title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Development of an online sulfur-oxidizing bacteria biosensor for the monitoring of water toxicity. | A toxicity monitoring system based on the metabolic properties of sulfur-oxidizing bacteria (SOB) in continuous and fed-batch modes has been applied for the detection of nitrite (NO2 (-)-N). In this study, the effects of different concentrations of NO2 (-)-N (0.1 to 5 mg/L) on the SOB bioreactors were tested. We found that 5 mg/L NO2 (-)-N was very toxic to the SOB bioreactors in both continuous (R1) and fed-batch (R2) modes, showing complete inhibition of SOB activity within 2 h of operation. R1 and R2 were operated in different ways; however, the EC inhibition and recovery patterns were very similar. The EC rate increased with an increasing NO2 (-)-N concentration in both continuous and fed-batch modes. The addition of 5 mg/L NO2 (-)-N in continuous mode decreased the average EC rate by 14.38 ± 2.1 μS/cm/min; while in fed-batch mode, the EC rate decreased by 23 μS/cm/min. Although the toxicity monitoring system could detect 0.5-5 mg/L NO2 (-)-N, it could not detect 0.1 mg/L NO2 (-)-N in either continuous or fed-batch operation. Thus, the SOB biosensor method presented is useful to detect toxic agents such as NO2 (-)-N within a few minutes or hours. | 25,253,265 | [
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Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies. | Psychostimulant and opioid addiction are poorly treated. The majority of abstinent users relapse back to drug-taking within a year of abstinence, making 'anti-relapse' therapies the focus of much current research. There are two fundamental challenges to developing novel treatments for drug addiction. First, there are three key stimuli that precipitate relapse back to drug-taking: stress, presentation of drug-conditioned cue, taking a small dose of drug. The most successful novel treatment would be effective against all three stimuli. Second, a large number of drug users are poly-drug users: taking more than one drug of abuse at a time. The ideal anti-addiction treatment would, therefore, be effective against all classes of drugs of abuse. In this review, the authors discuss the clinical need and animal models used to uncover potential novel treatments. There is a very broad range of potential treatment approaches and targets currently being examined as potential anti-relapse therapies. These broadly fit into two categories: 'memory-based' and 'receptor-based' and the authors discuss the key targets here within. Opioid receptors and ligands have been widely studied, and research into how different opioid subtypes affect behaviours related to addiction (reward, dysphoria, motivation) suggests that they are tractable targets as anti-relapse treatments. Regarding opioid ligands as novel 'anti-relapse' medication targets, research suggests that a 'non-selective' approach to targeting opioid receptors will be the most effective. | 25,253,272 | [
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Comparison of the safety and efficacy of anterior 'skip' corpectomy versus posterior decompression in the treatment of cervical spondylotic myelopathy. | The aim of this study was to compare the therapeutic effects of anterior 'skip' corpectomy with posterior decompression for treating four-level cervical spondylotic myelopathy. Operation time and blood loss during the operation for the anterior and posterior approach groups were recorded. Patients were examined with cervical lateral radiography before and after the operation to measure Cobb's angle and postoperatively to monitor bony fusion. Surgery-, instrumentation-, and graft-related complications were assessed and recorded. The surgical aspects of both anterior 'skip' corpectomy and posterior decompression went smoothly, with mean durations of 2.5 and 2.1 h, respectively, and mean blood loss volumes of 250 and 380 mL, respectively. In the anterior approach group, the complications included axial pain in five cases and transient hoarseness in two. Radiography revealed titanium mesh subsidence in two cases and plate or screw dislodgement in one case. In the posterior approach group, C5 nerve root palsy was present in 2 patients, axial pain in 15, and cerebrospinal fluid leakage in 3. The mean Japanese Orthopaedic Association scores showed that the recovery rate was significantly higher in the anterior approach group than in the posterior approach group (p < 0.05). 'Skip' corpectomy has comparable safety and better efficacy than posterior decompression in the treatment of four-level cervical spondylotic myelopathy. | 25,253,289 | [
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Putting the 6Cs into Practice: Conversation Cards Holt Lynda Putting the 6Cs into Practice: Conversation Cards £14.99 9780992693848 0992693845 Fink in Organisations Second edition 52 cards [Formula: see text]. | IN ITS drive to ensure core values are at the heart of the NHS and the public health and care sectors, the Department of Health produced a three-year vision and strategy for nursing, midwifery and care staff aimed at compassion in practice. | 25,253,321 | [
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Does self-scheduling increase nurses' job satisfaction? An integrative literature review. | Flexible work schedules give nurses the freedom and control to manage the demands of work and home, allow organisations to meet their staffing needs and can improve job satisfaction. This article reports the results of an integrative review of published peer-reviewed research and personal narratives that examined nurses' perceptions of the relationship between job satisfaction and a self-scheduling system. Results suggest that self-scheduling is one of a number of factors that influence job satisfaction, but that implementing and sustaining such a system can be challenging. The review also found that self-scheduling programmes underpin more flexible work schedules and can benefit nurses and their organisations. | 25,253,331 | [
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Hyperglycosylated stable core immunogens designed to present the CD4 binding site are preferentially recognized by broadly neutralizing antibodies. | The HIV-1 surface envelope glycoprotein (Env) trimer mediates entry into CD4(+) CCR5(+) host cells. Env possesses conserved antigenic determinants, such as the gp120 primary receptor CD4 binding site (CD4bs), a known neutralization target. Env also contains variable regions and protein surfaces occluded within the trimer that elicit nonneutralizing antibodies. Here we engineered additional N-linked glycans onto a cysteine-stabilized gp120 core (0G) deleted of its major variable regions to preferentially expose the conformationally fixed CD4bs. Three, 6, 7, and 10 new NXT/S glycan (G) motifs were engineered into 0G to encode 3G, 6G, 7G, and 10G cores. Following purification, most glycoproteins, except for 10G, were recognized by broadly neutralizing CD4bs-directed antibodies. Gel and glycan mass spectrometry confirmed that additional N-glycans were posttranslationally added to the redesigned cores. Binding kinetics revealed high-affinity recognition by seven broadly neutralizing CD4bs-directed antibodies and low to no binding by non-broadly neutralizing CD4bs-directed antibodies. Rabbits inoculated with the hyperglycosylated cores elicited IgM and IgG responses to each given protein that were similar in their neutralization characteristics to those elicited by parental 0G. Site-specific glycan masking effects were detected in the elicited sera, and the antisera competed with b12 for CD4bs-directed binding specificity. However, the core-elicited sera showed limited neutralization activity. Trimer priming or boosting of the core immunogens elicited tier 1-level neutralization that mapped to both the CD4bs and V3 and appeared to be trimer dependent. Fine mapping at the CD4bs indicated that conformational stabilization of the cores and addition of N-glycans altered the molecular surface of Env sites of vulnerability to neutralizing antibody, suggesting an explanation for why the elicited neutralization was not improved by this rational design strategy. Major obstacles to developing an effective HIV-1 vaccine include the variability of the envelope surface glycoproteins and its high-density glycan shield, generated by incorporation of host (human) glycosylation. HIV-1 does harbor highly conserved sites on the exposed envelope protein surface of gp120, one of which is the virus receptor (CD4) binding site. Several broadly neutralizing antibodies elicited from HIV patients do target this gp120 CD4 binding site (CD4bs); however, gp120 immunogens do not elicit broadly neutralizing antibodies. In this study, we targeted the CD4bs by conformational stabilization and additional glycan masking. We used the atomic-level structure to reengineer gp120 cores to preferentially present the cysteine-stabilized CD4bs and to mask (by glycan) nonneutralizing determinants. Importantly, glycan masking did successfully focus antibody responses to the CD4bs; however, the elicited CD4bs-directed antibodies did not neutralize HIV or bind to unmodified gp120, presumably due to the structure-guided modifications of the modified gp120 core. | 25,253,346 | [
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Ascites and spontaneous bacterial peritonitis: recommendations from two United States centers. | Cirrhosis affects millions of people throughout the world. Two of the most serious complications of liver cirrhosis are ascites and spontaneous bacterial peritonitis (SBP). The development of ascites is related to the severity of portal hypertension and is an indicator of increased mortality. Although sodium restriction and diuretic therapy have proven effective, some patients may not respond appropriately or develop adverse reactions to diuretic therapy. In such cases, interventions such as transjugular intrahepatic portosystemic shunt (TIPS) placement are warranted. SBP is a complication of ascites that confers a very high mortality rate. Recognition and prompt treatment of this condition is essential to prevent serious morbidity and mortality. Initiation of prophylaxis in SBP remains controversial. Given the burden of liver cirrhosis on the health care system, ascites and SBP will continue to provide challenges for the primary care provider, hospitalist, internist, and gastroenterologist alike. | 25,253,362 | [
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Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. | Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury. Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure. The I/R group's TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes. Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery. | 25,253,365 | [
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Heteroarylboronates in rhodium-catalyzed 1,4-addition to enones. | Rhodium(I)-catalyzed 1,4-addition of aryl and alkenylboronic acids to α,β-unsaturated carbonyl compounds is well established, but the transfer of heteroaryl residues in this reaction remains underdeveloped. We have studied heteroaryl MIDA and pinacol boronates as alternatives to the labile boronic acid counterparts. Under racemic conditions, 12 adducts with heteroaryl residues, among them unsubstituted 3- and 4-pyridinyl, 2-furanyl, thienyl, and pyrrolyl groups, were obtained in moderate to excellent yields. The enantioselective version of the reaction proved highly sensitive to the electronic character of the heteroaryl substituents, with boronates carrying electron-rich residues giving modest to high yields but consistently high enantiomeric excesses. | 25,253,388 | [
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Sequence-motif detection of NAD(P)-binding proteins: discovery of a unique antibacterial drug target. | Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins. | 25,253,464 | [
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Dynamic changes of twitchlike responses to successive stimuli studied by decomposition of motor unit tetanic contractions in rat medial gastrocnemius. | Unfused tetanic contractions evoked by trains of stimuli at variable interpulse intervals (IPIs) were recorded for 10 fast fatigable (FF), 10 fast resistant (FR), and 10 slow (S) motor units (MUs) and subsequently decomposed with a mathematical algorithm into trains of twitch-shape responses to successive stimuli. The mean stimulation frequencies were matched for each MU to evoke tetani of similar fusion degrees, whereas the variability range of IPIs was in each case 50-150% of the mean IPI. Force and time parameters of decomposed twitches were analyzed and related to the first response. Considerable variability of the analyzed twitch parameters was observed in each MU, although the largest range of variability occurred in slow MUs. In general, the decomposed twitch responses had longer duration and higher force than single-twitch contractions, although for nine FF and six FR MUs some of the decomposed responses were slightly weaker (but not faster) than the first twitches of these MUs. Comparison of the strongest decomposed twitch to the first decomposed twitch revealed ratios of forces up to 2.35, 3.33, and 6.89 for FF, FR, and S MUs and ratios of force-time areas up to 3.54, 4.67, and 14.26 for FF, FR, and S MUs, whereas for the contraction times the ratios of the longest decomposed twitch to the first twitch amounted to 2.46, 2.07, and 3.52 for FF, FR, and S MUs, respectively. The results indicate that contractile responses to successive action potentials are considerably variable, especially for slow MUs. | 25,253,476 | [
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The neural basis of tactile motion perception. | The manipulation of objects commonly involves motion between object and skin. In this review, we discuss the neural basis of tactile motion perception and its similarities with its visual counterpart. First, much like in vision, the perception of tactile motion relies on the processing of spatiotemporal patterns of activation across populations of sensory receptors. Second, many neurons in primary somatosensory cortex are highly sensitive to motion direction, and the response properties of these neurons draw strong analogies to those of direction-selective neurons in visual cortex. Third, tactile speed may be encoded in the strength of the response of cutaneous mechanoreceptive afferents and of a subpopulation of speed-sensitive neurons in cortex. However, both afferent and cortical responses are strongly dependent on texture as well, so it is unclear how texture and speed signals are disambiguated. Fourth, motion signals from multiple fingers must often be integrated during the exploration of objects, but the way these signals are combined is complex and remains to be elucidated. Finally, visual and tactile motion perception interact powerfully, an integration process that is likely mediated by visual association cortex. | 25,253,479 | [
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Acute onset and rapid progression of multiple organ failure in a young adult with undiagnosed disseminated colonic adenocarcinoma. | Colourectal cancer (CRC) is the fourth most common cause of death from cancer worldwide. While rates for CRC in adults age 50 and older have been declining, incidence rates in young adults, a population routinely not screened, has been increasing. We report a rare case of high-grade CRC in a previously healthy 27-year-old man, presented to us with symptoms of increasing abdominal pain and distension. Extensive diagnostic investigation revealed hepatomegaly with multiple processes, signs of vasculitis, extensive liver necrosis, enlarged retroperitoneal and mesenteric lymph nodes, splenomegaly, ascites and multiple vein thrombosis. The patient passed away shortly after admission due to treatment-resistant tumour lysis syndrome and multiple organ failure. Biopsy results revealed disseminated adenocarcinoma of the colon, with metastases to lymph nodes, liver, lungs and pleura. CRC in younger patients tend to present at a later stage and appears to be more aggressive, with a poorer pathological differentiation. | 25,253,481 | [
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Bifidobacterium--friend or foe? A case of urinary tract infection with Bifidobacterium species. | Bifidobacterium-a commensal of the human intestine is considered non-pathogenic and has been advocated as a probiotic due to its potential beneficial effects. However, there have been case reports implicating bifidobacteria as pathogenic agents in a variety of different infectious conditions. We discuss here one such case of a complicated urinary tract infection associated with Bifidobacterium spp. | 25,253,483 | [
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Musical hallucinations responding to a further increase of carbamazepine. | A 73-year-old woman outpatient with mild cognitive impairment, parasomnia and depressive state with musical hallucinations failed to respond to 400 mg/day of valproate. Once she was admitted to a university hospital, her musical hallucinations partially responded to 1 mg/day of clonazepam and sufficiently improved on 100 mg/day of carbamazepine. Two months after discharge, however, her musical hallucinations recurred probably as a consequence of psychological stress. The increase of carbamazepine from 100 to 200 mg/day completely remitted her musical hallucinations. This case suggests that musical hallucinations respond in a dose-dependent manner to increasing carbamazepine, and that gradual titration from small doses of carbamazepine is required because optimal doses appear to be smaller than those required for epilepsy and bipolar disorder. Further studies are warranted to determine the therapeutic levels of carbamazepine for musical hallucinations. | 25,253,486 | [
