Lipoprotein abnormalities in well-treated type II diabetic patients.
To investigate lipoprotein levels and composition in well-treated type II diabetic patients. Cholesterol and triglyceride levels were measured in plasma, VLDL, LDL, and HDL in 120 type II diabetic patients in good to fair metabolic control (HbA1c, 7.2 +/- 1.6%) and in 30 normal control subjects. ApoAI, AII, B, CII, CIII, and E levels in plasma were also determined. The diabetic patients have significantly higher levels of mean plasma cholesterol (5.85 vs. 5.43 mM, P = 0.03), LDL triglycerides (0.41 vs. 0.31 mM, P = 0.003), and HDL triglycerides (0.24 vs. 0.19 mM, P = 0.02), whereas total triglycerides, VLDL cholesterol and triglycerides, LDL cholesterol, and HDL cholesterol are not significantly different from normal control subjects. ApoB (150 vs. 135 mg/dl, P = 0.02) and apoCIII (10.6 vs. 8.4 mg/dl, P = 0.01) are significantly higher in diabetic patients compared with control subjects. No significant differences are observed in all the parameters among diabetic patients treated with diet only, sulphonylurea, sulphonylurea plus biguanides, or insulin. Body weight is significantly related to VLDL lipids. The VLDL triglycerides are inversely related to the HDL cholesterol in both diabetic patients and control subjects. The VLDL triglycerides are directly related to the HDL triglycerides only in diabetic patients. No other lipid or lipoprotein parameters are significantly related to body weight or metabolic control. Type II diabetic patients in good to fair metabolic control are characterized by minor alterations of the plasma lipids, but LDL and HDL triglycerides, apoB, and apoCIII are increased, thus indicating that the lipoprotein composition is altered, possibly because of an abnormal triglyceride metabolism and/or lipid transfer activity.


Turbo spin-echo diffusion-weighted MR of ischemic stroke.
Our objective was to determine whether a multisection technique, diffusion-weighted half-Fourier single-shot turbo spin-echo (HASTE) imaging, can compensate for the drawbacks common to other diffusion-weighted techniques; specifically, the need for echo-planar technology and the presence of susceptibility artifacts in areas close to the skull base. Forty subjects who were referred to the stroke service with signs of acute (less than 24 hour) neurologic dysfunction were included in this prospective study. MR imaging of the brain was performed with diffusion-weighted echo-planar and diffusion-weighted HASTE sequences. The images obtained with both sequences were analyzed for the presence of hyperintensities corresponding to ischemic lesions as well as for the presence of image artifacts and distortions. Diffusion-weighted HASTE images showed areas of hyperintensity corresponding to the infarcts present on diffusion-weighted echo-planar imaging studies without distortion or susceptibility artifacts in all the patients who had a stroke. Twelve patients had no acute ischemic lesions; of these, five had other findings, six had normal findings, and in one patient, a hyperintensity seen on diffusion-weighted echo-planar images proved to be an artifact on diffusion-weighted HASTE images. Diffusion-weighted HASTE is equal to diffusion-weighted echo-planar imaging in the detection of early ischemia. Because of the absence of significant image distortions and other artifacts, diffusion-weighted HASTE permits fast multiplanar imaging in artifact-prone regions, such as the posterior fossa and the inferior frontal and temporal lobes. Diffusion imaging can be performed on conventional systems with strengths of 1.5 T that do not have echo-planar imaging capabilities.


Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies.
Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.


Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase.
Human manganese containing superoxide dismutase (MnSOD) cDNA was transfected into a human breast cancer cell line (MCF-7) in order to examine the effect of increased functional MnSOD on the cellular phenotype. A MnSOD-overexpressing clone was compared to control vector-transfected cells and to wild type MCF-7 cells. Southern blotting indicated incorporation of MnSOD cDNA into genomic DNA in the MnSOD overexpressing cell line. The MnSOD overexpressing cell line showed a 5.7-fold increase in MnSOD activity compared to wild type MCF-7 cells. Similar increases in MnSOD immunoreactive protein and mRNA levels were observed by Western and Northern blotting as well as using RT-PCR. The plating efficiency of cells grown in different concentrations of serum (1 to 20%) was decreased in the MnSOD overexpressing cell line. The clonogenic fraction in soft agar culture was also decreased after MnSOD cDNA transfection. When inoculated in nude mice, tumor growth was markedly inhibited in MnSOD overexpressing cells compared to wild type MCF-7 cells or plasmid control cells. These results support the hypothesis that increased MnSOD expression suppresses the malignant phenotype of human breast cancer cells and suggests that the MnSOD gene is a tumor suppressor gene in human breast cancer.


Weighted constraints in generative linguistics.
Harmonic Grammar (HG) and Optimality Theory (OT) are closely related formal frameworks for the study of language. In both, the structure of a given language is determined by the relative strengths of a set of constraints. They differ in how these strengths are represented: as numerical weights (HG) or as ranks (OT). Weighted constraints have advantages for the construction of accounts of language learning and other cognitive processes, partly because they allow for the adaptation of connectionist and statistical models. HG has been little studied in generative linguistics, however, largely due to influential claims that weighted constraints make incorrect predictions about the typology of natural languages, predictions that are not shared by the more popular OT. This paper makes the case that HG is in fact a promising framework for typological research, and reviews and extends the existing arguments for weighted over ranked constraints.


Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution flow cytometry.
Submicron-sized vesicles released by cells are increasingly recognized for their role in intercellular communication and as biomarkers of disease. Methods for high-throughput, multi-parameter analysis of such extracellular vesicles (EVs) are crucial to further investigate their diversity and function. We recently developed a high-resolution flow cytometry-based method (using a modified BD Influx) for quantitative and qualitative analysis of EVs. The fact that the majority of EVs is <200 nm in size requires special attention with relation to specific conditions of the flow cytometer, as well as sample concentration and event rate. In this study, we investigated how (too) high particle concentrations affect high-resolution flow cytometry-based particle quantification and characterization. Increasing concentrations of submicron-sized particles (beads, liposomes, and EVs) were measured to identify coincidence and swarm effects, caused by the concurrent presence of multiple particles in the measuring spot. As a result, we demonstrate that analysis of highly concentrated samples resulted in an underestimation of the number of particles and an interdependent overestimation of light scattering and fluorescence signals. On the basis of this knowledge, and by varying nozzle size and sheath pressure, we developed a strategy for high-resolution flow cytometric sorting of submicron-sized particles. Using the adapted sort settings, subsets of EVs differentially labeled with two fluorescent antibodies could be sorted to high purity. Moreover, sufficient numbers of EVs could be sorted for subsequent analysis by western blotting. In conclusion, swarm effects that occur when measuring high particle concentrations severely hamper EV quantification and characterization. These effects can be easily overlooked without including proper controls (e.g., sample dilution series) or tools (e.g., oscilloscope). Providing that the event rate is well controlled, the sorting strategy we propose here indicates that high-resolution flow cytometric sorting of different EV subsets is feasible.


Contribution of Arabic Medicine and Pharmacy to the Development of Health Care Protection in Bosnia and Herzegovina - the First Part.
The time interval from the 9th to the 13th century remained known as the "Golden period of the Arab science", and a significant place among the taught sciences are occupied by Medicine and Pharmacy. In the history of medicine, Islamic medicine, also known as Arabic medicine, refers to the science of medicine developed in the Islamic Golden Age, and written in Arabic Arabs were able to use their cultural and natural resources and trade links to contribute to the strong development of pharmacy. After the collapse of the Arab rule, the Arab territorial expanses and cultural heritage were taken over by the Turks. Although scientific progress in the Turkish period slowed down due to numerous unfavorable political-economic and other circumstances, thanks to the Turks, Arab culture and useful Islamic principles expanded to the territory of our homeland of Bosnia and Herzegovina. Significant role in the transfer of Arabic medical and pharmaceutical knowledge was also attributed to the Sephardic Jews who, with their arrival, continued to perform their attar activities, which were largely based on Arab achievements. However, insufficiently elaborated, rich funds of oriental medical and pharmaceutical handwriting testify that Oriental science has nurtured in these areas as well, and that the Arab component in a specific way was intertwined with other cultures and traditions of Bosnia and Herzegovina.


The impact of organizational changes on work stress, sleep, recovery and health.
The study objective was to investigate the impact of different kinds of organizational changes, as well as anticipation of such changes, on work-related stress, sleep, recovery and health. It was hypothesized that impaired sleep and recovery increase the adverse health consequences of organizational changes. The data consisted of cross sectional questionnaire data from a random sample of 1,523 employees in the Swedish police force. It could be shown that extensive organizational changes including downsizing or a change in job tasks were associated with a small increase in work stress, disturbed sleep, incomplete recovery and health complaints. However, less extensive organizational changes like relocation did not affect these outcome variables. Anticipation of extensive organizational changes had almost the same effect as actual changes. Furthermore a moderating effect of sleep and work stress on gastrointestinal complaints and depressive symptoms was found. Thus, like former studies already suggested, extensive organizational changes resulted in increased stress levels, poorer health and impaired sleep and recovery. Furthermore, organizational instability due to anticipation of changes was as negative as actual changes. There was also some evidence that disturbed sleep increased these adverse health effects, in particular with respect to anticipation of organizational changes.


