants LDH levels. Taken together, our data show that P-I and P-III SVMPs presented comparable effects except for the hemorrhagic activity, suggesting that hydrolysis of coagulation factors or damage to endothelial cells are not sufficient for induction of local bleeding.


Carotid intima-media thickness and the prediction of vascular events.
Carotid intima-media thickness (cIMT) has received interest as a predictor of cardiovascular events in recent years. Use of cIMT in a clinical setting is limited by the variability in measurement and the lack of evidence for its use in clinical risk prediction. This review examines the major studies that have assessed the relationship between cIMT and cardiovascular event risk and discusses the current role of IMT in cardiovascular risk prediction.


Use of cytomegalovirus (CMV) hyperimmune globulin for prevention of CMV disease in CMV-seropositive lung transplant recipients.
Our data suggest that CMVIG in combination with ganciclovir effectively reduces the incidence, and delays the onset of CMV infections in seropositive lung transplant recipients. In addition, its use may be associated with less severe CMV infection and a lower incidence of bacterial or fungal opportunistic infection. Although the number of patients in the study is small, high-titer CMVIG may be more effective than standard titer immunoglobulin in the prevention of CMV disease in lung transplant recipients. Several questions remain in addition to these: What is the optimal dosage and duration of treatment with CMVIG for prophylaxis of CMV infection and disease in lung transplant recipients; Is this strategy cost-effective; Will it reduce the incidence of obliterative bronchiolitis following lung transplantation and enhance allograft survival? A prospective, random-assignment trial is warranted to answer these questions.


Fibronectin does not enhance epidermal growth factor-mediated acceleration of corneal epithelial wound closure.
Concomitant use of epidermal growth factor and fibronectin for the treatment of corneal epithelial wounds has a putative advantage of promoting complementary aspects of wound healing: epidermal growth factor enhances mitosis, while fibronectin increases cell-to-substrate adhesiveness and possibly cell motility. To determine if the combination of epidermal growth factor and fibronectin is synergistic in accelerating the speed of corneal epithelial wound coverage, epithelial wound closure rates were compared in serum-free rat corneal organ cultures among epidermal growth factor alone, fibronectin alone, their combination, and drug-free controls. Epidermal growth factor (50 to 1000 ng/mL) significantly increased the rate of wound closure over that of the drug-free controls, while fibronectin (50 to 100 micrograms/mL) had not significant effect. Wound closure rates with combined epidermal growth factor and fibronectin were no faster than with epidermal growth factor alone. The results indicate that fibronectin does not accelerate the rate of corneal epithelial migration when used alone or in combination with epidermal growth factor. This may reflect that the major role of fibronectin may be in the enhancement of cell-to-substrate adhesion and not of migration per se.


Bilateral Candida parapsilosis endophthalmitis.
We describe a patient with bilateral, delayed endophthalmitis who underwent bilateral pars plana vitrectomy, total capsulectomy, intraocular lens exchange, intravitreal injection of amphotericin B, and oral fluconazole therapy. The long-term inflammation resolved, and vitreous cultures from both eyes yielded Candida parapsilosis. Histopathologic examination revealed sequestered yeast forms in the capsular bags.


Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis.
Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient's prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.


Early pregnancy failure management among family physicians.
Family physicians, as primary care providers for reproductive-aged women, frequently initiate or refer patients for management of early pregnancy failure (EPF). Safe and effective options for EPF treatment include expectant management, medical management with misoprostol, and aspiration in the office or operating room. Current practice does not appear to reflect patient preferences or to utilize the most cost-effective treatments. We compared characteristics and practice patterns among family physicians who do and do not provide multiple options for EPF care. We performed a secondary analysis of a national survey of women's health providers to describe demographic and practice characteristics among family physicians who care for women with EPF. We used multivariate logistic regression to identify correlates of providing more than one option for EPF management. The majority of family physicians provide only one option for EPF; expectant management was most frequently used among our survey respondents. Misoprostol and office-based aspiration were rarely used. Providing more than one option for EPF management was associated with more years in practice, smaller county population, larger proportions of Medicaid patients, intrauterine contraception provision, and prior training in office-based aspiration. Family physicians are capable of providing a comprehensive range of options for EPF management in the outpatient setting but few providers currently do so. To create a more patient-centered and cost-effective model of care for EPF, additional resources should be directed at education, skills training, and system change initiatives to prepare family physicians to offer misoprostol and office-based aspiration to women with EPF.


Right ventricle to pulmonary artery conduit reduces interim mortality after stage 1 Norwood for hypoplastic left heart syndrome.
Despite significant improvement in survival after stage 1 Norwood, interim mortality before the second-stage operation remains significant. On the basis of reports of improved circulatory stability associated with the use of a right ventricle to pulmonary artery conduit, the difference between two physiologically different sources of pulmonary blood flow on interim mortality was investigated. Data collection of 96 consecutive hospital survivors after stage 1 Norwood surgery was undertaken. The source of pulmonary blood flow was a modified right Blalock-Taussig shunt in 46 (BTS) and a right ventricle to pulmonary artery conduit in 50 patients. The same follow-up protocol was used in both groups. Data analysis was performed to identify variables associated with interim mortality. Analysis of patient-related and procedure-related variables revealed no differences in age, weight, diagnosis, presence of aortic atresia, lowest perioperative pH, duration of cardiopulmonary bypass, circulatory arrest, length of mechanical ventilation, or hospital stay at the time of stage 1 Norwood between groups. Respiratory rate and systolic blood pressure were the only differences detected between groups at the time of discharge. Interim mortality was higher in the Blalock-Taussig shunt group. Statistical analysis identified aortic atresia, a modified Blalock-Taussig shunt, and the presence of perioperative dysrhythmias to be associated with interim mortality. The use of a right ventricle to pulmonary artery shunt decreases the incidence of interim mortality among hospital survivors after stage 1 Norwood for hypoplastic left heart syndrome. Aortic atresia, the use of a modified Blalock-Taussig shunt, and perioperative dysrhythmias are independently associated with a higher mortality before superior cavopulmonary connection.


Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling.
In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of α- and γ-actin isoforms. Jasplakinolide stabilized γ-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous α- and γ-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms regulating thromboxane-mediated actin polymerization are potential targets for future PPHN pharmacotherapy.


Sensorimotor experience and verb-category mapping in human sensory, motor and parietal neurons.
Semantic grounding is the process of relating meaning to symbols (e.g., words). It is the foundation for creating a representational symbolic system such as language. Semantic grounding for verb meaning is hypothesized to be achieved through two mechanisms: sensorimotor mapping, i.e., directly encoding the sensorimotor experiences the verb describes, and verb-category mapping, i.e., encoding the abstract category a verb belongs to. These two mechanisms were investigated by examining neuronal-level spike (i.e. neuronal action potential) activities from the motor, somatosensory and parietal areas in two human participants. Motor and a portion of somatosensory neurons were found to be involved in primarily sensorimotor mapping, while parietal and some somatosensory neurons were found to be involved in both sensorimotor and verb-category mapping. The time course of the spike activities and the selective tuning pattern of these neurons indicate that they belong to a large neural network used for semantic processing. This study is the first step towards understanding how words are processed by neurons.


[Clinical analysis of 75 patients with severe influenza A H1N1 in Qinghai Province].
To observe clinical features of severe influenza A H1N1 in Qinghai Province. The clinical data of 75 severe influenza A H1N1 patients were analyzed retrospectively in regard to common features, clinical symptoms, signs, laboratory data and treatments hospitalized in Qinghai Hospital for Infectious Diseases during September 4, 2009 to December 31, 2009. The first case with severe influenza A H1N1 was diagnosed on October 14, and up to 75 patients (47.78%) on December 31. Among 75 patients, 45 patients were from rural areas (60.00%) and 30 patients were urbanites, 48 patients were male, and 27 female. Fifty-three patients were complicated with pneumonia (70.67%) and 41 patients with pre-existing medical conditions (54.67%), 65 patients with fever (86.67%), 63 patients with cough and sputum (84.00%), 61 patients with dyspnea (81.33%), 1 patients with meningitis as the main manifestation, 2 patients with acute pulmonary edema and left heart failure, 28 patients with leucopenia (37.33%), 28 patients with myocardial enzyme abnormalities (37.33%), 23 patients with blood glucose abnormalities (30.67%), 8 patients with coagulopathy (10.67%), 4 patients with lipid abnormalities (5.33%), 51 patients with increased C-reactive protein (68.00%). Forty-eight patients received oseltamivir, 27 patients received anti-virus "Jun Ke Ao Wei" capsules. Low molecular weight heparin was given to 27 patients for anticoagulation, and 22 were treated with methylprednisolone. In 33 patients who underwent non-invasive mechanical ventilation, among them it was switched to invasive mechanical ventilation in 10 patients. Second-line antibiotics were used, and sputum culture was done. In 8 patients with fungal infection anti-fungal therapy was given. Except 1 patient out of 75 patients died, and the rest were cured. In Qinghai Province, cases with influenza A H1N1 peaked early with relative high incidence of severe cases. Patients suffering from influenza A H1N1 are susceptible to pulmonary complications. The condition of patients rapidly deteriorate, and they are prone to develop respiratory failure, disseminated intravascular coagulation and multiple organ failure.


Utilizing Green Design as Workplace Innovation to Relieve Service Employee Stress in the Luxury Hotel Sector.
This study is an empirical endeavor to provide a clear comprehension regarding how hotel green design as a workplace innovation contributes to relieving employee stress and emotional fatigue and improves job satisfaction and involvement in the formation of organizational citizenship behavior. A quantitative process was employed to attain the research goal. Our empirical findings demonstrated that a green design as a workplace innovation boosts the stress resilience that leads to the decreased emotional exhaustion and increased job satisfaction. In addition, job satisfaction and job involvement were the crucial drivers of the organizational citizenship behavior among the luxury hotel service employees. Moreover, stress resilience, satisfaction and involvement were significant mediators. Job satisfaction and involvement had the strongest influence on organizational citizenship behavior than other variables. The findings of our research will help hotel proprietors to invent efficient strategies to minimize employee stress and maximize fulfillment at work, which will eventually enhance the organizational citizenship behavior.


New Therapeutic Options for the Treatment of Sickle Cell Disease.
Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.


3/2 harmonic generation by femtosecond laser pulses in steep-gradient plasmas.
The onset of an electron parametric instability and 3/2 harmonic generation in variable-scale-length plasmas on solid surfaces using femtosecond pulses is observed. With the intensity approaching 10(18) W/cm(2), the instability threshold is already reached at plasma scale lengths of the order of the laser wavelength. A well-collimated harmonic emission with unusually broad spectrum is obtained.