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The perception of nanotechnology and nanomedicine: a worldwide social media study. | We explore at a world level the awareness of nanotechnology expressed through the most popular online social media: Facebook. We aimed at identifying future trends, the most interested countries and the public perception of ethics, funding and economic issues. We found that graphene and carbon nanotubes are the most followed nanomaterials. Our poll showed that the continents with the most interest are Asia and Africa. A total of 43% would like to have a world commission regulating nanomedicine. In addition, 43% would give priority to theranostics. Over 90% believe that nanomedicine has an economic impact. Finally, we observed that the continents of living and origin of poll contributors correlated with ethic and funding opinions. This study highlights the potential of online social media to influence scientific communities, grant committees and nanotechnology companies, spreading nanotechnology awareness in emerging countries and among new generations. | 25,253,496 | [
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Multifunctional nanocarriers for simultaneous encapsulation of hydrophobic and hydrophilic drugs in cancer treatment. | Combination therapy for cancer patients is an important standard of care protocol because it can elicit synergistic therapeutic effects and reduce systemic toxicity by simultaneously modulating multiple cell-signaling pathways and overcoming multidrug resistance. Nanocarriers are expected to play a major role in delivering multiple drugs to tumor tissues by overcoming biological barriers. However, especially considering the different physical chemistry of chemotherapeutic drugs, it is highly desirable to develop a codelivery nanocarrier for controlled and targeted delivery of both hydrophobic and hydrophilic drugs. This review reports the recent developments in various combinational drug delivery systems and the simultaneous use of combinational drug delivery systems with functional agents. | 25,253,498 | [
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Synthetic and bioinspired cage nanoparticles for drug delivery. | Nanotechnology has the potential to revolutionize drug delivery, but still faces some limitations. One of the main issues regarding conventional nanoparticles is their poor drug-loading and their early burst release. Thus, to overcome these problems, researchers have taken advantage of the host-guest interactions that drive some assemblies to form cage molecules able to strongly entrap their cargo and design new nanocarriers called cage nanoparticles. These systems can be classified into two categories: bioinspired nanosystems such as virus-like particles, ferritin, small heat shock protein: and synthetic host-guest supramolecular systems that require engineering to actually form supramolecular nanoassemblies. This review will highlight the recent advances in cage nanoparticles for drug delivery with a particular focus on their biomedical applications. | 25,253,501 | [
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Conduction abnormality and arrhythmia after transcatheter closure of atrial septal defect. | The aim of this study was to prospectively perform ambulatory 24-h ECG monitoring to assess the effects of transcatheter closure of atrial septal defect (ASD). A total of 235 consecutive subjects (female, n=163; male, n=72; age, 44.6±14.4 years) were enrolled in the study, who were due undergo ASD closure. Holter monitoring was performed before procedure and at 1, 6 and 12 months of follow-up. During the procedure transient supraventricular arrhythmia occurred in 8 patients (3.4%), and bradycardia in 3 (1.3%). In 3 patients (1.3%) an episode of atrial fibrillation occurred in the first hour after the procedure. In 8 patients (3.4%) transient first-degree atrioventricular block was noted. A significant increase in number of supraventricular extrasystoles (SVES)/24 h was noted 1 month after the procedure (P<0.001). On multiple forward stepwise regression analysis, device size and fluoroscopy time had an influence on increase in number of SVES seen 1 month after the procedure (P<0.001). Transcatheter closure of ASD is associated with a transient increase in supraventricular premature beats and a small risk of conduction abnormalities and paroxysmal atrial fibrillation in early follow-up. Transcatheter closure of ASD does not reduce arrhythmia that appears prior to ASD closure. Larger device size and longer procedure time are associated with increased risk of supraventricular arrhythmia on early follow-up. | 25,253,507 | [
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Probing the rate-limiting step for intramolecular transfer of a transcription factor between specific sites on the same DNA molecule by (15)Nz-exchange NMR spectroscopy. | The kinetics of translocation of the homeodomain transcription factor HoxD9 between specific sites of the same or opposite polarities on the same DNA molecule have been studied by (15)Nz-exchange NMR spectroscopy. We show that exchange occurs by two facilitated diffusion mechanisms: a second-order intermolecular exchange reaction between specific sites located on different DNA molecules without the protein dissociating into free solution that predominates at high concentrations of free DNA, and a first-order intramolecular process involving direct transfer between specific sites located on the same DNA molecule. Control experiments using a mixture of two DNA molecules, each possessing only a single specific site, indicate that transfer between specific sites by full dissociation of HoxD9 into solution followed by reassociation is too slow to measure by z-exchange spectroscopy. Intramolecular transfer with comparable rate constants occurs between sites of the same and opposing polarity, indicating that both rotation-coupled sliding and hopping/flipping (analogous to geminate recombination) occur. The half-life for intramolecular transfer (0.5-1 s) is many orders of magnitude larger than the calculated transfer time (1-100 μs) by sliding, leading us to conclude that the intramolecular transfer rates measured by z-exchange spectroscopy represent the rate-limiting step for a one-base-pair shift from the specific site to the immediately adjacent nonspecific site. At zero concentration of added salt, the intramolecular transfer rate constants between sites of opposing polarity are smaller than those between sites of the same polarity, suggesting that hopping/flipping may become rate-limiting at very low salt concentrations. | 25,253,516 | [
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Immunological disorders of diabetes mellitus in experimental rat models. | A comprehensive understanding of the pathogenic mechanism is the prerequisite for proper disease management. However, the mechanisms of diabetes mellitus and diabetic complication remain extremely complicated and unresolved. While immune reactions are involved in the pathogenesis of diabetes and diabetic complication, the diabetic condition itself can influence immune responses. Furthermore, both diabetes and immune reactions are regulated by genetic and environmental factors. As a result, animal models have evolved to be powerful research tools to elucidate the complicated mechanisms for the pathogenesis of diabetes. Recently, various animal models of diabetes have been developed in rats, which provide advantages over mouse models in the scale of tissue samples and variation in type 2 diabetes models. In this review, we introduced rat models of diabetes and summarized the immune reactions in diabetic rats to propose the relationship between immune reactions and diabetes. Type 1 diabetes is induced by self-reactive cellular immune reactions. On the other hand, type 2 diabetes in rat models is associated with augmentation of innate immune reactions and increased humoral immunity. For example, helper T (Th) 1/Th17 cells are prevalent in non-obese type 1 diabetes rats (diabetes-prone BioBreeding rats), while non-obese type 2 diabetes rats (Goto-Kakizaki rat) show higher levels of natural IgM and T cell ratios with elevated Th2 cells compared with Wister rats. The investigation of immunological disorders in various diabetic rat models is useful to elucidate complicated mechanisms for the pathophysiology of diabetes. In future studies, immunological experimentations altering Th1/Th17 or Th2 cell levels and natural immune reactions may lend support to understanding the causes of diabetes and predicting the pathological conditions in diabetes. | 25,253,518 | [
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Delineating fibronectin bioadhesive micropatterns by photochemical immobilization of polystyrene and poly(vinylpyrrolidone). | Bioadhesive micropatterns, capable of laterally confining cells to a 2D lattice, have proven effective in simulating the in vivo tissue environment. They reveal fundamental aspects of the role of adhesion in cell mechanics, proliferation, and differentiation. Here we present an approach based on photochemistry for the fabrication of synthetic polymer micropatterns. Perfluorophenyl azide (PFPA), upon deep-UV exposure, forms a reactive nitrene capable of covalently linking to a molecule that is in close proximity. PFPA has been grafted onto a backbone of poly(allyl amine), which readily forms a self-assembled monolayer on silicon wafers or glass. A film of polystyrene was applied by spin-coating, and by laterally confining the UV exposure through a chromium-on-quartz photomask, monolayers of polymers could be immobilized in circular microdomains. Poly(vinylpyrrolidone) (PVP) was attached to the background to form a barrier to nonspecific protein adsorption and cell adhesion. Micropatterns were characterized with high-lateral-resolution time-of-flight secondary ion mass spectrometry (TOF-SIMS), which confirmed the formation of polystyrene domains within a PVP background. Fluorescence-microscopy adsorption assays with rhodamine-labeled bovine serum albumin demonstrated the nonfouling efficiency of PVP and, combined with TOF-SIMS, allowed for a comprehensive characterization of the pattern geometry. The applicability of the micropatterned platform in single-cell assays was tested by culturing two cell types, WM 239 melanoma cells and SaOs-2 osteoblasts, on micropatterned glass, either with or without backfilling of the patterns with fibronectin. It was demonstrated that the platform was efficient in confining cells to the fibronectin-backfilled micropatterns for at least 48 h. PVP is thus proposed as a viable, highly stable alternative to poly(ethylene glycol) for nonfouling applications. Due to the versatility of the nitrene-insertion reaction, the platform could be extended to other polymer pairs or proteins and the surface chemistry adapted to specific applications. | 25,253,530 | [
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Novel N-amidinopiperidine-based proteasome inhibitor preserves dendritic cell functionality and rescues their Th1-polarizing capacity in Ramos-conditioned tumor environment. | The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt's lymphoma cells through proteasome inhibition. Here, we demonstrate that SPI-15 affected neither the viability of DCs nor their differentiation. In addition, the compound had no significant effect on their cytokine secretion or allostimulatory capacity. Moreover, DC functionality in the context of tumor microenvironment was also unaffected, as demonstrated by experiments performed on DCs differentiated in Ramos-conditioned media in the presence or absence of SPI-15. The cytokine profile and functional assays revealed that SPI-15 rescues DC differentiation from the immunosuppressive environment produced by Ramos cells; this was seen by their reacquired ability to induce IFN-γ-secretion from naïve CD4(+)CD45RA(+) T cells and the consequently induced Th1-effector differentiation. Herein, we present novel characteristics of an N-amidinopiperidine-based protease inhibitor whose anticancer properties are not associated with the immunosuppression of DCs. We propose future studies toward the design of structurally similar compounds with the aim of developing potent anticancer drugs with minimal negative effects on crucial factors involved in tumor immunity. | 25,253,531 | [
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Direct enzyme-substrate affinity determination by real-time hyperpolarized (13)C-MRS. | A specialized kinetic analysis of real-time hyperpolarized [1,1,2,2-D4, 1-(13)C]choline (13)C-magnetic resonance spectroscopy enabled the determination of initial rates of metabolic enzyme activity (choline oxidase), enzyme-substrate affinity (Km), and inhibition. In a clinical MRI scanner, metabolite levels lower than 16 μM were detected at a temporal resolution of 1 s. | 25,253,534 | [
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Correlation analysis of STAT3 and VEGF expression and eosinophil infiltration in nasal polyps. | The expression and distribution of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), and vascular endothelial growth factor (VEGF), as well as eosinophil infiltration in nasal polyps was detected to examine their roles and correlations in the nasal polyp pathogenesis. Using the streptavidin-biotin-peroxidase (SP) method, immunohistochemistry was performed on conventional paraffin sections of 30 surgery-resected polypous specimens and 10 inferior turbinate tissues that were resected during nasal septum deflection correction to detect the expression of STAT3, p-STAT3, and VEGF, as well as eosinophil infiltration. The rates of STAT3-, p-STAT3-, and VEGF-positive expression in the mucosal epithelium and glands of nasal polyps were 66.67, 56.67, and 76.67 %, respectively, values that were significantly higher than those in the inferior turbinate group. The number of eosinophils in the nasal polyps was significantly higher than in the inferior turbinate group. Expression of p-STAT3 and VEGF in nasal polyps and eosinophil infiltration was increased significantly and positively correlated, indicating that VEGF and eosinophil infiltration might be regulated by p-STAT3. Therefore, the expression of STAT3, p-STAT3, and VEGF, and eosinophil infiltration might be important factors in nasal polyp pathogenesis. | 25,253,546 | [
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Multifocal electroretinography in subjects with age-related macular degeneration. | To evaluate retinal function objectively in subjects with different stages of age-related macular degeneration (AMD) using multifocal electroretinography (mfERG) and compare it with age-matched control group. A total of 42 subjects with AMD and 37 age-matched healthy control group aged over 55 years were included in this prospective study. mfERG test was performed to all subjects. Average values in concentric ring analysis in four rings (ring 1, from 0° to 5° of eccentricity relative to fixation; ring 2, from 5° to 10°; ring 3, from 10° to 15°; ring 4, over 15°) and in quadrant analysis (superior nasal quadrant, superior temporal quadrant, inferior nasal quadrant and inferior temporal quadrant) were recorded. Test results were evaluated by one-way ANOVA test and independent samples t test. In mfERG concentric ring analysis, N1 amplitude, P1 amplitude and N2 amplitude were found to be lower and N1 implicit time, P1 implicit time and N2 implicit time were found to be delayed in subjects with AMD compared to control group. In quadrant analysis, N1, P1 and N2 amplitude was lower in all quadrants, whereas N1 implicit time was normal and P1 and N2 implicit times were prolonged in subjects with AMD. mfERG is a useful test in evaluating retinal function in subjects with AMD. AMD affects both photoreceptors and inner retinal function at late stages. | 25,253,559 | [
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Antiphosphatidylserine antibodies as diagnostic indicators of antiphospholipid syndrome. | Antiphospholipid syndrome (APS) is an autoimmune condition that is diagnosed by the presence of at least one of the clinical manifestations (thrombosis and/or pregnancy failure) and one of antiphospholipid antibodies (aPL) laboratory tests. The most relevant aPL are lupus anticoagulant (LA), anti-beta2 glycoprotein I (aβ2GPI) and anticardiolipin (aCL). The clinical significance of other antibodies like anti-phosphatidylserine antibodies (aPS) is still under investigation. The aim of the study was to assess the diagnostic value of aPS antibodies, and to compare their utility to that of other aPL antibodies. We conducted a prospective observational study consisting of 212 patients with suspected thrombosis, pregnancy failure, or unexplained, prolonged clotting time. Data on demography, clinical presentation and autoantibody levels were assessed. Descriptive analysis, accuracy analysis, sensitivity, specificity, predictive value and likelihood ratio were calculated for aPS in comparison to other aPL. The diagnostic value of aPS versus other aPL antibodies revealed the high specificity of aPS (87%), with 70% of aPS-positive patients being confirmed APS. When the aPS test was used as a single test, it was effective for detection of confirmed APS cases (p < 0.01). Among 28 confirmed primary APS cases, 75% of patients were positive for aPS (p < 0.003). Moreover, by using aPS we detected three additional confirmed APS cases and another three probable cases. Our findings reveal a significant association between aPS and APS, especially when used to diagnosis clinical cases with other negative aPL tests. There is an independent association between aPS and primary APS. In addition, these results demonstrated the advantages of using aPS as a diagnostic test for APS. | 25,253,571 | [