Memory impedance in TiO2 based metal-insulator-metal devices.
Large attention has recently been given to a novel technology named memristor, for having the potential of becoming the new electronic device standard. Yet, its manifestation as the fourth missing element is rather controversial among scientists. Here we demonstrate that TiO2-based metal-insulator-metal devices are more than just a memory-resistor. They possess resistive, capacitive and inductive components that can concurrently be programmed; essentially exhibiting a convolution of memristive, memcapacitive and meminductive effects. We show how non-zero crossing current-voltage hysteresis loops can appear and we experimentally demonstrate their frequency response as memcapacitive and meminductive effects become dominant.


The Relationship between Hand Therapy and Long-Term Outcomes after Distal Radius Fracture in Older Adults: Evidence from the Randomized Wrist and Radius Injury Surgical Trial.
Older patients are frequently referred to hand therapy after distal radius fracture. Supervised therapy sessions place a transportation burden on patients and are costly on both the individual and systematic levels. Furthermore, there is little evidence that supervised therapy or home exercises improve long-term outcomes. Data were collected for the Wrist and Radius Injury Surgical Trial, a multicenter, international, pragmatic, randomized trial of distal radius fracture treatment in patients aged 60 years and older. Referral to therapy and therapy protocol were at the discretion of the treating surgeon and therapist. The authors examined outcomes between participants who underwent therapy and those who did not and assessed the duration of therapy. The authors also analyzed the effect of therapy on subgroups at risk for poor outcomes: older participants and those who had more comorbidities or lower baseline activity. Eighty percent of participants underwent therapy; 70 percent participated in both supervised therapy and home exercises. Participants had a mean 9.2 supervised sessions over 14.2 weeks. There were no differences in patient-reported outcomes between participants who underwent therapy and those who did not. Participants who did not have therapy recovered more grip strength. Participants who engaged in therapy for a shorter time reported greater function, ability to work, and satisfaction. There were no relationships revealed in subgroup analyses. Hand therapy after distal radius fracture may not be necessary for older patients. Encouraging participants to resume activities of daily living as soon as possible may be as effective as formal therapy. Therapeutic, II.


Magnetic resonance imaging of structure, diffusivity, and copper immobilization in a phototrophic biofilm.
Magnetic resonance imaging (MRI) was used to spatially resolve structure, water diffusion, and copper transport and fate in a phototrophic biofilm [corrected]. MRI was able to resolve considerable structural heterogeneity, ranging from classical laminations approximately 500 mum thick to structures with no apparent ordering. Pulsed-field gradient (PFG) analysis spatially resolved water diffusion coefficients which exhibited relatively little or no attenuation (diffusion coefficients ranged from 1.7 x 10(-9) m(2) s(-1) to 2.2 x 10(-9) m(2) s(-1)). The biofilm was then reacted with a 10-mg liter(-1) Cu(2+) solution, and transverse relaxation time parameter maps [corrected].were used to spatially and temporally map copper immobilization within the biofilm. Significantly, a calibration protocol similar to that used in biomedical research successfully quantified copper concentrations throughout the biofilm. Variations in Cu concentrations were controlled by the biofilm structure. Copper immobilization was most rapid (approximately 5 mg Cu liter(-1) h(-1)) over the first 20 to 30 h and then much slower for the remaining 60 h of the experiment. The transport of metal within the biofilm is controlled by both diffusion and immobilization. This was explored using a Bartlett and Gardner model which examined both diffusion and adsorption through a hypothetical film exhibiting properties similar to those of the phototrophic biofilm. Higher adsorption constants (K) resulted in longer lag times until the onset of immobilization at depth but higher actual adsorption rates. MRI and reaction transport models are versatile tools which can significantly improve our understanding of heavy metal immobilization in naturally occurring biofilms.


Osteopontin-targeted probe detects orthotopic breast cancers using optoacoustic imaging.
Improved detection of breast cancer using highly sensitive, tumor-specific imaging would facilitate diagnosis, surveillance and assessment of response to treatment. We conjugated osteopontin peptide to an infrared fluorescent dye to serve as a contrast agent for detection of breast cancer by multispectral optoacoustic tomography (MSOT). Selective binding of the osteopontin-based probe was identified using flow cytometry and near infrared fluorescent imaging in triple negative and HER2 positive breast cancer cell lines in vitro. Osteopontin-750 accumulation was evaluated in vivo using MSOT with secondary confirmation of signal accumulation using near infrared fluorescent imaging. The osteopontin-based probe demonstrated binding to breast cancer cells in vitro. Similarly, after intravenous administration of the osteopontin-750 probe, it accumulated preferentially in the subcutaneous breast tumor in nude mice (557 MSOT a.u. compared to untargeted organs such as kidney (53.7 MSOT a.u.) and liver (32.1 MSOT a.u.). At 2.5 h post-injection, signal intensity within the tumor was 9.7 and 17 times greater in the tumor bed than in the kidney or liver, respectively. Fluorescence imaging ex vivo comparing tumor signal to that of nontarget organs confirmed the results in vivo. MSOT imaging demonstrated selective accumulation of the fluorescent osteopontin targeting probe to tumor sites both in vitro and in vivo, and provided high-resolution images. Further development of this tool is promising for advanced diagnostic imaging, disease surveillance and therapeutic models that limit nontarget toxicity.


Acetabular labral tears.
Acetabular labral tears rarely occur in the absence of a structural osseous abnormality. Labral tears are frequently associated with lesions of acetabular cartilage such as delamination. Hip arthroscopy is the preferred operative approach in the treatment of labral injuries in the absence of substantial structural osseous abnormalities.


The tomato RLK superfamily: phylogeny and functional predictions about the role of the LRRII-RLK subfamily in antiviral defense.
Receptor-like kinases (RLKs) play key roles during development and in responses to the environment. Despite the relevance of the RLK family and the completion of the tomato genome sequencing, the tomato RLK family has not yet been characterized, and a framework for functional predictions of the members of the family is lacking. To generate a complete list of all the members of the tomato RLK family, we performed a phylogenetic analysis using the Arabidopsis family as a template. A total of 647 RLKs were identified in the tomato genome, which were organized into the same subfamily clades as Arabidopsis RLKs. Only eight of 58 RLK subfamilies exhibited specific expansion/reduction compared to their Arabidopsis counterparts. We also characterized the LRRII-RLK family by phylogeny, genomic analysis, expression profile and interaction with the virulence factor from begomoviruses, the nuclear shuttle protein (NSP). The LRRII subfamily members from tomato and Arabidopsis were highly conserved in both sequence and structure. Nevertheless, the majority of the orthologous pairs did not display similar conservation in the gene expression profile, indicating that these orthologs may have diverged in function after speciation. Based on the fact that members of the Arabidopsis LRRII subfamily (AtNIK1, AtNIK2 and AtNIK3) interact with the begomovirus nuclear shuttle protein (NSP), we examined whether the tomato orthologs of NIK, BAK1 and NsAK genes interact with NSP of Tomato Yellow Spot Virus (ToYSV). The tomato orthologs of NSP interactors, SlNIKs and SlNsAK, interacted specifically with NSP in yeast and displayed an expression pattern consistent with the pattern of geminivirus infection. In addition to suggesting a functional analogy between these phylogenetically classified orthologs, these results expand our previous observation that NSP-NIK interactions are neither virus-specific nor host-specific. The tomato RLK superfamily is made-up of 647 proteins that form a monophyletic tree with the Arabidopsis RLKs and is divided into 58 subfamilies. Few subfamilies have undergone expansion/reduction, and only six proteins were lineage-specific. Therefore, the tomato RLK family shares functional and structural conservation with Arabidopsis. For the LRRII-RLK members SlNIK1 and SlNIK3, we observed functions analogous to those of their Arabidopsis counterparts with respect to protein-protein interactions and similar expression profiles, which predominated in tissues that support high efficiency of begomovirus infection. Therefore, NIK-mediated antiviral signaling is also likely to operate in tomato, suggesting that tomato NIKs may be good targets for engineering resistance against tomato-infecting begomoviruses.


Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study.
An increased risk of gallstone (GS) formation has been linked to obesity and to episodes of rapid and significant weight loss. Previous reports have suggested that bile salt therapy (ursodeoxycholic acid) or prostaglandin inhibition (ibuprofen) may prevent gallstone formation in this high-risk group. The purpose of this study was to investigate GS prevention following bariatric surgery. Randomized double blind controlled trial. Sixty patients without gallstones preoperatively (gender, 9 male, 51 female; average preop wt, 349.6 lb; mean age, 38 years) were randomly assigned to receive urso (600 mg/day, n = 20), ibuprofen (600 mg/d, n = 20), or placebo (n = 20). At the time of standard open gastric bypass, intraoperative ultrasonography confirmed the absence of stones or microcalculi, and bile samples were collected via puncture of the gallbladder for bile lipid analysis. Following recovery and resumption of a bariatric diet, study medication was prescribed for the first 6 months postop. Gallbladder emptying and GS formation were assessed using ultrasonograms preop and at 3, 6, 9, and 12 months postop (gallbladder emptying following a high-fat liquid test meal was assessed preop, and at 3 and 6 months postop). Forty-one (68.3%, 8 male, 33 female) of the original 60 patients completed all phases of the study (15 urso, 15 ibuprofen, 11 placebo). The average weight loss was 98.5 +/- 7.2 lb over the 12-month period following bariatric surgery. Twenty-nine (71%) of 41 patients who completed the study developed GS. Of those who formed stones, 12 (41%) developed symptomatic GS and 8/12 (67%) underwent cholecystectomy (4 refused operation). Preoperative gallbladder emptying studies showed no differences in emptying between groups (urso 29%, ibuprofen 32%, and placebo 30%). There was no correlation found between the cholesterol saturation index (CSI mean 205.15, range 67-360) and the incidence of GS. There was a statistical difference (P < 0.01) between the ursodeoxycholic acid group and the ibuprofen group with respect to the incidence of stone formation. There was correlation between weight loss (mean 99 lb, range 21-278 lb) and GS formation, in that patients who lost more weight had a greater tendency to form gallstones. Complete medical compliance was achieved in only 17/60 (28%) of patients originally enrolled. This pilot study confirms the high incidence of gallstone formation (71% of assessed patients) associated with rapid weight loss in patients undergoing gastric bypass. Despite active enrollment in a supervised prevention trial, the two therapies investigated to reduce gallstone formation were not efficacious, likely because compliance with medical therapy was poor. These findings highlight the significant risk of gallstone formation in this patient cohort even when prevention strategies are utilized.


Timely inhibition of Notch signaling by DAPT promotes cardiac differentiation of murine pluripotent stem cells.
The Notch signaling pathway plays versatile roles during heart development. However, there is contradictory evidence that Notch pathway either facilitates or impairs cardiomyogenesis in vitro. In this study, we developed iPSCs by reprogramming of murine fibroblasts with GFP expression governed by Oct4 promoter, and identified an effective strategy to enhance cardiac differentiation through timely modulation of Notch signaling. The Notch inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) alone drove the iPSCs to a neuronal fate. After mesoderm induction of embryoid bodies initiated by ascorbic acid (AA), the subsequent treatment of DAPT accelerated the generation of spontaneously beating cardiomyocytes. The timed synergy of AA and DAPT yielded an optimal efficiency of cardiac differentiation. Mechanistic studies showed that Notch pathway plays a biphasic role in cardiomyogenesis. It favors the early-stage cardiac differentiation, but exerts negative effects on the late-stage differentiation. Therefore, DAPT administration at the late stage enforced the inhibition of endogenous Notch activity, thereby enhancing cardiomyogenesis. In parallel, DAPT dramatically augmented the expression of Wnt3a, Wnt11, BMP2, and BMP4. In conclusion, our results highlight a practicable approach to generate cardiomyocytes from iPSCs based on the stage-specific biphasic roles of Notch signaling in cardiomyogenesis.


Charger: combination of signal processing and statistical learning algorithms for precursor charge-state determination from electron-transfer dissociation spectra.
Tandem mass spectrometry in combination with liquid chromatography has emerged as a powerful tool for characterization of complex protein mixtures in a high-throughput manner. One of the bioinformatics challenges posed by the mass spectral data analysis is the determination of precursor charge when unit mass resolution is used for detecting fragment ions. The charge-state information is used to filter database sequences before they are correlated to experimental data. In the absence of the accurate charge state, several charge states are assumed. This dramatically increases database search times. To address this problem, we have developed an approach for charge-state determination of peptides from their tandem mass spectra obtained in fragmentations via electron-transfer dissociation (ETD) reactions. Protein analysis by ETD is thought to enhance the range of amino acid sequences that can be analyzed by mass spectrometry-based proteomics. One example is the improved capability to characterize phosphorylated peptides. Our approach to charge-state determination uses a combination of signal processing and statistical machine learning. The signal processing employs correlation and convolution analyses to determine precursor masses and charge states of peptides. We discuss applicability of these methods to spectra of different charge states. We note that in our applications correlation analysis outperforms the convolution in determining peptide charge states. The correlation analysis is best suited for spectra with prevalence of complementary ions. It is highly specific but is dependent on quality of spectra. The linear discriminant analysis (LDA) approach uses a number of other spectral features to predict charge states. We train LDA classifier on a set of manually curated spectral data from a mixture of proteins of known identity. There are over 5000 spectra in the training set. A number of features, pertinent to spectra of peptides obtained via ETD reactions, have been used in the training. The loading coefficients of LDA indicate the relative importance of different features for charge-state determination. We have applied our model to a test data set generated from a mixture of 49 proteins. We search the spectra with and without use of the charge-state determination. The charge-state determination helps to significantly save the database search times. We discuss the cost associated with the possible misclassification of charge states.


Application of in situ ellipsometry in the fabrication of thin-film optical coatings on semiconductors.
Thin-film interference filters, suitable for use on GaAs- and InP-based lasers, have been fabricated by use of the electron-cyclotron resonance plasma-enhanced chemical vapor deposition technique. Multilayer film structures composed of silicon oxynitride material have been deposited at low temperatures with an in situ rotating compensator ellipsometer for monitoring the index of refraction and thickness of the deposited layers. Individual layers with an index of refraction from 3.3 to 1.46 at 633 nm have been produced with a run-to-run reproducibility of 0.005 and a thickness control of 10 A. Several filter designs have been implemented, including high-reflection filters, one- and two-layer anitreflection filters, and narrow-band high-reflection filters. It is shown that an accurate measurement of the filter optical properties during deposition is possible and that controlled reflectance spectra can be obtained.


A gain-field encoding of limb position and velocity in the internal model of arm dynamics.
Adaptability of reaching movements depends on a computation in the brain that transforms sensory cues, such as those that indicate the position and velocity of the arm, into motor commands. Theoretical consideration shows that the encoding properties of neural elements implementing this transformation dictate how errors should generalize from one limb position and velocity to another. To estimate how sensory cues are encoded by these neural elements, we designed experiments that quantified spatial generalization in environments where forces depended on both position and velocity of the limb. The patterns of error generalization suggest that the neural elements that compute the transformation encode limb position and velocity in intrinsic coordinates via a gain-field; i.e., the elements have directionally dependent tuning that is modulated monotonically with limb position. The gain-field encoding makes the counterintuitive prediction of hypergeneralization: there should be growing extrapolation beyond the trained workspace. Furthermore, nonmonotonic force patterns should be more difficult to learn than monotonic ones. We confirmed these predictions experimentally.


Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat.
Social stress in rats is known to induce long-lasting, adverse changes in behaviour and physiology, which seem to resemble certain human psychopathologies, such as depression and anxiety. The present experiment was designed to assess the influence of individual or group housing on the vulnerability of male Wildtype rats to long-term effects of inescapable social defeat. Group-housed rats were individually exposed to an aggressive, unfamiliar male conspecific, resulting in a social defeat. Defeated rats were then either individually housed or returned to their group. The changes in their behaviour and physiology were then studied for 3 weeks. Results showed that individually housed rats developed long-lasting, adverse behavioural and physiological changes after social defeat. Their body growth was significantly retarded (p < .05) between 7 and 14 days after defeat. When individually and group-housed rats were exposed to a mild stressor (sudden silence) 2 days after defeat, both groups became highly immobile. However, when exposure was repeated at day 21, individually housed rats were still highly immobile compared to group-housed rats which regained their normal mobility after only 7 days. In an open field test, also regularly repeated, individually housed rats took significantly longer to leave their home base and were also significantly less mobile than group-housed rats over the entire 3-week test period as well as at specific timepoints. When the rats were placed in an elevated plus-maze 14 days after defeat, those that were individually housed were significantly more anxious than those that were group-housed. When tested at 21 days after defeat in a combined dexamethasone (DEX)/corticotrophin-releasing factor (CRF) test, results showed that the hypothalamic-pituitary-adrenocortical (HPA) activity in individually housed rats was higher. This was evidenced in the latter animals by the fact that DEX was significantly less able to suppress the secretion of ACTH and corticosterone, and by a significantly higher release of ACTH after administration of CRF. Although the weights of the spleen and testes of the two groups did not differ, the adrenals of individually housed rats were larger and the thymus and seminal vesicles were smaller. We conclude that when rats are isolated after defeat, they show long-lasting, adverse behavioural and physiological changes that resemble symptoms of stress-related disorders. In contrast, when familiar rats are housed together these effects of a social defeat are greatly reduced. These findings show that housing conditions importantly influence the probability of long-term adverse behavioural and physiological effects of social defeat in male Wildtype rats.