Early ontogeny and sequence heterochronies in Leiuperinae frogs (Anura: Leptodactylidae).
The study of early development in Neotropical Leiuperinae frogs (Anura, Leptodactylidae) has been addressed by several works in recent times. However, a comparative developmental approach under a phylogenetic context was not available. Herein we analyzed the morphological and ontogenetic diversity of embryos belonging to 22 species of the three largest genera in Leiuperinae. We find that in most cases, variations fit with the phylogeny at the inter- and intrageneric levels. Embryo kyphosis and whitish color are synapomorphies for the clade grouping Physalaemus and Engystomops. The presence of a third lower tooth row on the oral disc is plesiomorphic for Leiuperinae, only changing in derived clades. The configurations and developmental trajectories of the lower lip are exceptionally diverse. The developmental sequences optimized on the phylogenetic tree recover an early differentiated first lower tooth row a synapomorphy of Pseudopaludicola and Physalaemus, and an early differentiated second row as synapomorphy of Pleurodema. On the other hand, few features are highly conserved in the subfamily, such as the adhesive glands universally present in a type-C configuration. Our results also suggest that the morphology and ontogeny of embryos is in some cases associated to the environment where they develop. A large body size, poorly developed transient respiratory structures, large yolk provision and delayed development of the digestive tract occur convergently in embryos inhabiting cold, oxygenated environments. Embryos that develop in warmer water bodies in xeric environments show more complex and persistent transient respiratory structures and an early onset of hind limbs development. Our survey highlights that morphology and early development of anurans can be a valuable source of information for phylogenetic studies, and provide fundamental bases to explore and discuss how evolutionary changes can be shaped by environmental conditions.


Reduced proliferation of cultured bladder cancer cells by indomethacin.
Indomethacin exerts complex influences on biological phenomena. Human bladder cancer cells cultured in medium containing indomethacin showed reduced cell proliferation, altered cell cycle, and a decrease in transition from G0/G1 to S phase.


[Parkinsonian hemi-syndrome as the initial manifestation of supratentorial cystic hemangioblastoma in a patient with Von Hippel-Lindau disease].
Retino-cerebellar hemangioblastomatosis or Von Hippel-Lindau (VHL) disease is a phacomatosis with a dominant autosomal pattern of inheritance, which is characterized by the presence of hemangioblastomas of the central nervous system (cerebellum and spinal medulla), retinal angiomas and tumors (pheochromocytoma, clear cell carcinoma) or cysts of the abdominal viscera. We present the case of a 22 year old female with Von Hippel-Lindau disease, in whom a cystic hemangioblastoma of the basal ganglia of the left hemisphere was diagnosed when she complained of difficulty in carrying out fine movements of the right hand and tremor for some months. The supratenorial site of cystic hemangioblastomas in the clinical context of Von Hippel-Lindau disease is very rare and clinical presentation of a parkinsonian hemisyndrome is exceptional. In our search through the literature we have found tumors with many types of histology (meningiomas, glial tumors, craniopharyngioma, epidermoid cysts) in the origin of tumoral parkinsonism. However, we have found no previous case of cystic hemangioblastomas. We also emphasize that there was full resolution of the condition after total removal of the tumour.


Self-expanding tracheobronchial stents in the management of major airway problems.
The management of patients with critical major airway obstruction has been made possible by the recent introduction of expandable metal stents as the sole treatment or as an adjunct to other treatment modalities. To alleviate the distressing symptoms from tracheobronchial obstructions Gianturco self-expanding stents were used successfully in the management of 16 patients. The indications were; stenosis from postoperative strictures and recurrent tumours (n = 6), extrinsic compression from metastatic disease (n = 4), inoperable primary tumours of central airways (n = 4), airway collapse from relapsing polychondritis (n = 1), and endobronchial non-Hodgkin's lymphoma (n = 1). Fourteen patients have immediate relief of stridor and the remaining two patients were successfully weaned from ventilatory support. The stents were inserted under general anaesthesia through a rigid bronchoscope under direct vision. The ease of insertion under radiological control, self-expanding nature of the stents and the lack of major complications on follow-up of up to 22 months are particular advantages. The self-expanding tracheobronchial stents are a useful addition to our armamentarium in maintenance of the airways in patients with major airway stenosis and collapse.


Locating nursing classification schemes within health information strategies for New Zealand.
The potential to use classification schemes to describe and measure nursing in a country that has previously not used them as a part of practice is fraught with issues. Such is the case for New Zealand. Without nursing specific classification scheme use in the information systems of day to day function, nursing cannot validate what it does and the difference it makes to health outcomes for New Zealanders. The local use of valid and reliable classification schemes as tools to capture locally generated data that is able to be used as quality data needs to be considered alongside the national use of reliable clinical reference tools that are consistent with international standards. This may make the difference to the potential for significant contribution of nursing practice specific data to health information collections in preference to a 'one fits all' approach to user interface nursing classification scheme adoption at a local level. Tensions between a top-down approach and a locally based bottoms-up practice based approach and associated issues provide the core to this paper.