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Current and investigational drugs for the prevention of migraine in adults and children. | There are only a handful of drugs that have been submitted for and received an indication for the preventative treatment of migraine by the US Food and Drug Administration, as well as international governmental regulatory agencies. However, there are a wide variety of agents that are used for this indication with different levels of evidence for efficacy and tolerability. Several guidelines have been published in recent years examining the evidence-based medicine of migraine preventative therapy and these provide guidance especially for the primary care clinician, but also for neurologists whose primary focus is not headache medicine. Some of the therapies are used in children and adolescents while others are used more commonly in adults. In the adult population, an evolutive state of migraine is more commonly seen than in young persons, that is chronic migraine. There is a paucity of evidence for medications for this stage of migraine but there is a single agent that is approved for this use but not for use in the treatment of episodic migraine. There have been few advances in the field of migraine-preventative medications in recent years but potential novel approaches are in development. | 25,253,573 | [
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Structure-based inhibition of protein-protein interactions. | Protein-protein interactions (PPIs) are emerging as attractive targets for drug design because of their central role in directing normal and aberrant cellular functions. These interactions were once considered "undruggable" because their large and dynamic interfaces make small molecule inhibitor design challenging. However, landmark advances in computational analysis, fragment screening and molecular design have enabled development of a host of promising strategies to address the fundamental molecular recognition challenge. An attractive approach for targeting PPIs involves mimicry of protein domains that are critical for complex formation. This approach recognizes that protein subdomains or protein secondary structures are often present at interfaces and serve as organized scaffolds for the presentation of side chain groups that engage the partner protein(s). Design of protein domain mimetics is in principle rather straightforward but is enabled by a host of computational strategies that provide predictions of important residues that should be mimicked. Herein we describe a workflow proceeding from interaction network analysis, to modeling a complex structure, to identifying a high-affinity sub-structure, to developing interaction inhibitors. We apply the design procedure to peptidomimetic inhibitors of Ras-mediated signaling. | 25,253,637 | [
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Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice. | Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17-19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment. | 25,253,649 | [
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Phase I/II randomized trial of safety and immunogenicity of LIPO-5 alone, ALVAC-HIV (vCP1452) alone, and ALVAC-HIV (vCP1452) prime/LIPO-5 boost in healthy, HIV-1-uninfected adult participants. | Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 μg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 μg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063. | 25,253,665 | [
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Clinical characteristics and antiretroviral treatment of older HIV-infected patients. | The number of Human Immunodeficiency Virus (HIV) patients aged 50 years or over is growing year on year, due to both late diagnoses and the chronicity of the illness. This increase is a new phenomenon. To describe the clinical and epidemiological characteristics of the older HIV infected population and determine if there are differences in antiretroviral treatment between younger and older patients. This study was conducted in the outpatient hospital pharmacy service of a University Hospital in Spain. A descriptive study involving HIV infected patients aged 50 years or older who received ambulatory antiretroviral therapy between January and December 2011. Variables related to HIV and to antiretroviral therapy were collected. A comparison of antiretroviral drugs used was made with the populations older and younger than 50 years. Antiretroviral therapy differences between older and younger HIV-patients. 130 patients (20% of the antiretroviral treated patients) were 50 or over and 77% of these was aged between 50 and 59. At the time of diagnosis, 50% suffered an advanced state of disease. At the end of the study period, 58% had CD4 lymphocyte levels of over 500 cells/mm(3) and 90% had an undetectable viral load. The antiretroviral therapy of the older group that was based on protease inhibitors was used in the 51.5% of the patients compared with 54.4% in the younger group. The figures for nonnucleoside reverse transcriptase inhibitors based therapy were 43.8 and 39.8%, respectively. The older population used treatments that included tenofovir (56.9 vs. 64.8%, p = 0.105) less frequently and used more treatments that included abacavir (26.9 vs. 19.1%, p = 0.054) than the under 50's. Half the older HIV-infected patients were diagnosed with an advanced disease and the majority showed a positive response to antiretroviral therapy. There are no statistically significant differences between the frequency of antiretroviral therapy use in older and younger HIV-patients, although older HIV-patients has less often used treatments with tenofovir and more often used treatments with abacavir. | 25,253,678 | [
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Distinct Patterns of Everyday Executive Function Problems Distinguish Children With Tourette Syndrome From Children With ADHD or Autism Spectrum Disorders. | The aim is to investigate the everyday executive function (EF) in children with Tourette syndrome (TS), Inattentive or Combined presentations of ADHD (ADHD-I/ADHD-C), autism spectrum disorders (ASD), and typically developing children (TDC). Nineteen TS, 33 ADHD-C, 43 ADHD-I, 34 ASD, and 50 TDC participated (8-17 years). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). TS, ADHD-C, ADHD-I, or ASD were rated with significantly more regulation problems on all scales compared with TDC. Considerable overlap of symptoms between clinical groups made differentiation difficult on individual scales. Scale configurations showed children with TS to have more problems with emotional control (EC) than cognitive flexibility in relation to children with ASD, more problems with EC than inhibitory control in relation to ADHD-C, and more problems with EC than planning/organizing in relation to ADHD-I. Paired BRIEF scales dissociated EF problems in children with TS from children with ADHD-C, ADHD-I, or ASD. Clinical relevance is discussed. | 25,253,683 | [
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Structural and biochemical characterization of Chlamydia trachomatis hypothetical protein CT263 supports that menaquinone synthesis occurs through the futalosine pathway. | The obligate intracellular human pathogen Chlamydia trachomatis is the etiological agent of blinding trachoma and sexually transmitted disease. Genomic sequencing of Chlamydia indicated this medically important bacterium was not exclusively dependent on the host cell for energy. In order for the electron transport chain to function, electron shuttling between membrane-embedded complexes requires lipid-soluble quinones (e.g. menaquionone or ubiquinone). The sources or biosynthetic pathways required to obtain these electron carriers within C. trachomatis are poorly understood. The 1.58Å crystal structure of C. trachomatis hypothetical protein CT263 presented here supports a role in quinone biosynthesis. Although CT263 lacks sequence-based functional annotation, the crystal structure of CT263 displays striking structural similarity to 5'-methylthioadenosine nucleosidase (MTAN) enzymes. Although CT263 lacks the active site-associated dimer interface found in prototypical MTANs, co-crystal structures with product (adenine) or substrate (5'-methylthioadenosine) indicate that the canonical active site residues are conserved. Enzymatic characterization of CT263 indicates that the futalosine pathway intermediate 6-amino-6-deoxyfutalosine (kcat/Km = 1.8 × 10(3) M(-1) s(-1)), but not the prototypical MTAN substrates (e.g. S-adenosylhomocysteine and 5'-methylthioadenosine), is hydrolyzed. Bioinformatic analyses of the chlamydial proteome also support the futalosine pathway toward the synthesis of menaquinone in Chlamydiaceae. This report provides the first experimental support for quinone synthesis in Chlamydia. Menaquinone synthesis provides another target for agents to combat C. trachomatis infection. | 25,253,688 | [
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Secreted Frizzled-related protein 1 (Sfrp1) regulates the progression of renal fibrosis in a mouse model of obstructive nephropathy. | Renal fibrosis is responsible for progressive renal diseases that cause chronic renal failure. Sfrp1 (secreted Frizzled-related protein 1) is highly expressed in kidney, although little is known about connection between the protein and renal diseases. Here, we focused on Sfrp1 to investigate its roles in renal fibrosis using a mouse model of unilateral ureteral obstruction (UUO). In wild-type mice, the expression of Sfrp1 protein was markedly increased after UUO. The kidneys from Sfrp1 knock-out mice showed significant increase in expression of myofibrobast markers, α-smooth muscle actin (αSMA). Sfrp1 deficiency also increased protein levels of the fibroblast genes, vimentin, and decreased those of the epithelial genes, E-cadherin, indicated that enhanced epithelial-to-mesenchymal transition. There was no difference in the levels of canonical Wnt signaling; rather, the levels of phosphorylated c-Jun and JNK were more increased in the Sfrp1(-/-) obstructed kidney. Moreover, the apoptotic cell population was significantly elevated in the obstructed kidneys from Sfrp1(-/-) mice following UUO but was slightly increased in those from wild-type mice. These results indicate that Sfrp1 is required for inhibition of renal damage through the non-canonical Wnt/PCP pathway. | 25,253,698 | [
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Coordination and plasticity in leaf anatomical traits of invasive and native vine species. | • Plant invasiveness can be promoted by higher values of adaptive traits (e.g., photosynthetic capacity, biomass accumulation), greater plasticity and coordination of these traits, and by higher and positive relative influence of these functionalities on fitness, such as increasing reproductive output. However, the data set for this premise rarely includes linkages between epidermal-stomatal traits, leaf internal anatomy, and physiological performance.• Three ecological pairs of invasive vs. noninvasive (native) woody vine species of South-East Queensland, Australia were investigated for trait differences in leaf morphology and anatomy under varying light intensity. The linkages of these traits with physiological performance (e.g., water-use efficiency, photosynthesis, and leaf construction cost) and plant adaptive traits of specific leaf area, biomass, and relative growth rates were also explored.• Except for stomatal size, mean leaf anatomical traits differed significantly between the two groups. Plasticity of traits and, to a very limited extent, their phenotypic integration were higher in the invasive relative to the native species. ANOVA, ordination, and analysis of similarity suggest that for leaf morphology and anatomy, the three functional strategies contribute to the differences between the two groups in the order phenotypic plasticity > trait means > phenotypic integration.• The linkages demonstrated in the study between stomatal complex/gross anatomy and physiology are scarce in the ecological literature of plant invasiveness, but the findings suggest that leaf anatomical traits need to be considered routinely as part of weed species assessment and in the worldwide leaf economic spectrum. | 25,253,703 | [
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An agent-based model for mRNA export through the nuclear pore complex. | mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood. The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known. It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the nuclear pore complex. Using previously published biophysical and biochemical parameters of mRNA export, we implemented a three-dimensional, coarse-grained, agent-based model of mRNA export in the nanosecond regime to gain insight into these issues. On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA and that there is a rate-limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel. Of note, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport. This has implications for future experimental design to study mRNA transport dynamics. | 25,253,717 | [
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Platelet-activating factor: a role in preterm delivery and an essential interaction with Toll-like receptor signaling in mice. | Platelet-activating factor (PAF), a potent phospholipid activator of inflammation that signals through its cognate receptor (platelet-activating factor receptor, PTAFR), has been shown to induce preterm delivery in mice. Toll-like receptors (TLRs) are transmembrane receptors that mediate innate immunity. We have shown previously that Escherichia coli-induced preterm delivery in mice requires TLR signaling via the adaptor protein myeloid differentiation primary response gene 88 (MyD88), but not an alternative adaptor, Toll/IL-1 receptor domain-containing adapter protein-inducing interferon-beta (TRIF). In the present work, we analyzed the role of endogenously produced PAF in labor using mice lacking (knockout [KO]) PAF acetylhydrolase (PAF-AH; the key degrading enzyme for PAF). PAF-AH KO mice are more susceptible to E. coli-induced preterm delivery and inflammation than controls. In peritoneal macrophages, the PTAFR agonist carbamyl PAF induces production of inflammatory markers previously demonstrated to be upregulated during bacterially induced labor, including: inducible nitric oxide synthase (Nos2), the chemokine Ccl5 (RANTES), tumor necrosis factor (Tnf), and level of their end-products (NO, CCL5, TNF) in a process dependent upon both IkappaB kinase and calcium/calmodulin-dependent protein kinase II. Interestingly, this induced expression was completely eliminated not only in macrophages deficient in PTAFR, but also in those lacking either TLR4, MyD88, or TRIF. The dependence of PAF effects upon TLR pathways appears to be related to production of PTAFR itself: PAF-induced expression of Ptafr mRNA was eliminated completely in TLR4 KO and partially in MyD88 and TRIF KO macrophages. We conclude that PAF signaling plays an important role in bacterially induced preterm delivery. Furthermore, in addition to its cognate receptor, PAF signaling in peritoneal macrophages requires TLR4, MyD88, and TRIF. | 25,253,732 | [
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Amino acid 72 of mouse and human GDF9 mature domain is responsible for altered homodimer bioactivities but has subtle effects on GDF9:BMP15 heterodimer activities. | Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted paralogs of the transforming growth factor beta (TGFbeta) superfamily. In mammals, these two growth factors play critical roles in folliculogenesis. As previously reported, an arginine in the pre-helix loop of GDF5 defines the high binding specificity to its type 1 receptor. Interestingly, bioactive mouse GDF9 and human BMP15 share the conserved arginine in the pre-helix loop, but their low-activity counterparts (mouse BMP15 and human GDF9) have a glycine or a proline instead. To address the question of whether the arginine residue defines the different activities of GDF9 and BMP15 homodimers and their heterodimers in human and mouse, we used site-directed mutagenesis to change the species-specific residues in human and mouse proteins, and examined their activities in our in vitro assays. Although amino acid 72 of mature GDF9 is responsible for altered homodimer bioactivities, neither the corresponding BMP15 amino acid 62 nor the intact pre-helix loop is indispensable for BMP15 homodimer activity. However, amino acid 72 in GDF9 only has only subtle effects on GDF9:BMP15 heterodimer activity. Based on previous studies and our recent findings, we provide hypothetical models to understand the molecular mechanism to define activities of the homodimeric and heterodimeric ligands. The arginine residue in the pre-helix loop of GDF9 homodimer may prevent the inhibition from its pro-domain or directly alter receptor binding, but this residue in GDF9 does not significantly affect the heterodimer activity, because of suggested conformational changes during heterodimer formation. | 25,253,739 | [