Fusion of airways during avian lung development constitutes a novel mechanism for the formation of continuous lumena in multicellular epithelia.
During development of the avian lung, the initially terminally branched epithelial tree later forms a continuous network of airways. This occurs via a large-scale epithelial fusion event, wherein airways that originate proximally collide with those that originate distally to form one continuous lumen. Here, we found that prior to fusion, the epithelium of the embryonic chicken lung undergoes a shape change to permit the initiation and extension of new branches which contain the cells that initiate contact. These changes in epithelial shape coincide with the differentiation of smooth muscle cells that wrap the airways. From these nascent epithelial branches, individual cells form cytoskeletal protrusions that extend toward and form a bridge with their target airway. Additional cells then join the fusion site, forming a bilayered epithelium. During this process, the basement membrane around the prefusion epithelium degrades and then reforms after fusion. The epithelial bilayer then undergoes apoptosis, clearing the path between the two lumens. The process of airway epithelial fusion in the developing chicken lung constitutes a novel mechanism for the generation of complex multicellular tubes and suggests a conserved role for smooth muscle in the shaping of airway epithelia.


Seizures in the elderly: etiology and prognosis.
To determine the etiology, early mortality, predictors of prognosis and diagnostic yields of EEG and CT scans of the head in new-onset seizures in elderly patients. EEG records for the north-central region of Saskatchewan, between 01/94 and 12/95 were reviewed to identify all adults aged 60 years or older with new-onset seizures. Information on demographics, seizure type, etiology, EEG and neuroimaging studies, anti-epileptic treatment and course of epilepsy was obtained by review of medical records and interview with the patient and/or family member. Of 88 eligible subjects, 61 (69%) were contacted for follow-up, 19 (22%) were deceased (12 of whom who had a serious underlying etiology to their seizures, which was obvious at the time of initial presentation and led shortly to their demise), 4 (5%) were lost to follow-up and 4 (5%) refused participation. Excluding those refusing participation, 74/84 (88%) patients presented with partial or secondarily generalized seizures. Seizures were cryptogenic in 38/84 (45%), and due to stroke in 19/84 (23%). EEGs were abnormal in 61/84 (73%) cases, with epileptiform discharge in 33/84 (39%). CT scans were abnormal in 57/84 (68%) cases with acute pathology in 29/84 (35%). Of the 61 patients participating in the follow-up interview, 54 (89%) were treated with anti-epileptic medication and seizure control was usually successful. Predictors for ongoing seizures were more than 3 seizures at presentation, epileptiform activity on initial EEG and discontinuation of anti-epileptic medication for lack of efficacy. Prognosis of new-onset seizures in elderly patients is favorable if seizures are not symptomatic of a life-threatening disorder.


Evidence for a requirement for both phospholipid and phosphotyrosine binding via the Shc phosphotyrosine-binding domain in vivo.
The adapter protein Shc is a critical component of mitogenic signaling pathways initiated by a number of receptors. Shc can directly bind to several tyrosine-phosphorylated receptors through its phosphotyrosine-binding (PTB) domain, and a role for the PTB domain in phosphotyrosine-mediated signaling has been well documented. The structure of the Shc PTB domain demonstrated a striking homology to the structures of pleckstrin homology domains, which suggested acidic phospholipids as a second ligand for the Shc PTB domain. Here we demonstrate that Shc binding via its PTB domain to acidic phospholipids is as critical as binding to phosphotyrosine for leading to Shc phosphorylation. Through structure-based, targeted mutagenesis of the Shc PTB domain, we first identified the residues within the PTB domain critical for phospholipid binding in vitro. In vivo, the PTB domain was essential for localization of Shc to the membrane, as mutant Shc proteins that failed to interact with phospholipids in vitro also failed to localize to the membrane. We also observed that PTB domain-dependent targeting to the membrane preceded the PTB domain's interaction with the tyrosine-phosphorylated receptor and that both events were essential for tyrosine phosphorylation of Shc following receptor activation. Thus, Shc, through its interaction with two different ligands, is able to accomplish both membrane localization and binding to the activated receptor via a single PTB domain.


Polymers in the gut compress the colonic mucus hydrogel.
Colonic mucus is a key biological hydrogel that protects the gut from infection and physical damage and mediates host-microbe interactions and drug delivery. However, little is known about how its structure is influenced by materials it comes into contact with regularly. For example, the gut abounds in polymers such as dietary fibers or administered therapeutics, yet whether such polymers interact with the mucus hydrogel, and if so, how, remains unclear. Although several biological processes have been identified as potential regulators of mucus structure, the polymeric composition of the gut environment has been ignored. Here, we demonstrate that gut polymers do in fact regulate mucus hydrogel structure, and that polymer-mucus interactions can be described using a thermodynamic model based on Flory-Huggins solution theory. We found that both dietary and therapeutic polymers dramatically compressed murine colonic mucus ex vivo and in vivo. This behavior depended strongly on both polymer concentration and molecular weight, in agreement with the predictions of our thermodynamic model. Moreover, exposure to polymer-rich luminal fluid from germ-free mice strongly compressed the mucus hydrogel, whereas exposure to luminal fluid from specific-pathogen-free mice-whose microbiota degrade gut polymers-did not; this suggests that gut microbes modulate mucus structure by degrading polymers. These findings highlight the role of mucus as a responsive biomaterial, and reveal a mechanism of mucus restructuring that must be integrated into the design and interpretation of studies involving therapeutic polymers, dietary fibers, and fiber-degrading gut microbes.


[Outbreak of bovine virus diarrhea on Dutch dairy farms induced by a bovine herpesvirus 1 marker vaccine contaminated with bovine virus diarrhea virus type 2].
On 23 February 1999, the Dutch Animal Health Service advised all Dutch veterinary practices to postpone vaccination against bovine herpesvirus 1 (BHV1) immediately. The day before severe disease problems were diagnosed on four dairy farms after vaccination with the same batch of BHV1 marker vaccine. Using monoclonal antibodies, bovine virus diarrhoea virus (BVDV) type 2 was found in the vaccine batch. This paper describes an outbreak of BVDV type 2 infection caused by the use of a batch of modified live BHV1 marker vaccine contaminated with BDVD. Sources of information used were reports of farm visits, minutes of meetings, laboratory results, and oral communications from the people involved. The first symptoms of disease were observed on average six days after vaccination. Morbidity was high on 11 of the 12 farms. On five farms more than 70% of the animals became ill, while on one farm no symptoms could be detected. During the first week after vaccination, feed intake and milk production decreased. During the second week, some animals became clinically diseased having nasal discharge, fever, and diarrhoea. At the end of the second week and at the start of the third week, the number of diseased animals increased rapidly, the symptoms became more severe, and some animals died. Mortality varied among herds. Necropsy most often revealed erosions and ulcers of the mucosa of the digestive tract. In addition, degeneration of the liver, hyperaemia of the abomasum, and swollen mesenterial lymph nodes and swollen spleen were found. On 11 of the 12 farms all animals were culled between 32 and 68 days after vaccination after an agreement was reached with the manufacturer of the vaccine. This was the third outbreak of BVD in cattle after administration of a contaminated vaccine in the Netherlands. The possibilities to prevent contamination of a vaccine as a consequence of infection of fetal calf serum with BVDV are discussed. Improvement of controls to prevent contamination before and during vaccine production, and improvement of the monitoring of side-effects is necessary.


Quantitative Magnetic Resonance Venography is Correlated With Intravenous Pressures Before and After Venous Sinus Stenting: Implications for Treatment and Monitoring.
Endovascular stenting is an effective treatment for patients with clinically significant cerebral venous sinus stenosis. Traditionally, stenting is indicated in elevated intravenous pressures on conventional venography; however, noninvasive monitoring is more desirable. Quantitative magnetic resonance angiography is an imaging modality that measures blood flow noninvasively. Established in the arterial system, applications to the venous sinuses have been limited. To examine quantitative magnetic resonance venography (qMRV) in the measurement of venous sinus flow in patients undergoing endovascular stenting and to identify a relationship with intravenous pressures. Five patients with intracranial hypertension secondary to venous sinus stenosis underwent cerebral venous stenting between 2009 and 2013 at a single institution. Preoperatively, venous sinus flow was determined by using qMRV, and intravenous pressure was measured during venography. After stenting, intravenous pressure, qMRV flow, and clinical outcomes were assessed and compared. A mean prestenotic intravenous pressure of 45.2 mm Hg was recorded before stenting, which decreased to 27.4 mm Hg afterward (Wilcoxon signed rank test P = .04). Total jugular outflow on qMRV increased by 260.2 mL/min. Analysis of the change in intravenous pressure and qMRV flow identified a linear relationship (Pearson correlation r = 0.926). All patients displayed visual improvement at 6 weeks. Venous outflow by qMRV increases after endovascular stenting and correlates with significantly improved intravenous pressures. These findings introduce qMRV as a potential adjunct to measure venous flow after stenting, and as a plausible tool in the selection and postoperative surveillance of the patient who has cerebral venous sinus stenosis.


SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM).
The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin inhibitor, in patients with unresectable MPM. MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression-free survival (PFS) by RECIST 1.1. A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate was 2% [95% confidence interval (CI): 0-12%] by RECIST 1.1 and 0% (0-10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17-41%) by RECIST 1.1, and 27% (95% CI: 16-39%) by modified RECIST. The median PFS was 2.8 months (95% CI: 1.8-3.4) by RECIST 1.1. The median overall survival was 6.3 months (95% CI: 4.0-8.0). There was no difference in PFS among patients who received one or two prior chemotherapy regimens (p = 0.74). There was no difference in overall survival between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3 to 4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%). Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.


Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors.
Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. These concepts are directly relevant to the development of targeted molecular therapy for other solid tumors. (Clin Cancer Res 2009;15(24):7510-8).


End-to-End Structure-Aware Convolutional Networks for Knowledge Base Completion.
Knowledge graph embedding has been an active research topic for knowledge base completion, with progressive improvement from the initial TransE, TransH, DistMult et al to the current state-of-the-art ConvE. ConvE uses 2D convolution over embeddings and multiple layers of nonlinear features to model knowledge graphs. The model can be efficiently trained and scalable to large knowledge graphs. However, there is no structure enforcement in the embedding space of ConvE. The recent graph convolutional network (GCN) provides another way of learning graph node embedding by successfully utilizing graph connectivity structure. In this work, we propose a novel end-to-end Structure-Aware Convolutional Network (SACN) that takes the benefit of GCN and ConvE together. SACN consists of an encoder of a weighted graph convolutional network (WGCN), and a decoder of a convolutional network called Conv-TransE. WGCN utilizes knowledge graph node structure, node attributes and edge relation types. It has learnable weights that adapt the amount of information from neighbors used in local aggregation, leading to more accurate embeddings of graph nodes. Node attributes in the graph are represented as additional nodes in the WGCN. The decoder Conv-TransE enables the state-of-the-art ConvE to be translational between entities and relations while keeps the same link prediction performance as ConvE. We demonstrate the effectiveness of the proposed SACN on standard FB15k-237 and WN18RR datasets, and it gives about 10% relative improvement over the state-of-the-art ConvE in terms of HITS@1, HITS@3 and HITS@10.


Derivation of phenotypically diverse neural culture from hESC by combining adherent and dissociation methods.
Differentiation of human embryonic stem cells (hESCs) into distinct neural lineages has been widely studied. However, preparation of mixed yet neurochemically mature populations, for the study of neurological diseases involving mixed cell types has received less attention. We combined two commonly used differentiation methods to provide robust and reproducible cultures in which a mixture of primarily GABAergic and Glutamatergic neurons was obtained. Detailed characterisation by immunocytochemistry (ICC) and quantitative real-time PCR (qPCR) assessed the neurochemical phenotype, and the maturation state of these neurons. We found that once neurospheres (NSs) had attached to the culture plates, proliferation of neural stem cell was suppressed. Neuronal differentiation and synaptic development then occurred after 21 days in vitro (DIV). By 49DIV, there were large numbers of neurochemically and structurally mature neurons. The qPCR studies indicated that expression of GABAergic genes increased the most (93.3-fold increase), followed by glutamatergic (51-fold increase), along with smaller changes in expression of cholinergic (3-fold increase) and dopaminergic genes (6-fold increase), as well as a small change in glial cell marker expression (5-fold increase). Existing methods isolate hESC-derived neural progenitors for onward differentiation to mature neurons using either migration or dissociative paradigms. These give poor survival or yield. By combining these approaches, we obtain high yields of morphologically and neurochemically mature neurons. These can be maintained in culture for extended periods. Our method provides a novel, effective and robust neural culture system with structurally and neurochemically mature cell populations and neural networks, suitable for studying a range of neurological diseases from a human perspective.


Efficient breathing circuit for use at altitude.
We describe a case report of a subject suffering high-altitude cerebral and pulmonary edema successfully treated with low flow rates of supplemental oxygen administered with a breathing system designed to conserve oxygen supplies at high altitude.


Postpartum management of women at increased risk of thrombosis--results of a Canadian pilot survey.
To determine current practice patterns in the postpartum management of women at increased risk of thrombosis. Physicians affiliated with the University of Toronto departments of Obstetrics and Gynecology, Rheumatology, Hematology, and Obstetric Medicine who provide care to pregnant women were mailed a questionnaire that presented 6 clinical scenarios involving postpartum management of a woman at risk for thrombosis, with (1) recurrent pregnancy loss and antiphospholipid antibody syndrome (APS) treated with aspirin (ASA) in the pregnancy; (2) 2 pregnancy losses and a low titer antiphospholipid antibody (aPL) treated with ASA and low molecular weight (LMW) heparin with placental insufficiency; (3) known APS and pregnancy loss treated with LMW heparin and delivered by cesarean section; (4) a previous 17 week fetal death and aPL; (5) a previous deep vein thrombosis while on oral contraception; and (6) systemic lupus erythematosus and secondary APS with a history of a stillbirth. Physicians were asked whether they would recommend postpartum coagulation, and if so to choose from a list of treatment options. Of the 71 questionnaires mailed, 44 were returned (62%). Three physicians replied that their practices do not include patients similar to those presented in the cases and chose not to respond to the clinical scenarios. Percentages of responders recommending treatment in each scenario were 29% for Case 1, 49% for Case 2, 63% for Case 3, 41% for Case 4, 51% for Case 5, and 58% for Case 6. Recommendation for treatment differed among medical specialties, with rheumatologists being less likely to treat in all cases. Prophylactic heparin was selected as the treatment of choice most frequently by those recommending anticoagulation 70% (84/120). Postpartum treatment recommendations for women at increased risk of thrombosis are variable across different practitioner specializations demonstrating clinical equipoise regarding therapy. More definitive research is needed and broader study of physicians involved in the care of these patients is planned to more accurately describe and understand the decision to treat these patients.


Three-year efficacy of complex insulin regimens in type 2 diabetes.
Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.)


Dietary glycemic load, glycemic index, and carbohydrate and risk of breast cancer in the Women's Health Initiative.
Dietary glycemic load (GL), glycemic index (GI), and carbohydrate could be associated with breast cancer risk by influencing long-term blood glucose and insulin concentrations. We examined associations between GL, GI, and carbohydrate and incident breast cancer in 148,767 Women's Heath Initiative (WHI) participants. Dietary variables were estimated from food frequency questionnaires administered at baseline. Self-reported breast cancers during follow-up were confirmed by medical records review. Cox proportional hazards regression modeled time to breast cancer within quintiles of GL, GI, and carbohydrate. There were 6,115 total breast cancers after a median follow-up of 8.0 yr. We observed no associations between GL, GI, or carbohydrate and total incident breast cancer, with hazard ratios and 95% confidence intervals for the highest vs. lowest quintiles of 1.08, 0.92-1.29 (P for trend = 0.27); 1.01, 0.91-1.12 (P = 0.74); and 0.95, 0.80-1.14 (P = 0.98), respectively. There was a trend toward significance for the positive association between GL and in situ cancers (1.40, 0.94-2.13; P = 0.07). Although there was no evidence of associations between GL, GI, or carbohydrate and total breast cancer risk in WHI participants, the suggestion of an association between GL and risk of in situ cancers requires further investigation.


Root-Associated Fungi Shared Between Arbuscular Mycorrhizal and Ectomycorrhizal Conifers in a Temperate Forest.
Arbuscular mycorrhizal and ectomycorrhizal symbioses are among the most important drivers of terrestrial ecosystem dynamics. Historically, the two types of symbioses have been investigated separately because arbuscular mycorrhizal and ectomycorrhizal plant species are considered to host discrete sets of fungal symbionts (i.e., arbuscular mycorrhizal and ectomycorrhizal fungi, respectively). Nonetheless, recent studies based on high-throughput DNA sequencing technologies have suggested that diverse non-mycorrhizal fungi (e.g., endophytic fungi) with broad host ranges play roles in relationships between arbuscular mycorrhizal and ectomycorrhizal plant species in forest ecosystems. By analyzing an Illumina sequencing dataset of root-associated fungi in a temperate forest in Japan, we statistically examined whether co-occurring arbuscular mycorrhizal (Chamaecyparis obtusa) and ectomycorrhizal (Pinus densiflora) plant species could share non-mycorrhizal fungal communities. Among the 919 fungal operational taxonomic units (OTUs) detected, OTUs in various taxonomic lineages were statistically designated as "generalists," which associated commonly with both coniferous species. The list of the generalists included fungi in the genera Meliniomyces, Oidiodendron, Cladophialophora, Rhizodermea, Penicillium, and Mortierella. Meanwhile, our statistical analysis also detected fungi preferentially associated with Chamaecyparis (e.g., Pezicula) or Pinus (e.g., Neolecta). Overall, this study provides a basis for future studies on how arbuscular mycorrhizal and ectomycorrhizal plant species interactively drive community- or ecosystem-scale processes. The physiological functions of the fungi highlighted in our host-preference analysis deserve intensive investigations for understanding their roles in plant endosphere and rhizosphere.