Online Real-Time Monitoring of Exhaled Breath Particles Reveals Unnoticed Transport of Nonvolatile Drugs from Blood to Breath.
We used online secondary electrospray ionization mass spectrometry to measure venlafaxine (VEN), a nonvolatile drug, in the exhaled air of mice intraperitoneally treated with VEN. The breath pharmacokinetic (PK) profile of VEN was recorded, which was in good agreement with that of the blood. Combined with online collection of exhaled breath particles (EBPs), it was shown that VEN existed as part of EBPs rather than gas molecules in the breath. Linear free-energy relationship analysis confirmed that almost completely ionized VEN at physiological conditions unlikely partition from the lung lining fluid (LLF) into breath air. This implies that the occurrence of VEN in exhaled air accompanies the formation of EBPs from the LLF. By comparison with the low breath signals of VEN metabolites, passive membrane permeability and lung/blood partition coefficient are suggested as the main influencing factors for the levels of drugs in the breath. This study advances our knowledge on the mechanism by which nonvolatile drugs are transferred from blood into exhaled breath, providing guidance for breath test-based therapeutic drug monitoring.


Vascular permeability to plasma, plasma proteins, and cells: an update.
The blood vasculature supplies tissues with nutrients, clears waste products, and carries and directs leukocytes to inflammatory sites. To accomplish these functions, microvessels regulate the extravasation of small molecules, plasma proteins and inflammatory cells. The mechanisms responsible for these events have been the subject of intense investigation and, often, dispute. Recent progress has contributed to a better understanding of the mechanisms by which microvessels of different types and in different vascular beds regulate the passage of small and large molecules and cells. Roles are shown for the glycocalyx, caveolae, perictyes, sphingosine-1-phosphate, and newly discovered signaling pathways. Vascular permeability is important for maintaining homeostasis and is greatly increased in acute and chronic inflammation, wound healing, and growing tumors. New work has contributed importantly to the mechanisms responsible for regulating permeability.


Larvicidal toxicity of Metarhizium anisopliae metabolites against three mosquito species and non-targeting organisms.
The fungal toxin acts as effective, low-cost chemical substances for pest control worldwide and also an alternative to synthetic insecticides. This study assessed the larvicidal potential of Metarhizium anisopliae fungi derived metabolites against Aedes aegypti, Anopheles stephensi, Culex quinquefasciatus and non-targeted organisms at 24hr post treatment. Isolation of entomopathogenic fungi M. anisopliae from natural traps confirmed by using 18s rDNA biotechnological tools. Crude extracts from M. anisopliae solvent extraction and their secondary metabolites were bio-assayed following WHO standard procedures against Ae. aegypti, An. stephensi and Cx. quinquefasciatus, Artemia nauplii, Eudrilus eugeniae, and Solanum lycopersicum after 24 hr exposure. Histopathological analysis of E. eugeniae treated with fungi metabolites toxicity compared to those treated with Monocrotophos after 24hrpost-treatment. M. anisopliae metabolites were characterized using GC-MS and FT-IR analysis. The larvicidal activity was recorded in highest concentration of 75μg/ml, with 85%, 97% and 89% mortality in Ae. aegypti, An. stephensi and Cx. quinquefasciatus respectively. M. anisopliae metabolites produced LC50 values in Ae. aegypti, 59.83μg/ml, in An. stephensi, 50.16μg/ml and in Cx. quinquefasciatus, 51.15μg/ml respectively. M. anisopliae metabolites produced lower toxic effects on A. nauplii, LC50 values were, 54.96μg/ml respectively. Bio-indicator toxicity results show 18% and 58% mortality was recorded in E. eugeniae and A. nauplii and also there is no phytotoxicity that was observed on S. lycopersicum L. under semi-field condition. E. eugeniae histopathological studies shows fungal metabolites showed lower sub-lethal effects compared to synthetic chemical pesticide at 24hrs of the treatment. The GC-MS and FT-IR analysis identified five major components of active ingredients. Findings of this study indicate that, M. anisopliae ethyl acetate derived secondary metabolites are effective against larvae of Ae. aegypti, An. stephensi and Cx. quinquefasciatus mosquito species, lower toxicity effects were observed on non-target organisms such as, Artemia nauplii, Eudrilus eugeniae as well as, no toxicity effect were observed on Solanum lycopersicum. Further research should be conducted in laboratory for separation of single pure molecule and be tested semifield conditions.


Complete heart block following transcatheter closure of perimembranous VSD using amplatzer duct occluder II.
Long term follow up studies have shown that transcatheter closure of perimembranous Ventricular Septal Defect (PmVSD) can be done safely and successfully. One of the most serious complications of VSD device closure is complete atrioventricular block which has been reported in 3-18% is various studies following VSD device closure. Amplatzar Duct Occluder II (ADO-II) device is now commonly being used for closure of small to moderate sized PmVSD. Complete heart block has not been reported with ADO-II device. We are reporting 2 cases of complete heart block following transcatheter closure of PmVSD using ADO-II device where sinus rhythm was established following early surgical removal of the device.


Studies on the incidence of Salmonella carriers in broiler flocks entering a poultry processing plant in Australia.
To evaluate the practical utility of competitive exclusion as an aid in controlling Salmonella, a survey was conducted in New South Wales, Australia to determine the incidence of Salmonella in 20 broiler flocks at time of slaughter during a 12-month period. The Salmonella incidence was determined by culturing the ceca of 50 randomly selected chickens per flock. The results demonstrated a high level of carriers (more than 30%) in 6 flocks, a moderate level of carriers (11 to 30%) in 4 flocks, a low level of carriers (1 to 10%) in 2 flocks, and 8 flocks from which no Salmonella were isolated. Five Salmonella serotypes, S. eimsbeutel , S. havana, S. luanshya , S. singapore, and S. typhimurium were isolated with S. typhimurium being the most common. Salmonellae were much less frequently isolated from flocks reared on old litter than on new litter.