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Reproducibility of retinal oxygen saturation in normal and treated glaucomatous eyes. | To measure the reproducibility of retinal oxygen saturation (SaO2) levels among treated glaucomatous eyes and normal controls in a prospective non-randomised study. Patients with perimetric glaucoma (PG) and normal controls were included. Exclusion criteria for both groups included visual acuity <20/30, unreliable visual fields, thyroidopathies, hemoglobinopathies, cardiovascular and pulmonary diseases. Retinal oximetry was performed twice consecutively on one randomly selected eye of PG and normal controls using spectrophotometric retinal oximeter (SRO; Oxymap ehf., Iceland). Four main retinal vessel pairs were analysed separately. Coefficients of variability (CoV), coefficients of repeatability (CoR) and intraclass correlation coefficients (ICCs) in arteries (a.SaO2) and veins (v.SaO2) were calculated. 23 PG (mean age 68.3±10.8 years) and 22 normal subjects (mean age 61.5±18.2 years; p=0.14) were included. The intraocular pressure and mean ocular perfusion pressure in glaucoma (14.4±4.2 mm Hg; 45.8±5.8 mm Hg) and controls (14.3±3.3 mm Hg; 45.8±6.1 mm Hg) were similar (p >0.05). In the PG group, the a.SaO2 had a CoV of 1.6%, a CoR of 4.7 and an ICC of 0.97; the v.SaO2 had a CoV of 5.9%, a CoR of 8.7 and an ICC of 0.96. In normals, the a.SaO2 had a CoV of 0.98%, a CoR of 3.3 and an ICC of 0.97; the v.SaO2 had a CoV of 4.8%, a CoR of 7.7 and an ICC of 0.93. Retinal oximetry measurements using SRO are highly reproducible in both treated glaucomatous and normal eyes. | 25,253,765 | [
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Triple-negative breast cancer patients treated at MD Anderson Cancer Center in phase I trials: improved outcomes with combination chemotherapy and targeted agents. | Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥ 6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤ 2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC. | 25,253,784 | [
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Clinical laboratory response to a mock outbreak of invasive bacterial infections: a preparedness study. | Large hospital-based clinical laboratories must be prepared to rapidly investigate potential infectious disease outbreaks. To challenge the ability of our molecular diagnostics laboratory to use whole-genome sequencing in a potential outbreak scenario and identify impediments to these efforts, we studied 84 invasive serotype emm59 group A streptococcus (GAS) strains collected in the United States. We performed a rapid-response exercise to the mock outbreak scenario using whole-genome sequencing, genome-wide transcript analysis, and mouse virulence studies. The protocol changes installed in response to the lessons learned were tested in a second iteration. The initial investigation was completed in 9 days. Whole-genome sequencing showed that the invasive infections were caused by multiple subclones of epidemic emm59 GAS strains likely spread to the United States from Canada. The phylogenetic tree showed a strong temporal-spatial structure with diversity in mobile genetic element content, features that are useful for identifying closely related strains and possible transmission events. The genome data informed the epidemiology, identifying multiple patients who likely acquired the organisms through direct person-to-person transmission. Transcriptome analysis unexpectedly revealed significantly altered expression of genes encoding a two-component regulator and the hyaluronic acid capsule virulence factor. Mouse infection studies confirmed a high-virulence capacity of these emm59 organisms. Whole-genome sequencing, coupled with transcriptome analysis and animal virulence studies, can be rapidly performed in a clinical environment to effectively contribute to patient care decisions and public health maneuvers. | 25,253,790 | [
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A Tradeoff Between Accuracy and Flexibility in a Working Memory Circuit Endowed with Slow Feedback Mechanisms. | Recent studies have shown that reverberation underlying mnemonic persistent activity must be slow, to ensure the stability of a working memory system and to give rise to long neural transients capable of accumulation of information over time. Is the slower the underlying process, the better? To address this question, we investigated 3 slow biophysical mechanisms that are activity-dependent and prominently present in the prefrontal cortex: Depolarization-induced suppression of inhibition (DSI), calcium-dependent nonspecific cationic current (ICAN), and short-term facilitation. Using a spiking network model for spatial working memory, we found that these processes enhance the memory accuracy by counteracting noise-induced drifts, heterogeneity-induced biases, and distractors. Furthermore, the incorporation of DSI and ICAN enlarges the range of network's parameter values required for working memory function. However, when a progressively slower process dominates the network, it becomes increasingly more difficult to erase a memory trace. We demonstrate this accuracy-flexibility tradeoff quantitatively and interpret it using a state-space analysis. Our results supports the scenario where N-methyl-d-aspartate receptor-dependent recurrent excitation is the workhorse for the maintenance of persistent activity, whereas slow synaptic or cellular processes contribute to the robustness of mnemonic function in a tradeoff that potentially can be adjusted according to behavioral demands. | 25,253,801 | [
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Effects of maternal protein or energy restriction during late gestation on immune status and responses to lipopolysaccharide challenge in postnatal young goats. | Knowledge of maternal malnutrition of ruminants and effects on development of the immune system of their offspring is lacking. A study was conducted to investigate the effects of maternal protein or energy restriction during late gestation on immune status of their offspring at different ages. Sixty-three pregnant goats (local breed, Liuyang black goat, 22.2 ± 1.5 kg at d 90 of gestation) were fed control (CON, ME = 9.34 MJ/kg and CP = 12.5%, DM basis), 40% protein restricted (PR), or 40% energy restricted (ER) diets from d 91 of gestation to parturition, after which all animals received an adequate diet for nutritional recovery. Plasma concentrations of complement components (C3, C4), C-reactive protein (CRP) and immunoglobulins (IgG and IgM), jejunum cytokines (IL-2, IL-6, and IL-10) expression levels and morphology in the offspring were measured. Additionally, plasma concentration of complement and IL-6, and cytokines expression levels in gastrointestinal tract obtained at 6 wk from young goats were assessed under saline or lipopolysaccharide (LPS) challenging conditions. Maternal PR or ER decreased (P < 0.05) plasma C3, C4, IgG, and IgM concentrations, and IL-2 and IL-6 mRNA expression in the jejunum from neonatal kids, but did not alter (P > 0.05) plasma CRP concentration. The IL-10 mRNA expression of jejunum from PR kids was also less (P < 0.01) than that from CON kids. Moreover, jejunum villous height (P < 0.10 in PR, P < 0.05 in ER) and crypt depth (P < 0.05 both in PR and ER) were reduced in neonatal kids from malnourished mothers. At 6 wk of age, there were no differences (P > 0.05) in any plasma or tissue immune parameters among the 3 treatments. However, when given a LPS challenge, ER and PR kids had greater (P = 0.02) IL-6 concentration compared with CON kids. Our results suggest that both PR and ER during late gestation induced short-term as well as long-lasting alterations on immune responses in their offspring, which may make the animals more susceptible to a bacterial pathogen challenge. The present findings expand the existing knowledge in immunological mechanisms responsible for the development of disease in later life. | 25,253,814 | [
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Predicting microbial protein synthesis in beef cattle: relationship to intakes of total digestible nutrients and crude protein. | Prediction of microbial CP (MCP) synthesis in the rumen is an integral part of the MP system. For the NRC beef model, MCP is calculated as 0.13 multiplied by TDN intake (TDNI), with adjustment for physically effective NDF (peNDF) concentrations less than 20%. Despite its application for nearly 2 decades, MCP predictions using this approach have not been extensively evaluated. We assembled a database of 285 treatment means from 66 published papers using beef cattle and dairy or dairy × beef crossbred steers, fed diets with a wide range of TDN, CP, and ether extract (EE) concentrations, in which MCP synthesis was measured. Fat-free TDN (FFTDN) concentration was calculated by subtracting 2.25 × percent EE from the TDN concentration. Based on initial model selection procedures indicating that DMI and concentrations of TDN, FFTDN, and CP were significantly (P < 0.04) related to MCP synthesis, linear and quadratic effects of TDNI and FFTDN intake (FFTDNI) and CP intake (CPI) were considered as potential independent variables. Mixed model regression methods were used to fit 1-, 2-, and 3-independent-variable models based on either TDNI or FFTDNI (e.g., TDNI only, TDNI and CPI, and TDNI, CPI, and the quadratic effect of TDNI; or FFTDNI only, FFTDNI and CPI, and FFTDNI, CPI, and the quadratic effect of FFTDNI). True ruminal OM digested (TROMD; g/d) was highly related (r(2) = 0.84 using citation-adjusted data) to MCP synthesis. Similarly, both TDNI and FFTDNI were highly related to citation-adjusted TROMD (r(2) > 0.96) and MCP synthesis (r(2) > 0.89). Models with FFTDNI were slightly more precise with slightly smaller prediction errors than those with TDNI. Randomly dividing the citations into Development (60%) and Evaluation (40%) data sets indicated that models such as those derived from the overall database accounted for 46 to 56% of the variation in MCP synthesis, with neither mean nor linear bias (P ≥ 0.26). In contrast, calculating MCP as 0.13 × TDNI, with or without adjustment for peNDF concentration, resulted in overprediction of MCP (P < 0.001 for both mean and linear bias). Cross-validation using 5,000 randomly drawn training and testing data sets yielded results similar to the Development/Evaluation approach. Recommended equations are provided, but the errors of prediction associated with these empirical regression equations were on the order of 25 to 30% of the mean MCP. | 25,253,815 | [
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Characteristics of patients with graves disease and intrathyroid hypovascularity compared to painless thyroiditis. | The purpose of this study was to assess the frequency and sonographic and laboratory characteristics of Graves disease with intrathyroid hypovascularity in Japanese patients and to compare these characteristics in patients with painless thyroiditis. A total of 194 consecutive patients with Graves disease and 21 patients with painless thyroiditis were enrolled. The patients underwent thyroid volume measurement, mean superior thyroid artery peak systolic velocity (PSV) measurement, power Doppler sonography, and proper blood testing to discriminate between Graves disease and painless thyroiditis. Based on the power Doppler sonographic findings, they were divided into 4 groups: from pattern 0 (most hypovascular thyroid) to pattern III (most hypervascular thyroid). Comparisons of multiple thyroid parameters were made among the groups. The prevalence of Graves disease with pattern 0 (n = 27) was 13.9% among the patients with Graves disease. The sonographic and laboratory data for patients with Graves disease and pattern 0 were compared to those of the 21 patients with painless thyroiditis, which typically shows intrathyroid hypovascularity. Free triiodothyronine and thyroxine levels and the superior thyroid artery PSV were significantly lower in patients with Graves disease and pattern 0 than those with patterns I, II, and III (P < .05). The thyroid volume and thyrotropin receptor antibody level were significantly lower in patients with Graves disease and pattern 0 than those with pattern III. In the comparison between patients with Graves disease and pattern 0 and those with painless thyroiditis and pattern 0, apart from thyrotropin receptor antibody, only the superior thyroid artery PSV was different. Although the clinical features of patients with Graves disease and intrathyroid hypovascularity were similar to those patients with painless thyroiditis, the superior thyroid artery PSV showed a moderate ability to discriminate these patients. | 25,253,825 | [
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Targeted neonatal echocardiography services: need for standardized training and quality assurance. | Targeted neonatal echocardiography refers to a focused assessment of myocardial performance and hemodynamics directed by a specific clinical question. It has become the standard of care in many parts of the world, but practice is variable, and there has been a lack of standardized training and evaluation to date. Targeted neonatal echocardiography was first introduced to Canada in 2006. The purpose of this study was to examine the characteristics of targeted neonatal echocardiography practice and training methods in Canadian neonatal intensive care units (NICUs). A total of 142 Canadian neonatologists were invited to participate in an online survey, which was conducted in September 2010. The survey consisted of questions related to the availability of targeted neonatal echocardiography, clinical indications, benefits and risks, and training methods. The overall survey response rate was 65%. Forty-eight respondents (34%) indicated that targeted neonatal echocardiography was available in their units, and the program was introduced within the preceding 1 to 5 years. In centers where it was unavailable, lack of on-site echocardiography expertise was cited as the major barrier to implementation. The most common indications for targeted neonatal echocardiography included evaluation of a hemodynamically significant ductus arteriosus, systemic or pulmonary blood flow, and response to cardiovascular treatments. Only 27% of respondents, working in centers where targeted neonatal echocardiography existed, actually performed the studies themselves; most individuals completed 11 to 20 studies per month. Almost half of the respondents said that training was available in their institutions, but methods of training and evaluation were inconsistent. Eighty-seven percent of respondents reported no formalized process for assessment of ongoing competency after the initial training period. Targeted neonatal echocardiography is becoming more widely available and is gaining acceptance in Canadian NICUs. Although training is provided in many institutions, the process is not well established, and formal evaluation is rarely performed. This study emphasizes the need for development of standards for formalized training, evaluation, and quality assurance. | 25,253,831 | [
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SonoGames: an innovative approach to emergency medicine resident ultrasound education. | SonoGames was created by the Academy of Emergency Ultrasound for the 2012 annual meeting of the Society for Academic Emergency Medicine. The assessment of resident knowledge and of the performance of point-of-care ultrasound examinations is an integral component of ultrasound education and is required in emergency medicine residency training. With that in mind, game organizers sought to assess and improve emergency medicine residents' point-of-care ultrasound knowledge, hands-on skills, and integration of knowledge into clinical decision making. SonoGames is an annual 4-hour competition consisting of 3 rounds. In this article, we provide a description of SonoGames and provide a blueprint for an effective and successful educational event. | 25,253,832 | [
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Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130. | After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons. | 25,253,866 | [
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Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates. | Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment. | 25,253,884 | [
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Grain setting defect1, encoding a remorin protein, affects the grain setting in rice through regulating plasmodesmatal conductance. | Effective grain filling is one of the key determinants of grain setting in rice (Oryza sativa). Grain setting defect1 (GSD1), which encodes a putative remorin protein, was found to affect grain setting in rice. Investigation of the phenotype of a transfer DNA insertion mutant (gsd1-Dominant) with enhanced GSD1 expression revealed abnormalities including a reduced grain setting rate, accumulation of carbohydrates in leaves, and lower soluble sugar content in the phloem exudates. GSD1 was found to be specifically expressed in the plasma membrane and plasmodesmata (PD) of phloem companion cells. Experimental evidence suggests that the phenotype of the gsd1-Dominant mutant is caused by defects in the grain-filling process as a result of the impaired transport of carbohydrates from the photosynthetic site to the phloem. GSD1 functioned in affecting PD conductance by interacting with rice ACTIN1 in association with the PD callose binding protein1. Together, our results suggest that GSD1 may play a role in regulating photoassimilate translocation through the symplastic pathway to impact grain setting in rice. | 25,253,885 | [