Diagnosis and management of pneumonia and bronchitis in outpatient primary care practices.
To understand which clinical criteria physicians use to diagnose pneumonia compared to bronchitis and upper respiratory tract infection (URTI). Retrospective chart review of adults diagnosed with pneumonia, bronchitis, or URTI. Logistic regression analysis identified rales, a temperature > 100 degrees F (37.8 degrees C), chest pain, dyspnoea, rhonchi, heart rate, respiratory rate, and rhinorrhoea, as the best explanation for the variation in diagnosis of pneumonia compared to either of the alternative diagnoses (R2 = 59.3), with rales and a temperature > 100 degrees F explaining 30% of the variation. Rales, chest pain, and a temperature > 100 degrees F best predicted the ordering of a chest x-ray (R2 = 20.0). However, 35% (59/175) of patients diagnosed with pneumonia had a negative chest x-ray. Abnormal breath sounds were the best predictors for prescribing antibiotics (R2 = 38%). A significant number of patients with acute bronchitis (93% excluding sinusitis) and URTI (42%) were given antibiotics. The presence of abnormal breath sounds and a temperature > 100 degrees F were the best predictors of a diagnosis of pneumonia.


The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms.
Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-α mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.


SlyA, a transcriptional regulator of Salmonella typhimurium, is required for resistance to oxidative stress and is expressed in the intracellular environment of macrophages.
Appropriate regulation of genes enables Salmonella typhimurium to adapt to the intracellular environment of the host. The Salmonella slyA gene is in a family of transcriptional regulators that may play an important role in this adaptation. We have previously shown that slyA mutant Salmonella strains are profoundly attenuated for virulence and do not survive in macrophages. In this study, we demonstrate that the expression of multiple Salmonella proteins is regulated by SlyA during stationary phase and during infection of macrophages. Both of these conditions also induced the expression of a slyA::lacZ transcriptional fusion. Expression of the slyA::lacZ transcriptional fusion increased 15-fold in stationary phase and was not dependent on the stationary-phase sigma factor, RpoS. slyA mutant Salmonella strains were sensitive to oxidative products of the respiratory burst, including hydrogen peroxide and the products of the redox cycling compound paraquat, but not to nitric oxide donors. These results suggest that the SlyA regulon is activated during infection of the host and is required for resistance to toxic oxidative products of the reticuloendothelial system.


Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.
Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.


Integrated metabolomics approach facilitates discovery of an unpredicted natural product suite from Streptomyces coelicolor M145.
Natural products exhibit a broad range of biological properties and have been a crucial source of therapeutic agents and novel scaffolds. Although bacterial secondary metabolomes are widely explored, they remain incompletely cataloged by current isolation and characterization strategies. To identify metabolites residing in unexplored chemical space, we have developed an integrated discovery approach that combines bacterial growth perturbation, accurate mass spectrometry, comparative mass spectra data analysis, and fragmentation spectra clustering for the identification of low-abundant, novel compounds from complex biological matrices. In this investigation, we analyzed the secreted metabolome of the extensively studied Actinomycete, Streptomyces coelicolor M145, and discovered a low-abundant suite of 15 trihydroxamate, amphiphilic siderophores. Compounds in this class have primarily been observed in marine microorganisms making their detection in the soil-dwelling S. coelicolor M145 significant. At least 10 of these ferrioxamine-based molecules are not known to be produced by any organism, and none have previously been detected from S. coelicolor M145. In addition, we confirmed the production of ferrioxamine D1, a relatively hydrophilic family member that has not been shown to be biosynthesized by this organism. The identified molecules are part of only a small list of secondary metabolites that have been discovered since sequencing of S. coelicolor M145 revealed that it possessed numerous putative secondary metabolite-producing gene clusters with no known metabolites. Thus, the identified siderophores represent the unexplored metabolic potential of both well-studied and new organisms that could be uncovered with our sensitive and robust approach.


Balloon surface temperature-controlled ablation using a second-generation radiofrequency HotBalloon: an in vivo feasibility study.
The first-generation radiofrequency HotBalloon (RHB) is a size-adjustable single-shot device used in atrial fibrillation. The energy output is determined by its central temperature and not by its balloon surface temperature (BST), thus limiting its efficacy and safety. Therefore, a second-generation RHB was developed to monitor BST and enable BST-controlled ablation. This animal study aims to evaluate the accuracy of a newly developed BST-monitoring system and validate the optimal BST for ablation. In Protocol 1, thermocapsules were attached to the superior vena cava (SVC) epicardium. The accuracy of BST monitoring was examined during SVC isolation. In Protocol 2, the efficacy and safety of different BST-controlled ablations were examined. In the acute model, electrophysiological and pathological findings were assessed after energy applications with BST at 51, 54, 57, and 60°C. In the chronic model, the lesion durability and pathological findings were assessed 8 weeks after BST-controlled ablation (57 and 60°C). A significant positive correlation was found between the epicardial temperature and the BST-monitoring value (r = 0.98). In the acute model, all target veins were electrically isolated with BST-controlled ablation at ≥57°C (18/18, 100%). In the chronic model, durable lesions were observed in all veins at 60°C, while 44% of the veins showed reconnection at 57°C. In both pathological analyses, significantly greater lesions were observed at 60°C than at 57°C. There were no significant differences in adverse events between the two groups. Balloon surface temperature-controlled ablation at 60°C using the second-generation RHB may be optimal for creating durable lesions without compromising safety.


Modulation of the reaction cycle of the Na+:Ca2+, K+ exchanger.
Ca(2+) concentration in retinal photoreceptor rod outer segment (OS) strongly affects the generator potential kinetics and the receptor light adaptation. The response to intense light stimuli delivered in the dark produce potential changes exceeding 40 mV: since the Ca(2+) extrusion in the OS is entirely controlled by the Na(+):Ca(2+), K(+) exchanger, it is important to assess how the exchanger ion transport rate is affected by the voltage and, in general, by intracellular factors. It is indeed known that the cardiac Na(+):Ca(2+) exchanger is regulated by Mg-ATP via a still unknown metabolic pathway. In the present work, the Na(+):Ca(2+), K(+) exchanger regulation was investigated in isolated OS, recorded in whole-cell configuration, using ionic conditions that activated maximally the exchanger in both forward and reverse mode. In all species examined (amphibia: Rana esculenta and Ambystoma mexicanum; reptilia: Gecko gecko), the forward (reverse) exchange current increased about linearly for negative (positive) voltages and exhibited outward (inward) rectification for positive (negative) voltages. Since hyperpolarisation increases Ca(2+) extrusion rate, the recovery of the dark level of Ca(2+) (and, in turn, of the generator potential) after intense light stimuli results accelerated. Mg-ATP increased the size of forward and reverse exchange current by a factor of approximately 2.3 and approximately 2.6, respectively, without modifying their voltage dependence. This indicates that Mg-ATP regulates the number of active exchanger sites and/or the exchanger turnover number, although via an unknown mechanism.


Oxidative Stability of Granola Bars Enriched with Multilayered Fish Oil Emulsion in the Presence of Novel Brown Seaweed Based Antioxidants.
Fucus vesiculosus extracts that have both radical scavenging activity and metal chelating ability in vitro were used as natural antioxidant in granola bars enriched with fish oil emulsion by using primary and secondary emulsion systems stabilized by sodium caseinate alone and sodium caseinate-chitosan. The bars were stored at 20 °C and evaluated over a period of 10 weeks by measuring the development of primary and secondary oxidation products. The samples prepared with secondary emulsion system developed less oxidation products probably due to increased interfacial layer thickness that would act as a barrier to the penetration and diffusion of molecular species that promote oxidation. The positive charge of oil droplets in the secondary emulsion may also inhibit iron-lipid interaction through electrostatic repulsion. Additional protection against lipid oxidation was obtained when fish oil emulsions were added to the granola bars especially in combination with acetone and ethanol extracts of Fucus vesiculosus.