Redefining essential fatty acids in the era of novel intravenous lipid emulsions.
The essentiality of fatty acids was determined by the Burrs in the 1920s. It is commonly accepted that provision of linoleic (LA) and alpha-linolenic acids (ALA) prevents and reverses essential fatty acid deficiency (EFAD). Development of alternative injectable lipid emulsions (ILE) low in LA and ALA has raised concern about their ability to prevent EFAD. This review provides biochemical evidence coupled with observations from animal and human studies that aim to characterize which fatty acids are truly essential to prevent EFAD. Retroconversion pathways and mobilization from body stores suggest that arachidonic and docosahexaenoic acids (ARA and DHA - the main derivatives of LA and ALA, respectively) also prevent EFAD. Our group first proposed the essentiality of ARA and DHA by feeding mice exclusively these fatty acids and proving that they prevent EFAD. Survival for 5 generations on this diet provides additional evidence that growth and reproductive capabilities are maintained. Moreover, the use of fish oil-based ILE, with minimal LA and ALA and abundant DHA and ARA, for treatment of intestinal failure-associated liver disease, does not result in EFAD. These findings challenge the essentiality of LA and ALA in the presence of ARA and DHA. Evidence discussed in this review supports the idea that ARA and DHA can independently fulfill dietary essential fatty acid requirements. The imminent introduction of new ILE rich in ARA and DHA in the United States highlights the importance of understanding their essentiality, especially when provision of ALA and LA is below the established daily minimum requirement.


BMS284756 (formerly T-3811, a des-fluoroquinolone) potency and spectrum tested against over 10,000 bacterial bloodstream infection isolates from the SENTRY antimicrobial surveillance programme (2000).
BMS284756 is a novel des-F (6)-quinolone, which has a wide range of activity against many species of Gram-positive and -negative organisms. The potency of BMS284756 was compared with that of other quinolones, including ciprofloxacin, gatifloxacin and levofloxacin, and was tested against >10,000 bloodstream isolates from the year 2000 SENTRY antimicrobial surveillance programme. Twelve pathogens accounted for nearly all of the referred isolates and included Staphylococcus aureus, coagulase-negative staphylococci, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Serratia spp., Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus spp., Streptococcus pneumoniae and beta-haemolytic or viridans group streptococci. Of the four quinolones tested, BMS284756 was the most active overall against Staphylococcus spp. (MIC(50) < or = 0.03 mg/L) and Streptococcus spp. (MIC(50) 0.06 mg/L). In contrast, BMS284756 was less potent than the other quinolones against the enteric Gram-negative bacilli (MIC(50) < or = 0.03-1 mg/L). With a proposed breakpoint of < or =4 mg/L, BMS284756 may be a therapeutic alternative pending the results of clinical trials.


Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity.
It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms-those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa), the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.


The combined antimicrobial activity of citrus honey and fosfomycin on multidrug resistant Pseudomonas aeruginosa isolates.
Infections with Pseudomonas aeruginosa (P. aeruginosa) have become a real fear in hospital-acquired infections, especially in critically ill and immunocompromised patients. Thus, advance of novel anti-infectives is currently pursued. The aim of the present study was to evaluate the antibacterial effect of each of citrus honey and fosfomycin in comparison to the combined effect of both of them on multidrug resistant (MDR) P. aeruginosa. 50 MDR P. aeruginosa isolates were tested for the antibacterial effect of citrus honey. Screening for potential synergistic activity of fosfomycin and honey combinations by E test. Molecular detection of the virulent exoenzyme U (exoU) genotype by conventional PCR was done. The present study found that 50 % (v/v) concentration of citrus honey was sufficient to inhibit the growth of most isolates (33/50, 66%). Minimal inhibitory concentration (MIC) for fosfomycin tested by E test was found to be >128 µg/mL in 50(100%) of MDR P. aeruginosa isolates but after repeating E test with Mueller-Hinton agar (MHA) containing sublethal concentration of citrus honey (29/50,58%) isolates were sensitive. Also, there was a significant correlation between the presence of exoU gene and positive synergy of citrus honey-fosfomycin combination. This study showed that citrus honey has antibacterial effect and synergy with fosfomycin antibiotic against MDR P. aeruginosa isolates. Also, exoU positive genotype is associated with MDR phenotype. In conclusion, our results revealed that the citrus honey-fosfomycin combination showed highly statistically significant effect on MDR P. aeruginosa fosfomycin susceptibility pattern. exoU positive P. aeruginosa isolates were detected mostly in burn unit and ICUs. Also, there was a statistically significant correlation between the presence of exoU gene and positive result of honey-fosfomycin combination E test.


Atypical CT Findings in Plexiform Ameloblastoma.
Ameloblastoma is an uncommon epithelial odontogenic neoplasm that is nonmineralized, locally aggressive, and, in most cases, benign. Most ameloblastomas develop in the molar-ramus region of the mandible with 70% of them arising in the molar-ramus area. Radiologically they are unilocular or multilocular radiolucency with a honeycomb or soap bubble appearance. The radiographic appearance of ameloblastoma can vary according to the type of tumor. CT is usually helpful in determining the contours of the lesion, its contents, and its extension into soft and hard tissues. Through this case we would bring to light some of the unusual CT findings which include the destruction of the surrounding structures by the lesion which appeared to be normal routine lesion when viewed clinically.