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Perinatal Risks in "Late Motherhood" Defined Based On Parity and Preterm Birth Rate - an Analysis of the German Perinatal Survey (20th Communication). | <bAim:</b "Late motherhood" is associated with greater perinatal risks but the term lacks precise definition. We present an approach to determine what "late motherhood" associated with "high risk" is, based on parity and preterm birth rate. <bMaterials and Methods:</b Using data from the German Perinatal Survey of 1998-2000 we analysed preterm birth rates in women with zero, one, or two previous live births. We compared groups of "late" mothers (with high preterm birth rates) with "control" groups of younger women (with relatively low preterm birth rates). Data of 208 342 women were analysed. For women with zero (one; two) previous live births, the "control" group included women aged 22-26 (27-31; 29-33) years. Women in the "late motherhood" group were aged > 33 (> 35; > 38) years. <bResults:</b The "late motherhood" groups defined in this way were also at higher risk of adverse perinatal events other than preterm birth. For women with zero (one; two) previous live births, normal cephalic presentation occurred in 89 % (92.7 %; 93.3 %) in the "control" group, but only in 84.5 % (90 %; 90.4 %) in the "late motherhood" group. The mode of delivery was spontaneous or at most requiring manual help in 71.3 % (83.4 %; 85.8 %) in the "control" group, but only in 51.4 % (72.2 %; 76.4 %) in the "late motherhood" group. Five-minute APGAR scores were likewise worse for neonates of "late" mothers and the proportion with a birth weight ≤ 2499 g was greater. <bConclusion:</b "Late motherhood" that is associated with greater perinatal risks can be defined based on parity and preterm birth rate. | 25,253,904 | [
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The Effect of High Dose Methylprednisolone on Experimental Ovarian Torsion/Reperfusion Injury in Rats. | <bPurpose:</b Aim of the study was to evaluate the effects of high dose methylprednisolone on experimental ovarian torsion-detorsion injury in rats. <bMaterials and Methods:</b Twenty-two Sprague-Dawley rats were randomly divided into three groups. Group 1 (ischemia group, 8 rats) were subjected to left adnexal torsion for 2 h but received no treatment. Group 2 (methylprednisolone group, 8 rats) were subjected to left adnexal torsion for 2 h and received methylprednisolone (30 mg/kg, administered intraperitoneally) at the end of a 2-hour ischemic period followed by 24-hour reperfusion. Group 3 (control group, 6 rats) underwent a sham operation with no adnexal torsion and no treatment. <bResults:</b Serum malondialdehyde (MDA), ischemia-modified albumin (IMA), total oxidant status (TOS) and tissue MDA levels were increased in Group 1 rats; total antioxidant status (TAS) levels and oxidative stress index (OSI) were significantly decreased compared with rats in Groups 2 and 3 (p < 0.05). MDA, IMA, TOS and tissue MDA levels were lower and TAS levels and OSI were higher in Group 3 compared to Group 2. Ovarian damage scores in Group 1 were significantly higher compared with Groups 2 and 3 (p < 0.05). <bConclusion:</b This study demonstrated that high dose methylprednisolone reduces ovarian ischemia/reperfusion injury. | 25,253,907 | [
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Toxicological and pathological review of concurrent occurrence of nitrite toxicity and Swine Fever in pigs. | Plant associated nitrate/nitrite poisoning in buffalo, cattle, goat and sheep had been reported from various parts of the world. Horses and pigs are considered less susceptible to nitrate poisoning. In this study epidemiology of rare outbreak of nitrate poisoning in combination with classical swine fever in a small pig farm was investigated for development of strategies to control and prevent such incidents in future. Concurrent infection of nitrate toxicity and classical swine fever were recorded in district Nawanshahar, Punjab. Eight pigs suddenly fell sick and died 2 days after feeding barseem + oats and marriage waste food. Twelve pigs were sick exhibiting symptoms of anorexia, fever (104-105(o)F), depression, constipation followed by diarrhea, respiratory difficulty, tremors and staggering gait with recumbency in four completely off-feed pigs. Blotchy discolorations of the skin of extremities (ears and snout) were observed in three pigs. Hematological examination revealed marked leucopenia. Postmortem examination revealed dark brown colored blood evident on opening the carcass and presence of barseem, oats in stomach and intestines. Lymph nodes were swollen and hemorrhagic. Serosal surface of spleen show various infarcts and button ulcers were recorded in cecum and colon, pathognomic lesion of classical swine fever. Nitrate toxicity was confirmed on the basis of quantitative determination of nitrate in the biological material of sick and dead animals. Fodder samples were (barseem + oats) positive for diphenylamine blue (DPB) test, Nitrate concentration in offended barseem and oats were found to be 2612 ppm and 3344 ppm as nitrate nitrogen (No3-N), respectively. Excessive amount of nitrate in stomach contents (924-1365 ppm), liver (22-48 ppm) and kidney (17-22 ppm) of dead animals (n = 8) confirmed that death of pigs was due to toxicity induced by nitrate/nitrite. The green fodder should be used cautiously in pigs and screening of fodder with DPB test prior offering to animals is strongly recommended to contain the nitrate/nitrite toxicity risk. | 25,253,929 | [
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Pharmacodynamic Interaction of Green Tea Extract with Hydrochlorothiazide against Cyclophosphamide-Induced Myocardial Damage. | Treatment of ischemic hypertensive patients with hydrochlorothiazide can precipitate cardiac arrhythmias. Green tea by virtue of its antioxidant potential is responsible for cardio-protective activity. The present study was undertaken to evaluate the pharmacodynamic interaction of green tea extract with hydrochlorothiazide against cyclophosphamide-induced myocardial toxicity. Rats were treated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of green tea extract in alone and interactive groups for 10 days. Standard, high, and low dose of interactive groups received hydrochlorothiazide (10 mg/kg, p.o.) for last 7 days. Apart from normal control, all other groups were subjected to cyclophosphamide (200 mg/kg, i.p.) toxicity on day first and the effects of different treatments were evaluated by changes in electrocardiographic parameters, serum biomarkers, and tissue antioxidant levels. Apart from that, lipid profile and histological studies were also carried out. Compared to cyclophosphamide control group, both high and low dose of green tea exhibited significant decrease in serum biomarkers and increase in tissue antioxidant levels. Green tea treatment was also responsible for significant improvement in echocardiography (ECG) parameter, lipid profile, and histological score. Incorporation of high and low dose of green tea with hydrochlorothiazide-exhibited significant protection compared to hydrochlorothiazide-alone-treated group. The present findings clearly suggested that green tea extract dose dependently reduces cyclophosphamide-induced myocardial toxicity. Green tea when combined with hydrochlorothiazide can reduce the associated side effects and exhibits myocardial protection. | 25,253,931 | [
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A study of clinical profile of snake bite at a tertiary care centre. | Snake bite is an important occupational and rural hazard because India has always been a land of Exotic snakes. In Maharashtra, common poisonous snakes are Cobra, Russell's Viper, Saw Scaled Viper, and Krait. It is a fact that inspite of heavy morbidity and mortality, very little attention is paid by the clinicians to this occupational hazard. To study the prevalence of poisonous and non-poisonous snake bites in part of Western Maharashtra with reference to age, sex, occupation, part of body bitten, time of bite and seasonal variation, and the types of poisonous snakes common in this locality and their clinical manifestations along with the systemic envenomation from various types of poisonous snakes and their effective management in reducing the mortality rate. This was a retrospective study conducted between May 2010 to May 2012 at a tertiary health care center in Maharashtra. A total of 150 patients were studied in our hospital. Out of 150, 76 patients were of poisonous snake bite and 74 patients were of non-poisonous snake bite. Out of these 76 poisonous snake bites, 42 were viperine snake bites, 21 were neuroparalytic snake bites and 13 were locally toxic (LT) snake bites. Snake bite is a common life-threatening emergency in the study area. Delay in hospitalization is associated with poor prognosis and increased mortality rate due to consumptive coagulopathy, renal failure, and respiratory failure. Unusual complications like pulmonary edema, intracerebral hemorrhage, Disseminated intravascular coagulation (DIC) were observed in present study. | 25,253,932 | [
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Botulinum toxin type-A injection to treat patients with intractable anismus unresponsive to simple biofeedback training. | To evaluate the efficacy of botulinum toxin type A injection to the puborectalis and external sphincter muscle in the treatment of patients with anismus unresponsive to simple biofeedback training. This retrospective study included 31 patients suffering from anismus who were unresponsive to simple biofeedback training. Diagnosis was made by anorectal manometry, balloon expulsion test, surface electromyography of the pelvic floor muscle, and defecography. Patients were given botulinum toxin type A (BTX-A) injection and pelvic floor biofeedback training. Follow-up was conducted before the paper was written. Improvement was evaluated using the chronic constipation scoring system. BTX-A injection combined with pelvic floor biofeedback training achieved success in 24 patients, with 23 maintaining persistent satisfaction during a mean period of 8.4 mo. BTX-A injection combined with pelvic floor biofeedback training seems to be successful for intractable anismus. | 25,253,964 | [
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Successful esophagectomy in a patient with combined esophageal cancer and hemophilia B. | Patients with esophageal cancer often require esophagectomy with esophagogastrostomy. However, the incidence of complications, such as hemorrhage, during operations for esophageal cancer is high, even with minimally invasive surgery. Without the appropriate interventions, the risk of major intraoperative and postoperative hemorrhage is very high in patients with esophageal cancer and hemophilia. We report the case of a 45-year-old man with esophageal cancer and hemophilia B who underwent a successful hybrid, minimally invasive Ivor-Lewis esophagectomy with appropriate perioperative management. | 25,253,980 | [
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Multiplex bead array assay of plasma cytokines in type 2 diabetes mellitus with diabetic retinopathy. | The aim of this study was to assess the roles of plasma cytokines in diabetic retinopathy (DR) and their relationship with the severity of DR. This study included 59 diabetic patients and 19 non-diabetic controls. The plasma concentrations of endothelial growth factor (EGF), eotaxin, fibroblast growth factor 2 (FGF-2), Flt-3 ligand (Flt-3L), fractalkine, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene (GRO), interferon (IFN)-α2, IFN-γ, interleukin (IL)-1α, IL-1β, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IFN-inducible protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage-derived cytokine (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1β, sCD40L, sIL-2Rα, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)- α, TNF-β, and VEGF were measured with Luminex multiplex bead immunoassay. The levels of these cytokines were investigated according to the DR stage. The plasma level of ten cytokines-MCP-1, IL-6, IL-7, IL-9, IL-13, IL-15, IL-17, sCD40L, sIL-2Rα and TNF-β-increased significantly in the diabetic group compared to the controls. The Flt-3L, IL-1Ra, IL-3, IL-5, and IL-12 (p40) levels were lower in the diabetic group than in the control group. The TNF-α plasma level was significantly elevated in patients with proliferative diabetic retinopathy (PDR) compared with the levels in patients with non-proliferative diabetic retinopathy (NPDR) and patients with no apparent diabetic retinopathy (NDR). TNF-α might be involved in the progression of DR, especially in the pathogenesis of PDR. TNF-α is a potential cytokine for the prognosis of DR and might act as a therapeutic target in DR. | 25,253,986 | [
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Assessment of the usefulness of dihydrotestosterone in the diagnostics of patients with androgenetic alopecia. | Androgenetic alopecia (AGA) is the most common form of hair loss. Clinically observed hair loss is due to the continuous miniaturization of affected hair follicles. Genetic factors and androgenic factors especially dihydrotestosterone (DHT), which is a testosterone tissue metabolite, play major roles in the pathogenesis of AGA. However, expert opinions about the usefulness of DHT in the diagnosis of this type of alopecia are divided. To evaluate the usefulness of DHT level in patients with androgenetic alopecia compared with the control group. The study comprised 49 subjects: 19 women and 9 men with androgenetic alopecia. The control group consisted of 17 healthy women and 4 men without hair loss. Increased serum concentrations of DHT were observed in patients with androgenetic alopecia (17 women, 5 men), but also in the control group. The differences in mean values of DHT were not significant according to the types of alopecia and the control group. Increased serum concentrations of DHT were not correlated with the advance of alopecia. Dihydrotestosterone is the most influential androgen and seems to play a very important role in the pathogenesis of androgenetic alopecia. Based on the results of our study and others, the most important factors would appear to be the genetically-determined sensitivity of the follicles to DHT and their different reactions to androgen concentration. | 25,254,005 | [
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Impact of chronic kidney disease and anemia on physical function in patients with chronic heart failure. | The aim of this study was to confirm the effects of chronic kidney disease (CKD) and anemia on physical function and to clarify whether the interaction between CKD and anemia has an additive effect. Eligible subjects were chronic heart failure (HF) patients who were discharged between March 2007 and August 2009. A total of 102 chronic HF patients (33% females; mean age: 68 ± 14 years) were enrolled in the present study. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2), and anemia was defined as a hemoglobin level of <12 g/dl in males and of <11 g/dl in females. The Short Physical Performance Battery (SPPB) was used to assess physical function. The adjusted mean SPPB score was lower in patients with both CKD and anemia than in those with neither of the diseases or with either disease alone (p < 0.05). This study found that CKD and anemia are independently associated with reduced physical function. | 25,254,028 | [
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Aging and others' pain processing: implications for hospitalization. | Objectives. While self-pain perception has been widely investigated in aging, the perception as well as memory of pain in others has received little attention. Methods. The study was designed as a cross-sectional behavioral study in which a group of 41 younger and a group of 41 older adults evaluated a series of valenced and pain-related pictures and were later required to recall them. Results. We found that older adults judge the stimuli as being less intense compared to their younger counterparts. However, older adults remembered a larger number of pictures with individuals expressing pain compared to pictures with individuals who have neutral or positive facial expressions. Conclusions. Older adults may underestimate emotional intensity in others, but they seem to remember painful information in others as well as younger adults. These data are discussed in terms of theories of pain perception and implications for hospitalization. | 25,254,040 | [
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Impact of NRAS Mutations on the Diagnosis of Follicular Neoplasm of the Thyroid. | Background. Most patients with a preoperative diagnosis of thyroid follicular neoplasm (FN) undergo diagnostic surgery to determine whether the nodule is benign or malignant. Point mutations at NRAS codon 61 are the most common mutations observed in FN. However, the clinical significance of NRAS mutation remains unclear. Methods. From 2012 to 2013, 123 consecutive patients undergoing thyroidectomy for FN were evaluated prospectively. Molecular analyses for NRAS codon 61 were performed with pyrosequencing. Results. The overall malignancy rate in FN was 48.8% (60/123). Of 123 FNs, 33 (26.8%) were positive for the NRAS mutation. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRAS mutation-positive FN specimen to predict malignancy were 37%, 83%, 67%, and 58%, respectively. Patients with a NRAS-positive FN had a higher malignancy rate in additional thyroid nodules beyond the FN than patients with a NRAS-negative FN. The overall malignancy rate of patients with a NRAS-positive FN was significantly higher than that of patients with a NRAS-negative FN (79% versus 52%; P = 0.008). Conclusions. Determining NRAS mutation status in FN helps to improve the accuracy of thyroid cancer diagnosis and to predict cancer risk in accompanying thyroid nodules. | 25,254,041 | [