Metagenome-Based Metabolic Reconstruction Reveals the Ecophysiological Function of Epsilonproteobacteria in a Hydrocarbon-Contaminated Sulfidic Aquifer.
The population genome of an uncultured bacterium assigned to the Campylobacterales (Epsilonproteobacteria) was reconstructed from a metagenome dataset obtained by whole-genome shotgun pyrosequencing. Genomic DNA was extracted from a sulfate-reducing, m-xylene-mineralizing enrichment culture isolated from groundwater of a benzene-contaminated sulfidic aquifer. The identical epsilonproteobacterial phylotype has previously been detected in toluene- or benzene-mineralizing, sulfate-reducing consortia enriched from the same site. Previous stable isotope probing (SIP) experiments with (13)C6-labeled benzene suggested that this phylotype assimilates benzene-derived carbon in a syntrophic benzene-mineralizing consortium that uses sulfate as terminal electron acceptor. However, the type of energy metabolism and the ecophysiological function of this epsilonproteobacterium within aromatic hydrocarbon-degrading consortia and in the sulfidic aquifer are poorly understood. Annotation of the epsilonproteobacterial population genome suggests that the bacterium plays a key role in sulfur cycling as indicated by the presence of an sqr gene encoding a sulfide quinone oxidoreductase and psr genes encoding a polysulfide reductase. It may gain energy by using sulfide or hydrogen/formate as electron donors. Polysulfide, fumarate, as well as oxygen are potential electron acceptors. Auto- or mixotrophic carbon metabolism seems plausible since a complete reductive citric acid cycle was detected. Thus the bacterium can thrive in pristine groundwater as well as in hydrocarbon-contaminated aquifers. In hydrocarbon-contaminated sulfidic habitats, the epsilonproteobacterium may generate energy by coupling the oxidation of hydrogen or formate and highly abundant sulfide with the reduction of fumarate and/or polysulfide, accompanied by efficient assimilation of acetate produced during fermentation or incomplete oxidation of hydrocarbons. The highly efficient assimilation of acetate was recently demonstrated by a pulsed (13)C2-acetate protein SIP experiment. The capability of nitrogen fixation as indicated by the presence of nif genes may provide a selective advantage in nitrogen-depleted habitats. Based on this metabolic reconstruction, we propose acetate capture and sulfur cycling as key functions of Epsilonproteobacteria within the intermediary ecosystem metabolism of hydrocarbon-rich sulfidic sediments.


Studies of SARM1 uncover similarities between immune and neuronal responses to danger.
Toll-interleukin-1 receptor (TIR) domain-containing proteins are best known as critical players in vertebrate immune defense against pathogens. Four of the five members of this family are required for the activation of immune cells downstream of the engagement of Toll-like receptors (TLRs) by microbial molecules. Mice deficient in any one of these four molecules show greatly enhanced susceptibility to specific classes of pathogens. However, the physiological function of the fifth mammalian protein, sterile alpha and TIR motif-containing 1 [SARM1, also known as myeloid differentiation marker 88-5 (MyD88-5)], has remained elusive. Now, the study of the SARM1 reporter and SARM1-deficient mice has uncovered an unanticipated function of this molecule in the regulation of neuronal survival in response to metabolic stress. Together with pioneering observations on the functions of TIR-1, the worm ortholog of SARM1, and other reports on the role of TLRs in neuronal development and responses to injury in mammals, these exciting results suggest that further studies of SARM1-deficient animals may uncover unexpected similarities between the ways in which neurons and immune cells sense and respond to danger.


Revisiting an IgG Fc Loss-of-Function Experiment: the Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity.
The role of the complement system in HIV-1 immunity and pathogenesis is multifaceted, and an improved understanding of complement activities mediated by HIV-1-specific antibodies has the potential to inform and advance clinical development efforts. A seminal nonhuman primate challenge experiment suggested that complement was dispensable for the protective effect of the early broadly neutralizing antibody (bnAb) b12, but recent experiments have raised questions about the breadth of circumstances under which this conclusion may hold. Here, we reassess the original observation using Fc variants of IgG1 b12 that enhance complement activity and report that complement fixation on recombinant antigen, virions, and cells and complement-dependent viral and cellular lysis in vitro vary among bnAbs. Specifically, while the clinically significant V3 glycan-specific bnAb 10-1074 demonstrates activity, we found that b12 does not meaningfully activate the classical complement cascade. Consistent with avid engagement by C1q and its complex system of regulatory factors, these results suggest that complement-mediated antibody activities demonstrate a high degree of context dependence and motivate revisiting the role of complement in antibody-mediated prevention of HIV-1 infection by next-generation bnAbs in new translational studies in animal models. IMPORTANCE Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies.


New archaeozoological data from the Fayum "Neolithic" with a critical assessment of the evidence for early stock keeping in Egypt.
Faunal evidence from the Fayum Neolithic is often cited in the framework of early stock keeping in Egypt. However, the data suffer from a number of problems. In the present paper, large faunal datasets from new excavations at Kom K and Kom W (4850-4250 BC) are presented. They clearly show that, despite the presence of domesticates, fish predominate in the animal bone assemblages. In this sense, there is continuity with the earlier Holocene occupation from the Fayum, starting ca. 7350 BC. Domesticated plants and animals appear first from approximately 5400 BC. The earliest possible evidence for domesticates in Egypt are the very controversial domesticated cattle from the 9th/8th millennium BC in the Nabta Playa-Bir Kiseiba area. The earliest domesticates found elsewhere in Egypt date to the 6th millennium BC. The numbers of bones are generally extremely low at this point in time and only caprines are present. From the 5th millennium BC, the numbers of sites with domesticates dramatically increase, more species are also involved and they are usually represented by significant quantities of bones. The data from the Fayum reflect this two phase development, with very limited evidence for domesticates in the 6th millennium BC and more abundant and clearer indications in the 5th millennium BC. Any modelling of early food production in Egypt suffers from poor amounts of data, bias due to differential preservation and visibility of sites and archaeological remains, and a lack of direct dates for domesticates. In general, however, the evidence for early stock keeping and accompanying archaeological features shows large regional variation and seems to be mainly dependent on local environmental conditions. The large numbers of fish at Kom K and Kom W reflect the proximity of Lake Qarun.


Making waves in the stream of consciousness: entraining oscillations in EEG alpha and fluctuations in visual awareness with rhythmic visual stimulation.
Rhythmic events are common in our sensory world. Temporal regularities could be used to predict the timing of upcoming events, thus facilitating their processing. Indeed, cognitive theories have long posited the existence of internal oscillators whose timing can be entrained to ongoing periodic stimuli in the environment as a mechanism of temporal attention. Recently, recordings from primate brains have shown electrophysiological evidence for these hypothesized internal oscillations. We hypothesized that rhythmic visual stimuli can entrain ongoing neural oscillations in humans, locking the timing of the excitability cycles they represent and thus enhancing processing of subsequently predictable stimuli. Here we report evidence for entrainment of neural oscillations by predictable periodic stimuli in the alpha frequency band and show for the first time that the phase of existing brain oscillations cannot only be modified in response to rhythmic visual stimulation but that the resulting phase-locked fluctuations in excitability lead to concomitant fluctuations in visual awareness in humans. This entrainment effect was dependent on both the amount of spontaneous alpha power before the experiment and the level of 12-Hz oscillation before each trial and could not be explained by evoked activity. Rhythmic fluctuations in awareness elicited by entrainment of ongoing neural excitability cycles support a proposed role for alpha oscillations as a pulsed inhibition of cortical activity. Furthermore, these data provide evidence for the quantized nature of our conscious experience and reveal a powerful mechanism by which temporal attention as well as perceptual snapshots can be manipulated and controlled.


Loss of oral self-care ability results in a higher risk of pneumonia in older inpatients: A prospective cohort study in a Japanese rural hospital.
To identify significant risk factors associated with incidence of mortality and pneumonia in whole-community-based older inpatients resident in Japanese rural region. Patients older than 65 years admitted between 1 April and 15 April 2010 to a core hospital located in a rural region were exhaustively recruited, and incidence of mortality and pneumonia during the 32-month follow-up period were evaluated. Independent variables at baseline measurement included age, gender, body mass index, Charlson comorbidity index, functional dependency, oral self-care ability index, number of remaining teeth, hyposalivation and nutritional status. Dependent variables were incidence of mortality and pneumonia. Survival and non-pneumonia curves were drawn using Kaplan-Meier analysis. Cox proportional hazards analysis was performed to identify the risk factors related to incidence of mortality and pneumonia. The survival rate of 46 patients (male/female: 11/35; mean age: 83.8 ± 6.8 years) was 52.1%, and the incidence of pneumonia was 60.9%. Malnutrition and gender (male) were identified as significant risk factors for mortality (odds ratio [OR]: 8.18 and 4.90; 95% confidence interval [CI]: 1.77-37.3 and 1.50-16.0; P < 0.01 and <0.01, respectively). Loss of oral self-care ability and gender (male) were identified as significant risk factors for incidence of pneumonia (OR: 8.97 and 4.58; 95% CI: 1.70-47.4 and 1.50-14.0; P = 0.01 and <0.01, respectively). Malnutrition and loss of oral self-care ability were significant risk factors for incidence of mortality and pneumonia, respectively. In response, supplying nutrition with appropriate diet and personalised oral care might contribute to reduction in mortality and prevention of pneumonia.