Neonatal toxicity following maternal citalopram treatment.
Late gestational exposure to citalopram, may be associated with a neonatal toxicity syndrome with immediate onset at birth or soon after birth and sometimes may be mistaken for neonatal withdrawal syndrome. A 3860 g infant was delivered at 40 weeks gestation. The mother had been taking citalopram 20 mg/day until the day of delivery. Fifteen minutes after birth, the baby became hypertonic. Neonatal serotonin toxicity due to citalopram seems the most likely mechanism, though an important differential diagnosis is a citalopram withdrawal syndrome. We suggest the hypothesis that neonatal withdrawal syndrome may follow citalopram serotonin toxicity.


Does Cation Size Affect Occupancy and Electrostatic Screening of the Nucleic Acid Ion Atmosphere?
Electrostatics are central to all aspects of nucleic acid behavior, including their folding, condensation, and binding to other molecules, and the energetics of these processes are profoundly influenced by the ion atmosphere that surrounds nucleic acids. Given the highly complex and dynamic nature of the ion atmosphere, understanding its properties and effects will require synergy between computational modeling and experiment. Prior computational models and experiments suggest that cation occupancy in the ion atmosphere depends on the size of the cation. However, the computational models have not been independently tested, and the experimentally observed effects were small. Here, we evaluate a computational model of ion size effects by experimentally testing a blind prediction made from that model, and we present additional experimental results that extend our understanding of the ion atmosphere. Giambasu et al. developed and implemented a three-dimensional reference interaction site (3D-RISM) model for monovalent cations surrounding DNA and RNA helices, and this model predicts that Na(+) would outcompete Cs(+) by 1.8-2.1-fold; i.e., with Cs(+) in 2-fold excess of Na(+) the ion atmosphere would contain an equal number of each cation (Nucleic Acids Res. 2015, 43, 8405). However, our ion counting experiments indicate that there is no significant preference for Na(+) over Cs(+). There is an ∼25% preferential occupancy of Li(+) over larger cations in the ion atmosphere but, counter to general expectations from existing models, no size dependence for the other alkali metal ions. Further, we followed the folding of the P4-P6 RNA and showed that differences in folding with different alkali metal ions observed at high concentration arise from cation-anion interactions and not cation size effects. Overall, our results provide a critical test of a computational prediction, fundamental information about ion atmosphere properties, and parameters that will aid in the development of next-generation nucleic acid computational models.


FGF2 stimulation of the pyrophosphate-generating enzyme, PC-1, in pre-osteoblast cells is mediated by RUNX2.
Pyrophosphate is an established inhibitor of hydroxyapatite deposition and crystal growth, yet when hydrolyzed into phosphate, it becomes a substrate for hydroxyapatite deposition. Pyrophosphate-generating enzyme (PC-1), Ank, and tissue nonspecific alkaline phosphatase (Tnap) are three factors that regulate extracellular pyrophosphate levels through its generation, transport, and hydrolysis. We previously showed that fibroblast growth factor 2 (FGF2) induces PC-1 and Ank while inhibiting Tnap expression and mineralization in MC3T3E1(C4) calvarial pre-osteoblast cells. In this study, we showed similar FGF2 regulation of these genes in primary pre-osteoblast cultures. In contrast to Ank and Tnap that are regulated by FGF2 in multiple cell types, we found regulation of PC-1 to be selective to pre-osteoblastic cells and to require the osteoblast-related transcription factor, Runx2. Specifically, FGF2 was unable to induce PC-1 expression in Runx2-negative nonbone cells or in calvarial cells from Runx2-deficient mice. Transfection of these cells with a Runx2 expression vector restored FGF2 responsiveness. FGF2 was also shown to stimulate recruitment of Runx2 to the endogenous PC-1 promoter in MC3T3E1(C4) cells, as measured by chromatin immunoprecipitation. Taken together, our results establish that FGF2 is a specific inducer of PC-1 in pre-osteoblast cells and that FGF2 induces PC-1 expression through a mechanism involving Runx2.


Histamine and astrocyte function.
Astrocytes support the brain through numerous functional interactions in health and disease. The recent advances in our knowledge of astrocyte involvement in various neurological disorders raised up several questions about their role and functioning in the central nervous system. From the evidence discussed in this review, we show that histamine importantly influences the main astrocytic activities such as ion homeostasis, energy metabolism, neurotransmitter clearance, neurotrophic activity and immune response. These processes are mediated through at least three histamine receptor subtypes, H1, H2 and H3, expressed on the astrocyte surface. Thus, we recognize histamine as an important player in the modulation of astrocytic functions that deserves further considerations in exploring involvement of astrocytes in neurological disorders.


Dentist, "heal thyself": modification of life style.
In the late 1960's, preventive health care began to gain in popularity in the United States and the movement carried over into the 1970's. During this time, sizable decreases in deaths from heart disease, strokes, and accidents have been noted. As a result, the lowest death rate in the history of this country (8.9 per 1000) occurred in both 1975 and 1976. Since 1970, an increase in longevity has been documented and it can be said that Americans are living longer--not just longer but hopefully better! People are beginning to learn that "it is not so much that we die, we kill ourselves!" With proper weight, diet, and exercise, avoiding tobacco, early detection and treatment of high blood pressure, use of seat belts, and control of stimulants and drugs, thousands of lives are being saved annually. In today's busy and demanding society, success in any field requires more than just education and hard work. It requires good health, both mental and physical. Pursue these goals vigorously and remember, "It is always cheaper and much easier to maintain good health than it is to regain it once it is lost!"