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Positive relationship between total antioxidant status and chemokines observed in adults. | Human evidence is limited regarding the interaction between oxidative stress biomarkers and chemokines, especially in a population of adults without overt clinical disease. The current study aims to examine the possible relationships of antioxidant and lipid peroxidation markers with several chemokines in adults. We assessed cross-sectional associations of total antioxidant status (TAS) and two lipid peroxidation markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS) with a suite of serum chemokines, including CXCL-1 (GRO-α), CXCL-8 (IL-8), CXCL-10 (IP-10), CCL-2 (MCP-1), CCL-5 (RANTES), CCL-8 (MCP-2), CCL-11 (Eotaxin-1), and CCL-17 (TARC), among 104 Chinese adults without serious preexisting clinical conditions in Beijing before 2008 Olympics. TAS showed significantly positive correlations with MCP-1 (r = 0.15751, P = 0.0014), MCP-2 (r = 0.3721, P = 0.0001), Eotaxin-1 (r = 0.39598, P < 0.0001), and TARC (r = 0.27149, P = 0.0053). The positive correlations remained unchanged after controlling for age, sex, body mass index, smoking, and alcohol drinking status. No associations were found between any of the chemokines measured in this study and MDA or TBARS. Similar patterns were observed when the analyses were limited to nonsmokers. Total antioxidant status is positively associated with several chemokines in this adult population. | 25,254,081 | [
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Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates. | Paradoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-residue cytosolic all-β MSP by the ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, the P56S major sperm protein (MSP) domain becomes largely embedded in the membrane environment with high backbone rigidity. Furthermore it is composed of five helices with amphiphilicity comparable to those of the partly-soluble membrane toxin mellitin and α-synuclein causing Parkinson's disease. Consequently, the mechanism underlying this chameleon transformation becomes clear: by disrupting the specific tertiary interaction network stabilizing the native all-β MSP fold to release previously-locked amphiphilic segments, the P56S mutation acts to convert the classic MSP fold into a membrane-active protein that is fundamentally indistinguishable from mellitin and α-synuclein which are disordered in aqueous solution but spontaneously partition into membrane interfaces driven by hydrogen-bond energetics gained from forming α-helix in the membrane environments. As segments with high amphiphilicity exist in all proteins, our study successfully resolves the paradox by deciphering that the proteins with a higher tendency to aggregate have a stronger potential to partition into membranes through the same mechanism as α-synuclein to initially attack membranes to trigger pathogenesis without needing aggregates. This might represent the common first step for various kinds of aggregated proteins to trigger familiar, sporadic and aging diseases. Therefore the homeostasis of aggregated proteins in vivo is the central factor responsible for a variety of human diseases including aging. The number and degree of the membrane attacks by aggregated proteins may act as an endogenous clock to count down the aging process. Consequently, a key approach to fight against them is to develop strategies and agents to maintain or even enhance the functions of the degradation machineries. | 25,254,094 | [
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An analysis on the entity annotations in biological corpora. | Collection of documents annotated with semantic entities and relationships are crucial resources to support development and evaluation of text mining solutions for the biomedical domain. Here I present an overview of 36 corpora and show an analysis on the semantic annotations they contain. Annotations for entity types were classified into six semantic groups and an overview on the semantic entities which can be found in each corpus is shown. Results show that while some semantic entities, such as genes, proteins and chemicals are consistently annotated in many collections, corpora available for diseases, variations and mutations are still few, in spite of their importance in the biological domain. | 25,254,099 | [
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Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients. | Some somatic single nucleotide variants (SNVs) are thought to be pathogenic, leading to neurological disease. We hypothesized that heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an autoantigen associated with multiple sclerosis (MS) would contain SNVs. MS patients develop antibodies to hnRNP A1 (293-304), an epitope within the M9 domain (AA (268-305)) of hnRNP A1. M9 is hnRNP A1's nucleocytoplasmic transport domain, which binds transportin-1 (TPNO-1) and allows for hnRNP A1's transport into and out of the nucleus. Genomic DNA sequencing of M9 revealed nine novel SNVs that resulted in an amino acid substitution in MS patients that were not present in controls. SNVs occurred within the TPNO-1 binding domain (hnRNP A1 (268-289)) and the MS IgG epitope (hnRNP A1 (293-304)), within M9. In contrast to the nuclear localization of wild type (WT) hnRNP A1, mutant hnRNP A1 mis-localized to the cytoplasm, co-localized with stress granules and caused cellular apoptosis. Whilst WT hnRNP A1 bound TPNO-1, mutant hnRNP A1 showed reduced TPNO-1 binding. These data suggest SNVs in hnRNP A1 might contribute to pathogenesis of MS. | 25,254,102 | [
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False memory susceptibility is correlated with categorisation ability in humans. | Our memory is often surprisingly inaccurate, with errors ranging from misremembering minor details of events to generating illusory memories of entire episodes. The pervasiveness of such false memories generates a puzzle: in the face of selection pressure for accuracy of memory, how could such systematic failures have persisted over evolutionary time? It is possible that memory errors are an inevitable by-product of our adaptive memories and that semantic false memories are specifically connected to our ability to learn rules and concepts and to classify objects by category memberships. Here we test this possibility using a standard experimental false memory paradigm and inter-individual variation in verbal categorisation ability. Indeed it turns out that the error scores are significantly negatively correlated, with those individuals scoring fewer errors on the categorisation test being more susceptible to false memory intrusions in a free recall test. A similar trend, though not significant, was observed between individual categorisation ability and false memory susceptibility in a word recognition task. Our results therefore indicate that false memories, to some extent, might be a by-product of our ability to learn rules, categories and concepts. | 25,254,105 | [
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Strategies of the honeybee Apis mellifera during visual search for vertical targets presented at various heights: a role for spatial attention? | When honeybees are presented with a colour discrimination task, they tend to choose swiftly and accurately when objects are presented in the ventral part of their frontal visual field. In contrast, poor performance is observed when objects appear in the dorsal part. Here we investigate if this asymmetry is caused by fixed search patterns or if bees can use alternative search mechanisms such as spatial attention, which allows flexible focusing on different areas of the visual field. We asked individual honeybees to choose an orange rewarded target among blue distractors. Target and distractors were presented in the ventral visual field, the dorsal field or both. Bees presented with targets in the ventral visual field consistently had the highest search efficiency, with rapid decisions, high accuracy and direct flight paths. In contrast, search performance for dorsally located targets was inaccurate and slow at the beginning of the test phase, but bees increased their search performance significantly after a few learning trials: they found the target faster, made fewer errors and flew in a straight line towards the target. However, bees needed thrice as long to improve the search for a dorsally located target when the target's position changed randomly between the ventral and the dorsal visual field. We propose that honeybees form expectations of the location of the target's appearance and adapt their search strategy accordingly. Different possible mechanisms of this behavioural adaptation are discussed. | 25,254,109 | [
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A systematic review of cognitive remediation therapy for anorexia nervosa - development, current state and implications for future research and clinical practice. | To systematically review studies of cognitive remediation therapy (CRT) for anorexia nervosa (AN), and to discuss findings with references to clinical practice and future research. The literature was reviewed using the PubMed, Web of Science and PsycINFO search terms "cognitive remediation therapy" AND "anorexia nervosa". Papers published online between 2005 and 2013 were selected on the basis of three inclusion criteria: 1) studies of any design focusing on CRT for AN, 2) papers that were written in English or had an available published English translation, and 3) papers published in peer reviewed journals. A total of 45 papers were identified of which 21 were recognized as being relevant for the review. Relevant papers were divided into three different categories 1) single case reports, 2) case series and 3) randomised controlled trials (RCTs). Single case studies and case series yielded strong evidence of feasibility and acceptability of CRT for AN despite great variety in sample compositions. Four RCTs demonstrate that CRT has the potential of enhancing the effectiveness of current treatments, reduce attrition, increase cognitive set-shifting abilities and quality of life, as well as reduce eating disorder psychopathology. The number of CRT studies published is growing rapidly, in particular RCTs. Further research is needed to define the primary aim of delivering CRT to patients with eating disorders, and to establish how to best measure the effect of the intervention. Moreover, researchers and clinicians should focus on identifying and assessing specific versus non-specific CRT contributions, and explore long-term effects of the intervention. It is imperative that adolescent RCTs are conducted to evaluate how CRT may be effective as a treatment for this young patient group. | 25,254,110 | [
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Perceived cognitive decline in multiple sclerosis impacts quality of life independently of depression. | Background/Aim. The aim of this study is to examine the effects of perceived cognitive dysfunction and of depression, on self-reported QoL, in a Greek population sample of MS patients. Methods. One hundred outpatients diagnosed with MS completed the Short-Form-36 Health Survey (SF-36), as well as the Perceived Deficits Questionnaire (PDQ) and the Depression subscale of the Mental Health Inventory (MHI), as part of a clinical evaluation which included the Expanded Disability Status Scale (EDSS) estimation. Multiple linear regression was conducted to determine the best linear combination of age, gender, education, EDSS, depression, attention/concentration, retrospective memory, prospective memory, and planning/organization, for predicting QoL scores. Results. In the multivariate regression analysis models, EDSS (P < 0.05), depression (P < 0.001), perceived planning/organization (P < 0.05), and perceived retrospective memory dysfunction (P < 0.05) independently predict quality of life scores. Age, sex, education level, and perceived attention/concentration dysfunction, as well as perceived prospective memory dysfunction, do not independently predict quality of life scores. Conclusions. Perceived planning/organization impairment and perceived retrospective memory impairment in MS patients predict QoL independently of the severity of disease and the severity of depression and therefore should be considered in the assessment of patient health status as well as in the design of treatment interventions and rehabilitation. | 25,254,118 | [
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Modulation at age of onset in tunisian huntington disease patients: implication of new modifier genes. | Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population. | 25,254,119 | [
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Complete bilateral gemination of maxillary incisors with separate root canals. | Developmental anomalies in the hard tissue are seen frequently in dental practice. Gemination and fusion are the most commonly encountered anomalies, and distinction between the two is always challenging. Gemination, also called double tooth, is an anomaly exhibiting two joined crowns and usually a single root. It represents an incomplete attempt of a single tooth germ to split. It is considered multifactorial in etiology, with genetic and environmental causes. This paper discusses a rare example of bilateral gemination (prevalence 0.04%) of maxillary central incisors with completely separated roots. Multidisciplinary care ensured a successful esthetic and functional outcome. | 25,254,121 | [
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A New Approach in Risk Stratification by Coronary CT Angiography. | For a decade, coronary computed tomographic angiography (CCTA) has been used as a promising noninvasive modality for the assessment of coronary artery disease (CAD) as well as cardiovascular risks. CCTA can provide more information incorporating the presence, extent, and severity of CAD; coronary plaque burden; and characteristics that highly correlate with those on invasive coronary angiography. Moreover, recent techniques of CCTA allow assessing hemodynamic significance of CAD. CCTA may be potentially used as a substitute for other invasive or noninvasive modalities. This review summarizes risk stratification by anatomical and hemodynamic information of CAD, coronary plaque characteristics, and burden observed on CCTA. | 25,254,142 | [
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Silent no more: Endogenous small RNA pathways promote gene expression. | Endogenous small RNA pathways related to RNA interference (RNAi) play a well-documented role in protecting host genomes from the invasion of foreign nucleic acids. In C. elegans, the PIWI type Argonaute, PRG-1, through an association with 21U-RNAs, mediates a genome surveillance process by constantly scanning the genome for potentially deleterious invading elements. Upon recognition of foreign nucleic acids, PRG-1 initiates a cascade of cytoplasmic and nuclear events that results in heritable epigenetic silencing of these transcripts and their coding genomic loci. If the PRG-1/21U-RNA genome surveillance pathway has the capacity to target most of the C. elegans transcriptome, what mechanisms exist to protect endogenous transcripts from being silenced by this pathway? In this commentary, we discuss three recent publications that implicate the CSR-1 small RNA pathway in the heritable activation of germline transcripts, propose a model as to why not all epialleles behave similarly, and touch on the practical implications of these findings. | 25,254,148 | [
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Fever management: Evidence vs current practice. | Fever is a very common complaint in children and is the single most common non-trauma-related reason for a visit to the emergency department. Parents are concerned about fever and it's potential complications. The biological value of fever (i.e., whether it is beneficial or harmful) is disputed and it is being vigorously treated with the belief of preventing complications such as brain injury and febrile seizures. The practice of alternating antipyretics has become widespread at home and on paediatric wards without supporting scientific evidence. There is still a significant contrast between the current concept and practice, and the scientific evidence. Why is that the case in such a common complaint like fever The article will discuss the significant contrast between the current concepts and practice of fever management on one hand, and the scientific evidence against such concepts and practice. | 25,254,165 | [
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Oral hygiene and gingival health status of children with Down syndrome in Yemen: A cross-sectional study. | The objective of the present study was to assess the oral hygiene and gingival health status among Yemeni children with Down syndrome. The study sample comprised 101 children with Down syndrome attending special needs schools in Sana'a, Yemen. The calculus index (CI), plaque index (PI), and the gingival index (GI) were used to assess oral hygiene and gingival health status. All subjects had gingivitis; the mean CI, PI, and GI scores were 0.58 ± 0.61, 1.45 ± 0.57, and 1.54 ± 0.64, respectively, with no significant difference found across gender. Stepwise linear regression analysis revealed that the best predictors in the descending order for CI were age and mother's education, and the best predictors for PI were IQ level, age, and father's education. Having severe mental retardation, older age, less educated parents were the most important predictors for poor gingival health status. These findings show that children with Down syndrome have poor oral hygiene and high levels of periodontal diseases. Hence, appropriate oral health education should be tailored to the needs of these children with the support of their teachers and parents. | 25,254,190 | [