Recurrent Longitudinally Extensive Myelitis and Aquaporin-4 Seronegativity - The Expanding Spectrum of Neuromyelitis Optica.
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a recently proposed unifying term for Neuromyelitis Optica (NMO), also known as Devic's disease and related syndromes. It is a relapsing inflammatory demyelinating disease that most commonly affects optic nerves and the spinal cord, leading to sudden vision loss or weakness in one or both eyes, and loss of sensation and bladder function. Though inflammation may also involve the brain, the lesions seen in NMO are different from Multiple Sclerosis (MS) which has a similar clinical course. Attacks of NMOSD tend to be more severe and often different in nature from MS. MS and NMOSD are often confused but require a different course of treatment for optimal results. Here, we describe a patient who had clinical features suggestive of NMO but showed seronegativity for anti-aquaporin antibodies, done twice. Initially he was managed on the lines of MS but showed a deteriorating clinical course on initiation of treatment with interferons. Later, his diagnosis was revised to seronegative NMO and he was started on immunosuppressive therapy with azathioprine to which he showed optimal response and achieved disease stabilization.


Limb Regeneration in the Eye Sockets of Crabs.
The eyestalks of crabs were removed and various tissues of the limbs were autotransplanted into the empty eye sockets to study the capacity of the limb tissue to regenerate in a heterotopic site. Autotransplantation of walking leg tissues into the eye sockets was able to regenerate complete walking legs in the new site. Autotransplantation of tissues of claw digit (dactyl and pollex) or more proximal claw segments (ischium and merus/carpus joint) could regenerate complete claws in the eye sockets. If the autotransplant of claw tissue was contralateral, claws could regenerate with host-site handedness. Sham operations or autotransplantation of frozen claw tissue did not induce regeneration in the eye sockets. These results demonstrate that complete crab claws can regenerate from the eye sockets by autotransplantation of live limb tissue and that the regeneration is not due to the traumatic effect of transplantation. The structure of the limbs regenerated in the eye sockets was determined by the source of the transplanted tissue. Complete claws resulted from autotransplantation of the tissues of the most distal claw segments (claw digits), and the most distal claw segments regenerated first, followed by the proximal claw segments in subsequent molts. Thus tissue from distal portions of crab claw can regenerate proximal portions of the claw in the eye sockets. Such a mode of regeneration is not consistent with the distalization rule of the polar coordinate model, which proposes that distal portions of the limb cannot regenerate proximal portions and that the direction of limb regeneration is always from proximal to distal.


Intraoperative occurrence of a pneumopericardium during double-lung transplantation.
Pneumopericardium is rare and has been reported secondary to chest trauma. We report a case of tension pneumopericardium occurring during double-lung transplantation, where intraoperative transoesophageal echocardiography first showed a hypokinetic left ventricle and a few minutes later a compression of its anterolateral portion due to pneumopericardium. Although the pericardium was opened, left ventricular function remained depressed, necessitating extracorporeal membrane oxygenation, which was withdrawn after 48 h of assistance when left ventricular function had recovered. The patient was extubated on the seventh postoperative day but died of multiorgan failure on the 64 th postoperative day.


High-performance liquid affinity chromatography: rapid immunoanalysis of transferrin in serum.
We describe a new method for quantitatively measuring substances of clinical interest by high-performance liquid affinity chromatography (HPLAC). As a model system we selected analysis for transferrin in human serum with immobilized antibodies in a high-performance liquid chromatographic system. SelectiSpher-10 Activated Tresyl columns (5 or 10 x 0.5 cm) were used for in situ coupling of polyclonal antibodies to transferrin. The amount of transferrin eluted was determined by integrating the eluted peak at 280 nm. The whole analytical procedure--including injection of sample, washing, elution, and analysis of data--takes only 7 min. We characterized the HPLAC system for analysis of transferrin in several ways: intra-assay CV approximately 3%; inter-assay CV 2-9%; linear response up to 1 mg/mL column volume; detection limit approximately 3 micrograms; analytical recovery 98% +/- 2%; purity of eluted sample greater than 95% (SDS-PAGE). The HPLAC method was compared with "rocket" immunoelectrophoresis, a commonly used method of analysis for transferrin, and there was excellent correlation between the two methods (r = 0.96, n = 60). Benefits of this HPLAC technique include high precision, rapid analysis, and simplified sample handling.


A novel surface-attached carvedilol solid dispersion with enhanced solubility and dissolution.
A novel surface-attached, spray-dried solid dispersion containing poorly water-soluble carvedilol (CV) without any change in the crystallinity was prepared using water, polyvinylpyrrolidone (PVP K30) and Tween 80. The solid dispersion was optimized by investigating the effects of the weight ratios of Tween 80/PVP K30 and carrier/drug on the aqueous solubility of CV. The optimum solid dispersion consisted of a relatively low carrier to drug weight ratio: the weight ratio of CV/PVP K30/Tween 80 was 12/4/2. Unlike conventional methods of solid dispersion preparation, this method yielded CV-loaded solid dispersion with no change in the crystallinity of the drug as was evident from SEM, DSC and XRD. It was demonstrated that the solid dispersions prepared had hydrophilic carriers attached to the surface of the drug, thus changing it from a hydrophobic to a hydrophilic form without changing the crystalline form. The optimized solid dispersion improved the drug solubility and dissolution rate by about 11,500-fold and twofold, respectively. It was further suggested that this method of solid dispersion preparation is better than conventional methods in terms of environmental and industrial standpoints. Thus, it was concluded that CV-loaded solid dispersion prepared using this method would be of use for delivering poorly water-soluble CV with enhanced solubility and dissolution, but without crystalline changes.