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Effectiveness of different tooth brushing techniques on the removal of dental plaque in 6-8 year old children of Gulbarga. | This study was undertaken to evaluate the respective effectiveness of the horizontal scrub, Fones, and modified Bass methods demonstrated on the cast to individual child within the classroom setting. A total of 180 healthy children studying in 1(st) and 2(nd) grades in the age range of 6-8 years were randomly selected from various schools of Gulbarga district, Karnataka, India. They were equally divided into three groups. Children in each group were demonstrated only one of the three brushing techniques, viz. horizontal scrub technique to group A, Fones technique to group B, and modified Bass technique to group C, using a cast model. All the children were re-examined and reviewed after 24 h and plaque index was re-assessed to obtain the follow-up data. The results were compared with the baseline data, and statistical analysis was carried out using paired t-test and intergroup comparison was made using analysis of variance (ANOVA) test. Statistically significant (P < 0.001) reduction in plaque score was seen in modified Bass technique followed by horizontal scrub technique and the least efficacy was seen in Fones technique. This study showed that modified Bass technique was the most effective brushing technique in children. | 25,254,196 | [
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Vasopressin in hemorrhagic shock: a systematic review and meta-analysis of randomized animal trials. | The latest European guidelines for the management of hemorrhagic shock suggest the use of vasopressors (norepinephrine) in order to restore an adequate mean arterial pressure when fluid resuscitation therapy fails to restore blood pressure. The administration of arginine vasopressin (AVP), or its analogue terlipressin, has been proposed as an alternative treatment in the early stages of hypovolemic shock. A meta-analysis of randomized controlled animal trials. A total of 433 animals from 15 studies were included. The ability of AVP and terlipressin to reduce mortality when compared with fluid resuscitation therapy, other vasopressors (norepinephrine or epinephrine), or placebo was investigated. Pooled estimates showed that AVP and terlipressin consistently and significantly improve survival in hemorrhagic shock (mortality: 26/174 (15%) in the AVP group versus 164/259 (63%) in the control arms; OR=0.09; 95% CI 0.05 to 0.15; P for effect<0.001; P for heterogeneity=0.30; I2=14%). Results suggest that AVP and terlipressin improve survival in the early phases of animal models of hemorrhagic shock. Vasopressin seems to be more effective than all other treatments, including other vasopressor drugs. These results need to be confirmed by human clinical trials. | 25,254,206 | [
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Autogenerator-based modelling framework for development of strategic games simulations: rational pigs game extended. | When considering strategic games from the conceptual perspective that focuses on the questions of participants' decision-making rationality, the very issues of modelling and simulation are rarely discussed. The well-known Rational Pigs matrix game has been relatively intensively analyzed in terms of reassessment of the logic of two players involved in asymmetric situations as gluttons that differ significantly by their attributes. This paper presents a successful attempt of using autogenerator for creating the framework of the game, including the predefined scenarios and corresponding payoffs. Autogenerator offers flexibility concerning the specification of game parameters, which consist of variations in the number of simultaneous players and their features and game objects and their attributes as well as some general game characteristics. In the proposed approach the model of autogenerator was upgraded so as to enable program specification updates. For the purpose of treatment of more complex strategic scenarios, we created the Rational Pigs Game Extended (RPGE), in which the introduction of a third glutton entails significant structural changes. In addition, due to the existence of particular attributes of the new player, "the tramp," one equilibrium point from the original game is destabilized which has an influence on the decision-making of rational players. | 25,254,228 | [
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Low complexity mode decision for 3D-HEVC. | High efficiency video coding- (HEVC-) based 3D video coding (3D-HEVC) developed by joint collaborative team on 3D video coding (JCT-3V) for multiview video and depth map is an extension of HEVC standard. In the test model of 3D-HEVC, variable coding unit (CU) size decision and disparity estimation (DE) are introduced to achieve the highest coding efficiency with the cost of very high computational complexity. In this paper, a fast mode decision algorithm based on variable size CU and DE is proposed to reduce 3D-HEVC computational complexity. The basic idea of the method is to utilize the correlations between depth map and motion activity in prediction mode where variable size CU and DE are needed, and only in these regions variable size CU and DE are enabled. Experimental results show that the proposed algorithm can save about 43% average computational complexity of 3D-HEVC while maintaining almost the same rate-distortion (RD) performance. | 25,254,237 | [
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A synthesized heuristic task scheduling algorithm. | Aiming at the static task scheduling problems in heterogeneous environment, a heuristic task scheduling algorithm named HCPPEFT is proposed. In task prioritizing phase, there are three levels of priority in the algorithm to choose task. First, the critical tasks have the highest priority, secondly the tasks with longer path to exit task will be selected, and then algorithm will choose tasks with less predecessors to schedule. In resource selection phase, the algorithm is selected task duplication to reduce the interresource communication cost, besides forecasting the impact of an assignment for all children of the current task permits better decisions to be made in selecting resources. The algorithm proposed is compared with STDH, PEFT, and HEFT algorithms through randomly generated graphs and sets of task graphs. The experimental results show that the new algorithm can achieve better scheduling performance. | 25,254,244 | [
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A new look at the coefficients of a reciprocal generating function. | We study a special property of free cumulants. We prove that coefficients of a reciprocal generating function correspond to "free cumulants with the first two elements in the same block." | 25,254,253 | [
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Network anomaly detection system with optimized DS evidence theory. | Network anomaly detection has been focused on by more people with the fast development of computer network. Some researchers utilized fusion method and DS evidence theory to do network anomaly detection but with low performance, and they did not consider features of network-complicated and varied. To achieve high detection rate, we present a novel network anomaly detection system with optimized Dempster-Shafer evidence theory (ODS) and regression basic probability assignment (RBPA) function. In this model, we add weights for each sensor to optimize DS evidence theory according to its previous predict accuracy. And RBPA employs sensor's regression ability to address complex network. By four kinds of experiments, we find that our novel network anomaly detection model has a better detection rate, and RBPA as well as ODS optimization methods can improve system performance significantly. | 25,254,258 | [
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Reflections: Neurology and The Humanities. The case of the locked house. The finished mystery. | After the death in 2012 of Dr. Robert Joynt, who served Neurology® as CPC Section Editor, an unfinished manuscript was found on his computer. It would have been his sixth Sherlock Holmes pastiche. Intrigued by the story but deflated at the lack of an ending, the editors published the case in the September 10, 2013, issue of Neurology and requested that readers finish it. A panel of editors reviewed over 30 submissions and the top 4 were posted online and on the iPad. Readers voted online, on the iPad, and during the 2014 American Academy of Neurology Annual Meeting in Philadelphia. The winning coauthors are Peter A. Kempster, from Melbourne, and Andrew J. Lees, from London. The runners-up are Anonymous (ending 1), Gerald Honch (ending 2), and Clifton Gooch (ending 4). The editors thank all participants and voters. The rule on page 662 indicates where the winning ending begins. | 25,254,262 | [
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Field note: comparative efficacy of a woody evapotranspiration landfill cover following the removal of aboveground biomass. | Woody vegetation cultivated for moisture management on evapotranspiration (ET) landfill covers could potentially serve a secondary function as a biomass crop. However, research is required to evaluate the extent to which trees could be harvested from ET covers without significantly impacting their moisture management function. This study investigated the drainage through a six-year-old, primarily poplar/cottonwood ET test cover for a period of one year following the harvest of all woody biomass exceeding a height of 30 cm above ground surface. Results were compared to previously reported drainage observed during the years leading up to the coppice event. In the first year following coppice, the ET cover was found to be 93% effective at redirecting moisture during the spring/summer season, and 95% effective during the subsequent fall/winter season. This was slightly lower than the 95% and 100% efficacy observed in the spring/summer and fall/winter seasons, respectively, during the final measured year prior to coppice. However, the post-coppice efficacy was higher than the efficacy observed during the first three years following establishment of the cover. While additional longer-term studies are recommended, this project demonstrated that woody ET covers could potentially produce harvestable biomass while still effectively managing aerial moisture. | 25,254,294 | [
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Proteomic study of pilocytic astrocytoma pediatric brain tumor intracystic fluid. | Liquid chromatography in coupling with high-resolution ESI-LTQ-Orbitrap mass spectrometry was applied for a proteomic study of pediatric pilocytic astrocytoma brain tumor intracystic fluid by an integrated top-down/bottom-up platform. Both of the proteomic strategies resulted complementary and support each other in contributing to a wide characterization of the protein and peptide content of the tumor fluid. Top-down approach allowed to identify several proteins and peptides involved in different biological activities together with the characterization of interesting proteoforms such as fibrinopeptide A and its truncated form, fibrinopeptide B, complement C3f fragments, β-thymosin peptides, ubiquitin, several apolipoproteins belonging to A and C families, apolipoprotein J and D, and cystatin C. Of particular interest resulted the identification of a N-terminal truncated cystatin C proteoform, likely involved in immune response mechanism modulations and the identification of oxidized and glycosylated apolipoproteins including disulfide bridge dimeric forms. The bottom-up approach confirmed some of the experimental data findings together with adding the characterization of high-molecular-mass proteins in the samples. These data could contribute to elucidate the molecular mechanisms involved in onset and progression of the disease and cyst development. | 25,254,300 | [
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An efficient approach for preprocessing data from a large-scale chemical sensor array. | In this paper, an artificial olfactory system (Electronic Nose) that mimics the biological olfactory system is introduced. The device consists of a Large-Scale Chemical Sensor Array (16; 384 sensors, made of 24 different kinds of conducting polymer materials)that supplies data to software modules, which perform advanced data processing. In particular, the paper concentrates on the software components consisting, at first, of a crucial step that normalizes the heterogeneous sensor data and reduces their inherent noise. Cleaned data are then supplied as input to a data reduction procedure that extracts the most informative and discriminant directions in order to get an efficient representation in a lower dimensional space where it is possible to more easily find a robust mapping between the observed outputs and the characteristics of the odors in input to the device. Experimental qualitative proofs of the validity of the procedure are given by analyzing data acquired for two different pure analytes and their binary mixtures. Moreover, a classification task is performed in order to explore the possibility of automatically recognizing pure compounds and to predict binary mixture concentrations. | 25,254,304 | [
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Barrier properties to surrogates of hydrogenated carbon nano-films deposited on PET by plasma-enhanced chemical vapour deposition. | Poly(ethylene terephthalate) resin was contaminated with a series of surrogates using a US Food and Drug Administration protocol. The contaminated samples were coated with two different kinds of hydrogenated amorphous carbon thin films (a-C:H): one with diamond-like hydrogenated amorphous carbon and another with polymer-like hydrogenated carbon (PLCH) phases. To evaluate the barrier properties of the a-C:H films, migration assays were performed using food simulants. After the tests, analysis by gas chromatography with different detectors was carried out. The appearance of the films before and after the migration experiments was studied by field emission scanning electron microscopy. The results showed that a-C:H films have good barrier properties for most of the evaluated compounds, mainly when they are deposited as PLCH phase. | 25,254,307 | [
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Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. | Long-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca(2+)]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca(2+)]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca(2+). Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca(2+)]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na(+)-Ca(2+) exchange. These results suggest that LQTS mutations act partly on cytosolic Ca(2+) cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site. | 25,254,341 | [
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Centre-based day care for children younger than five years of age in low- and middle-income countries. | Because of poverty, children and families in low- and middle-income countries often face significant impediments to health and well-being. Centre-based day care services may influence the development of children and the economic situation of parents by providing good quality early childhood care and by freeing parents to participate in the labour force. To assess the effects of centre-based day care without additional interventions (e.g. psychological or medical services, parent training) on the development, health and well-being of children and families in low- and middle-income countries (as defined by the World Bank 2011). In April 2014, we searched CENTRAL, Ovid MEDLINE, EMBASE, PsycINFO, ERIC and 16 other sources, including several World Health Organization (WHO) regional databases. We also searched two trials registers, websites of government and non-government agencies and reference lists of relevant studies. We included randomised and quasi-randomised controlled trials and prospective non-randomised studies with contemporaneous control groups and assessments both before and after intervention. We considered non-randomised controlled trials, as centre-based care in low- and middle-income countries is unlikely to be studied using randomised controlled trials (Higgins 2011). We included the following outcomes: child intellectual development, child psychosocial development, maternal and family outcomes and incidence of infectious diseases. Two review authors independently assessed risk of bias and extracted data from the single included study. Only one trial, involving 256 children, met the inclusion criteria for this review. This study was assessed as having high risk of bias because of non-random allocation, incomplete outcome data and insufficient control of confounding factors. Results from this study suggest that centre-based day care may have a positive effect on child cognitive ability compared with no treatment (care at home) (assessed using a modified version of the British Ability Scale-II (BAS-II) (standardised mean difference (SMD) 0.74, 95% confidence interval (CI) 0.48 to 1.00, 256 participants, 1 study, very low-quality evidence). This study did not measure other variables relevant to this review. The single study included in this review provides limited evidence on the effects of centre-based day care for children younger than five years of age in low- and middle-income countries. This study was at high risk of bias and may have limited generalisability to other low- and middle-income countries. Many of the studies excluded from this review paired day care attendance with co-interventions that are unlikely to be provided in normal day care centres. Effectiveness studies on centre-based day care without these co-interventions are few, and the need for such studies is significant. In future studies, comparisons might include home visits or alternative day care arrangements. | 25,254,354 | [
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Controlled incremental filtration: a simplified approach to design and fabrication of high-throughput microfluidic devices for selective enrichment of particles. | The number of microfluidic strategies aimed at separating particles or cells of a specific size within a continuous flow system continues to grow. The wide array of biomedical and other applications that would benefit from successful development of such technology has motivated the extensive research in this area over the past 15 years. However, despite promising advancements in microfabrication capabilities, a versatile approach that is suitable for a large range of particle sizes and high levels of enrichment, with a volumetric throughput sufficient for large-scale applications, has yet to emerge. Here we describe a straightforward method that enables the rapid design of microfluidic devices that are capable of enriching/removing particles within a complex aqueous mixture, with an unprecedented range of potential cutoff diameter (below 1 μm to above 100 μm) and an easily scalable degree of enrichment/filtration (up to 10-fold and well beyond). A simplified model of a new approach to crossflow filtration - controlled incremental filtration - was developed and validated for its ability to generate microfluidic devices that efficiently separate particles on the order of 1-10 μm, with throughputs of tens of μL min(-1), without the use of a pump. Precise control of the amount of fluid incrementally diverted at each filtration "gap" of the device allows for the gap size (~20 μm) to be much larger than the particles of interest, while the simplicity of the model allows for many thousands of these filtration points to be readily incorporated into a desired device design. This new approach should enable truly high-throughput microfluidic particle-separation devices to be generated, even by users only minimally experienced in fluid mechanics and microfabrication techniques. | 25,254,358 | [
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Evaluation of biochemical, hematological and parasitological parameters of protein-deficient hamsters infected with Ancylostoma ceylanicum. | Hookworms infect millions of people worldwide and can cause severe clinical symptoms in their hosts. Prospective cohort studies in Brazil show high rates of hookworm reinfection in malnourished children compared to well-nourished children, despite previous treatment. Additionally, soil-transmitted helminth (STH) infections can worsen the nutritional status of affected populations. Therefore, this study aims to clarify the effects of host malnutrition during Ancylostoma ceylanicum infection and how this infection affects host physiological parameters using a hamster model. Hamsters were divided into four experimental groups: normal diet or low-protein diet (also referred to as "malnourished") and A. ceylanicum infection or no infection. More severe pathogenesis was observed in the infected malnourished group, as demonstrated by significant decreases in the hemoglobin concentration, erythrocyte number and packed-cell volume compared to the non-infected malnourished group. Greater numbers of adult parasites and eggs were observed in the malnourished group compared to the control group; however, the oviposition rate was lower in the malnourished group. In general, greater values of total lipids were observed in malnourished animals compared to control animals, including lipids excreted in the stool. In this work, we have demonstrated that animals fed an isocaloric low-protein diet presented more severe pathogenesis when infected with A. ceylanicum. The increased lipid concentration in the liver and blood is related to the conversion of the excess carbohydrate into fatty acids that increase the concentration of triglycerides in general. Triglycerides were excreted in the feces, indicating that infection associated with malnutrition caused a greater loss of these molecules for this group of animals and confirming the hypothesis that both nutrition and infection are responsible for the malabsorption syndrome. Taken together, the results found in this work confirm the hypothesis that the nutritional condition of the host greatly influences the course of the infection. | 25,254,370 | [
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Systemic hypertension as a risk factor for open-angle glaucoma: a meta-analysis of population-based studies. | Systemic hypertension is thought to increase the risk for developing open-angle glaucoma (OAG) through several mechanisms. However, previous epidemiological studies have shown conflicting results regarding this potential association. We systematically evaluated this issue by conducting a meta-analysis of population-based studies. A comprehensive search for articles published before 31 March 2014 was performed using PubMed, Embase, and reference lists. The pooled odds ratio (OR) was calculated using the fixed- and random-effects models, and meta-regression was performed according to age. Subgroup analyses were also conducted, and publication bias was assessed using a funnel plot and Egger's regression test. This meta-analysis included 16 studies involving 60,084 individuals, with substantial homogeneity among the studies. The pooled OR for OAG was 1.22 (95% confidence interval, CI: 1.09-1.36) using the fixed-effects model and 1.22 (95% CI: 1.08-1.37) using the random-effects model in all included studies. For subgroup analyses, the pooled OR for high-tension glaucoma (HTG) was higher than that for normal-tension glaucoma (NTG) (OR=1.92 and 0.94, respectively). No significant difference was detected between Asian and Western populations, and no publication bias was detected in either analysis. Systemic hypertension increases the risk for developing OAG, especially in those with HTG. | 25,254,373 | [
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... |
Selection of nectar plants for use in ecological engineering to promote biological control of rice pests by the predatory bug, Cyrtorhinus lividipennis, (Heteroptera: Miridae). | Ecological engineering for pest management involves the identification of optimal forms of botanical diversity to incorporate into a farming system to suppress pests, by promoting their natural enemies. Whilst this approach has been extensively researched in many temperate crop systems, much less has been done for rice. This paper reports the influence of various plant species on the performance of a key natural enemy of rice planthopper pests, the predatory mirid bug, Cyrtorhinus lividipennis. Survival of adult males and females was increased by the presence of flowering Tagetes erecta, Trida procumbens, Emilia sonchifolia (Compositae), and Sesamum indicum (Pedaliaceae) compared with water or nil controls. All flower treatments resulted in increased consumption of brown plant hopper, Nilaparvata lugens, and for female C. lividipennis, S. indicum was the most favorable. A separate study with a wider range of plant species and varying densities of prey eggs showed that S. indicum most strongly promoted predation by C. lividipennis. Reflecting this, S. indicum gave a relatively high rate of prey search and low prey handling time. On this basis, S. indicum was selected for more detailed studies to check if its potential incorporation into the farming system would not inadvertently benefit Cnaphalocrocis medinalis and Marasmia patnalis, serious Lepidoptera pests of rice. Adult longevity and fecundity of both pests was comparable for S. indicum and water treatments and significantly lower than the honey solution treatment. Findings indicate that S. indicumis well suited for use as an ecological engineering plant in the margins of rice crops. Sesame indicum can be a valuable crop as well as providing benefits to C. lividipennis whilst denying benefit to key pests. | 25,254,377 | [
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Household transmission of influenza A(H1N1)pdm09 in the pandemic and post-pandemic seasons. | The transmission of influenza viruses occurs person to person and is facilitated by contacts within enclosed environments such as households. The aim of this study was to evaluate secondary attack rates and factors associated with household transmission of laboratory-confirmed influenza A(H1N1)pdm09 in the pandemic and post-pandemic seasons. During the 2009-2010 and 2010-2011 influenza seasons, 76 sentinel physicians in Navarra, Spain, took nasopharyngeal and pharyngeal swabs from patients diagnosed with influenza-like illness. A trained nurse telephoned households of those patients who were laboratory-confirmed for influenza A(H1N1)pdm09 to ask about the symptoms, risk factors and vaccination status of each household member. In the 405 households with a patient laboratory-confirmed for influenza A(H1N1)pdm09, 977 susceptible contacts were identified; 16% of them (95% CI 14-19%) presented influenza-like illness and were considered as secondary cases. The secondary attack rate was 14% in 2009-2010 and 19% in the 2010-2011 season (p=0.049), an increase that mainly affected persons with major chronic conditions. In the multivariate logistic regression analysis, the risk of being a secondary case was higher in the 2010-2011 season than in the 2009-2010 season (adjusted odds ratio: 1.72; 95% CI 1.17-2.54), and in children under 5 years, with a decreasing risk in older contacts. Influenza vaccination was associated with lesser incidence of influenza-like illness near to statistical significance (adjusted odds ratio: 0.29; 95% CI 0.08-1.03). The secondary attack rate in households was higher in the second season than in the first pandemic season. Children had a greater risk of infection. Preventive measures should be maintained in the second pandemic season, especially in high-risk persons. | 25,254,376 | [
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Sedative-hypnotics are widely abused by drivers apprehended for driving under the influence of drugs. | Sedative-hypnotics are commonly encountered in drivers apprehended for driving under the influence of drugs (DUID). Previous research has mainly concentrated on the residual effects of the drugs. In this study, the extent of sleep medication use and abuse among drivers apprehended on suspicion of DUID was assessed. Additionally, the prevalence and concentrations of the drugs, concomitant use of other drugs of abuse, and the age and sex of the drivers positive for the most commonly prescribed sedative-hypnotics (temazepam, midazolam, nitrazepam, zopiclone, and zolpidem) in DUID cases in Finland in 2009 to 2011 were examined. Sedative-hypnotics were found in 3155 samples of the 13,248 that were analyzed. Temazepam was present in over half of the cases (57.9%), along with other benzodiazepines such as midazolam (13.1%) and nitrazepam (7.0%) and the non-benzodiazepine hypnotics zopiclone (12.2%) and zolpidem (9.8%). The mean age of the drivers using the studied sedative-hypnotics was 33.5 years. Many of the drivers were polydrug users; concomitant stimulant use was found in nearly half of the cases. Cannabis and alcohol were also very common co-findings. In nearly 20% of the cases, the driver had taken more than 1 of the studied sedative-hypnotics; only 2.5% had no findings other than a single sedative-hypnotic in their blood. The drug use pattern of those positive for zopiclone and zolpidem was somewhat different from that of users of benzodiazepine sedative-hypnotics; their age was higher and the concomitant use of illegal stimulants was markedly less prevalent than among the users of temazepam, midazolam, and nitrazepam. There were very few cases in our study population where the positive sedative-hypnotic finding could have been due to appropriate medical use. The extremely prevalent concomitant use of other psychoactive drugs and the high median serum concentrations of the studied sedative-hypnotics suggest their widespread abuse among apprehended drivers. | 25,254,415 | [
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Development of a population PK model of tacrolimus for adaptive dosage control in stable kidney transplant patients. | Tacrolimus pharmacokinetics (PK) presents a high variability that hampers its therapeutic use. The aims of this study are to: (1) develop a population pharmacokinetic (PPK) model for tacrolimus and to identify the factors that contribute to the variability of tacrolimus PK in renal transplant patients; and (2) to establish a new Bayesian estimator that can easily and routinely be applied in the hospital. A new PPK model may allow efficacy to be optimized, improve dose regimens, minimize side effects, and decrease the cost of extensive area under the curve (AUC) monitoring. PPK analysis of the full PK profiles of 16 patients on 5 occasions was performed with NONMEM 7.2. Biochemical variables (hematocrit, hemoglobin, aspartate aminotransferase, and others) were analyzed. A 2-open-compartment model with interoccasion variability best described the PK of tacrolimus. Three transit compartments provided the best description of the absorption process. The hematocrit, aspartate aminotransferase, and alanine aminotransferase were not significant in the covariate analysis. External validation with 91 patients proved the good predictability of the model with a bias and precision of 0.37 mcg/L (CI 95%, -0.11 to 1.20 mcg/L) and 0.38 mcg/L (CI 95%, 0.02 to 1.21 mcg/L), respectively. A limited sampling strategy using 1 sampling point at predose (trough concentrations) showed a good performance in AUC0-12h estimation with a correlation between AUCfull and AUCLSS, bias and imprecision of r = 0.75, 6.78% (range, -16.26% to 30.06%) and 1.42% (IC 95%, 0.14%-3.61%), respectively. The PPK model developed provides reliable prior information for Bayesian adaptive control of dosage regimens of tacrolimus to achieve the desired AUC goals in stable renal transplant patients. | 25,254,416 | [
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SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. | SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the -745/-660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo. | 25,254,494 | [
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Rapid determination of cell mass and density using digitally controlled electric field in a microfluidic chip. | The density of a single cell is a fundamental property of cells. Cells in the same cycle phase have similar volume, but the differences in their mass and density could elucidate each cell's physiological state. Here we report a novel technique to rapidly measure the density and mass of a single cell using an optically induced electrokinetics (OEK) microfluidic platform. Presently, single cellular mass and density measurement devices require a complicated fabrication process and their output is not scalable, i.e., it is extremely difficult to measure the mass and density of a large quantity of cells rapidly. The technique reported here operates on a principle combining sedimentation theory, computer vision, and microparticle manipulation techniques in an OEK microfluidic platform. We will show in this paper that this technique enables the measurement of single-cell volume, density, and mass rapidly and accurately in a repeatable manner. The technique is also scalable - it allows simultaneous measurement of volume, density, and mass of multiple cells. Essentially, a simple time-controlled projected light pattern is used to illuminate the selected area on the OEK microfluidic chip that contains cells to lift the cells to a particular height above the chip's surface. Then, the cells are allowed to "free fall" to the chip's surface, with competing buoyancy, gravitational, and fluidic drag forces acting on the cells. By using a computer vision algorithm to accurately track the motion of the cells and then relate the cells' motion trajectory to sedimentation theory, the volume, mass, and density of each cell can be rapidly determined. A theoretical model of micro-sized spheres settling towards an infinite plane in a microfluidic environment is first derived and validated experimentally using standard micropolystyrene beads to demonstrate the viability and accuracy of this new technique. Next, we show that the yeast cell volume, mass, and density could be rapidly determined using this technology, with results comparable to those using the existing method suspended microchannel resonator. | 25,254,511 | [
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0.4184324,
0.1609533,
-0.020911... |
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