Appropriate timing for hypothermic machine perfusion to preserve livers donated after circulatory death.
Hypothermic machine perfusion (HMP) is a method that can be more effective in preserving donor organs compared with cold storage (CS). However, the optimal duration and the exact mechanisms of the protevtive effects of HMP remain unknow. The present study aimed to investigate the adequate perfusion time and mechanisms underlying HMP to protect livers donated after circulatory death (DCD). After circulatory death, adult male Sprague‑Dawley rat livers were subjected to 30 min of warm ischemia (WI) and were subsequently preserved by HMP or CS. To determine the optimal perfusion time, liver tissues were analyzed at 0, 1, 3, 5, 12 and 24 h post‑preservation to evaluate injury and assess the expression of relevant proteins. WI livers were preserved by HMP or CS for 3 h, and liver viability was evaluated by normothermic reperfusion (NR). During NR, oxygen consumption, bile production and the activities of hepatic enzymes in the perfusate were assessed. Following 2 h of NR, levels of inflammation and oxidative stress were determined in the livers and perfusate. HMP for 3 h resulted in the highest expression of myocyte enhancer factor 2C (MEF2C) and kruppel‑like factor 2 (KLF2) and the lowest expression of NF‑κB p65, tumor necrosis factor (TNF)‑α and interleukin (IL)‑1β among the different timepoints, which indicated that 3 h may be the optimal time for HMP induction of the KLF2‑dependent signaling pathway. Compared with CS‑preserved livers, HMP‑preserved livers displayed significantly higher oxygen consumption, lower hepatic enzyme levels in the perfusate following NR. Following HMP preservation, the expression levels of MEF2C, KLF2, endothelial nitric oxide synthase and nitric oxide were increased, whereas the expression levels of NF‑κB p65, IL‑1β and TNF‑α were decreased compared with CS preservation. The results indicated that 3 h may be the optimal time for HMP to protect DCD rat livers. Furthermore, HMP may significantly reduce liver inflammation and oxidative stress injury by mediating the KLF2/NF‑κB/eNOS‑dependent signaling pathway.


[Cutaneous immunofluorescence in B virus diseases. 100 cases].
Immunofluorescence tests in healthy skin were performed in 75 patients with hepatitis B virus diseases (group I), in 25 HBs-antigen negative patients with the same diseases (group II) and in 90 controls (group III). HB virus diseases included acute, prolonged hepatitis; chronic, persistent and active hepatitis; cirrhosis and periarteritis nodosa. The immunofluorescence test was positive (micro- or macrogranular deposits in the walls of dermal vessels of HBs-antigen associated or not with immunoglobulins and complement) in 8 patients of group I (prolonged hepatitis 1; chronic persistent hepatitis 2; chronic active hepatitis 3; periarteritis nodosa 2), 3 of whom had no clinical manifestations, and in 3 patients of group II (chronic active hepatitis 2, periarteritis nodosa 1). Although not all patients with extrahepatic HB virus disease have a skin test positive for HBs-antigen and, conversely, a positive skin test does not necessarily imply clinical manifestations, it seems that skin immunofluorescence should be systematically performed as part of immunological investigations in all diseases where the HB virus might be involved.


Glypican-6 promotes the growth of developing long bones by stimulating Hedgehog signaling.
Autosomal-recessive omodysplasia (OMOD1) is a genetic condition characterized by short stature, shortened limbs, and facial dysmorphism. OMOD1 is caused by loss-of-function mutations of glypican 6 (GPC6). In this study, we show that GPC6-null embryos display most of the abnormalities found in OMOD1 patients and that Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos. The Hh-stimulatory activity of GPC6 was also observed in cultured cells, where this GPC increased the binding of Hh to Patched 1 (Ptc1). Consistent with this, GPC6 interacts with Hh through its core protein and with Ptc1 through its glycosaminoglycan chains. Hh signaling is triggered at the primary cilium. In the absence of Hh, we observed that GPC6 is localized outside of the cilium but moves into the cilium upon the addition of Hh. We conclude that GPC6 stimulates Hh signaling by binding to Hh and Ptc1 at the cilium and increasing the interaction of the receptor and ligand.


Evaluation of antiglycosidase and anticholinesterase activities of Boehmeria nivea.
In this era, major community worldwide is suffering from diabetes type II, cancer and neurodegenerative disorders. To overcome these diseases, in the screening of Korean medicinal plants, we studied the whole plant of Boehmeria nivea (B. nivea). The methanolic leaf, stem and root extracts of B. nivea and their respective n-hexane, methylene chloride (CH(2)Cl(2)), ethyl acetate (EtOAc), n-butanol (BuOH) and aqueous fractions were investigated for their total phenolic content (TPC), 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibition activities. Profound TPC and DPPH free radical scavenging activities were observed in the EtOAc and BuOH fractions of root, where the BuOH fraction showed high-pitched alpha-glucosidase inhibition and the EtOAc layer showed the maximum beta-glucosidase inhibition. Furthermore, the leaf extract demonstrated the highest beta-galactosidase inhibitory activity, but no alpha-galactosidase inhibition was seen in any of the plant parts. Notable BChE and moderate AChE inhibitory activity was found in whole plant. It can be suggested that whole plant of B. nivea provides a strong biochemical rationale as one of the good choices for the treatment of diabetes type II, cancer and neurodegenerative diseases (AD, etc).