Imaging, core-loss, and low-loss electron-energy-loss spectroscopy mapping in aberration-corrected STEM.
High-angle annular dark-field and annular bright-field imaging experiments were carried out on an aberration-corrected transmission electron microscope. These techniques have been demonstrated on thin films of complex oxides Ba3.25La0.75Ti3O12 and on LaB6. The results show good agreement between theory and experiments, and for the case of LaB6 they demonstrate the detection of contrast from the B atoms in the annular bright-field images. Elemental mapping with electron-energy-loss spectroscopy has been used to deduce the distribution of Cr and Fe in a thin film of the complex oxide Bi2(Fe1/2Cr3/2)O6 at the unit cell level and the changes in the near-edge structure within the inequivalent regions in the crystalline unit cell. Energy-filtered images in the low-loss region of the energy-loss spectrum show contrast and resolution consistent with the modulation of the signals from elastic scattering. High-resolution contrast, mediated by phonon scattering, is observed for interband transitions. The limitations in terms of detection and signal are discussed.


Plasmonic routing in aperiodic graphene sheet arrays.
We discover deep-subwavelength, low-loss, and diffraction-free surface plasmon polariton (SPP) beam routing effects in aperiodic graphene sheet arrays (a-GSAs). The a-GSAs are constructed by varying either the interlayer spaces between graphene or the individual graphene chemical potentials. The SPP beams can be accelerated or decelerated in the a-GSAs, resulting in beam routing in different paths. The wave fronts of the beams are always parallel to the propagation direction, allowing the generation of transverse radiation pressure. All of these behaviors of SPPs are demonstrated by fully vectorial simulation and Hamilton optics analysis.


A 100-year average recurrence interval for the san andreas fault at wrightwood, california.
Evidence for five large earthquakes during the past five centuries along the San Andreas fault zone 70 kilometers northeast of Los Angeles, California, indicates that the average recurrence interval and the temporal variability are significantly smaller than previously thought. Rapid sedimentation during the past 5000 years in a 150-meter-wide structural depression has produced a greater than 21-meter-thick sequence of debris flow and stream deposits interbedded with more than 50 datable peat layers. Fault scarps, colluvial wedges, fissure infills, upward termination of ruptures, and tilted and folded deposits above listric faults provide evidence for large earthquakes that occurred in A.D. 1857, 1812, and about 1700, 1610, and 1470.


Pendrin stimulates a chloride absorption pathway to increase CFTR-mediated chloride secretion from Cystic Fibrosis airway epithelia.
Cystic Fibrosis (CF), an inherited multi-system disease, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that disrupt its ability to secrete anions from epithelia. Recovery of functional anion secretion may be curative for CF, so different components of the ion transport machinery have become attractive therapeutic targets. Several members of the SLC26 ion transporter family have been linked to epithelial ion flux, some through putative functional interactions with CFTR. Using a small-scale qPCR screen, we confirmed that the anion transporter SLC26A4 (pendrin) is downregulated in CF. Upregulation of pendrin using interleukins IL-4 or IL-13 increased Cl- secretion through CFTR in human bronchial epithelial cell (HBEC) derived epithelia differentiated in vitro and measured in the Ussing Chamber. Inhibition or knockdown of pendrin prevented this increased secretion. Increased CFTR activity was not driven by increases in CFTR protein or upstream regulatory pathway components. When basolateral Cl- absorption through NKCC1 was inhibited, a pendrin-dependent Cl- absorption pathway allowing CFTR to continue secreting Cl- from the epithelium was revealed. Although CFTR is often considered the bottleneck in the transepithelial Cl- transport pathway, these studies indicate that basolateral Cl- permeability becomes limiting as CFTR activity increases. Therefore, an increase of epithelial Cl- absorption via pendrin might have additional therapeutic benefit in combination with CFTR modulators.


Frequency and predictors of recurrence of bladder tumour on first check cystoscopy - a tertiary care hospital experience.
To determine the frequency and predictors of non-muscle invasive bladder tumour recurrence on first-check cystoscopy after transurethral resection of bladder tumour. This cross-sectional study was conducted at the Aga Khan University Hospital, Karachi, from April to November 2014, and comprised patients with a suspected newly-diagnosed urothelial cancer. Patients with non-muscle invasive disease with complete resection of all visible lesions along with deep biopsy from the tumour base were included. Patients received standard adjuvant intravesical therapy according to their risk stratification and underwent a white-light check cystoscopy at 3 months to look for tumour recurrence. Association between clinico-pathological variables and recurrence at first cystoscopy was determined. SPSS 20 was used for data analysis. The mean age of 84 patients at presentation was 63.3±12.5 years (range: 36-89 years). There were 75(89%) men and 9(11%) women. On initial transurethral resection, the size of tumour was less than 3cm in 32(38%) participants and equal to or above 3cm in 52(62%). Single tumour was found in 51(61%) subjects and multiple tumours in 33(39%). None of the resected tumours was primary carcinoma in situ and 35(42%) tumours were of high grade. The overall recurrence rate at first cystoscopy was 28(33.3%). Larger tumour, higher grade and tumour multifocality were factors associated with recurrence at check cystoscopy (p<0.05 each). Patients\' age, gender, smoking status and tumour stage did not correlate with early recurrence (p>0.05 each). The number, size and grade of the tumour strongly correlated with recurrence at check cystoscopy.


The Antioxidative Effect of Chamomile, Anthocyanoside and their Combination on Bleomycin-induced Pulmonary Fibrosis in Rat.
Bleomycin is a small peptide with 1500Daltun of molecular weight which has two junction areas in two molecule's opposite sides, one of them to relate to the DNA and the other to relate to the iron. Iron is a crucially important factor in free radical production and cytotoxic activity of bleomycin. The study attempts to study, and compare, the effect of using Chamomile, Anthocyanoside and their combination, as anti-inflammatory agent to ameliorates, to prevent or control the development of fibrosis due to Bleomycin (BLM). to prepare pulmonary fibrosis model, male Wistar rats weighting 180-220g were assigned to specific groups Rats of each group received intratracheally 1U/100 g of BLM. 20 rats were divided to five comparable groups, as(1) BLM group, (2) saline group, (3) Chamomile group, (4) Anthocyanoside group, (5) combination of Anthocyanoside and Chamomile group. Antioxidative combinations were given as pretreatment and treatment after the rats received Bleomycine. After 3 week, Malondialdehyde (MDA)was measured for each rat's lung. After three weeks, MDA was reduced, compared to BLM group, to 44.27%, 37.80% and 46.07% in Anthocyanoside, Chamomiland combination group, respectively. It was concluded from the present study that administration of combination of Chamomile and Anthocyanoside lead to a significant reduction in Bleomycin-induced MDA. The mechanism of the effect of these combinations is possibly the result of phenolic combinations as antioxidant and oxy free radical scavenger and inhibitor of lipid peroxidation.


Predictors of Treatment Failure among Adult Antiretroviral Treatment (ART) Clients in Bale Zone Hospitals, South Eastern Ethiopia.
Treatment failure defined as progression of disease after initiation of ART or when the anti-HIV medications can't control the infection. One of the major concerns over the rapid scaling up of ART is the emergence and transmission of HIV drug resistant strains at the population level due to treatment failure. This could lead to the failure of basic ART programs. Thus this study aimed to investigate the predictors of treatment failure among adult ART clients in Bale Zone Hospitals, South east Ethiopia. Retrospective cohort study was employed in four hospitals of Bale zone named Goba, Robe, Ginir and Delomena. A total of 4,809 adult ART clients were included in the analysis from these four hospitals. Adherence was measured by pill count method. The Kaplan Meier (KM) curve was used to describe the survival time of ART patients without treatment failure. Bivariate and multivariable Cox proportional hazards regression models were used for identifying associated factors of treatment failure. The incidence rate of treatment failure was found 9.38 (95% CI 7.79-11.30) per 1000 person years. Male ART clients were more likely to experience treatment failure as compared to females [AHR = 4.49; 95% CI: (2.61-7.73)].Similarly, lower CD4 count (<100 m3/dl) at initiation of ART was found significantly associated with higher odds of treatment failure [AHR = 3.79; 95% CI: (2.46-5.84).Bedridden [AHR = 5.02; 95% CI: (1.98-12.73)] and ambulatory [AHR = 2.12; 95% CI: (1.08-4.07)] patients were more likely to experience treatment failure as compared to patients with working functional status. TB co-infected clients had also higher odds to experience treatment failure [AHR = 3.06; 95% CI: (1.72-5.44)]. Those patients who had developed TB after ART initiation had higher odds to experience treatment failure as compared to their counter parts [AHR = 4.35; 95% CI: (1.99-9.54]. Having other opportunistic infection during ART initiation was also associated with higher odds of experiencing treatment failure [AHR = 7.0, 95% CI: (3.19-15.37)]. Similarly having fair [AHR = 4.99 95% CI: (1.90-13.13)] and poor drug adherence [AHR = 2.56; 95% CI: (1.12-5.86)]were significantly associated with higher odds of treatment failure as compared to clients with good adherence. The rate of treatment failure in Bale zone hospitals needs attention. Prevention and control of TB and other opportunistic infections, promotion of ART initiation at higher CD4 level, and better functional status, improving drug adherence are important interventions to reduce treatment failure among ART clients in Southeastern Ethiopia.


The U-ARE Protocol: A Pragmatic Approach to Decisional Capacity Assessment for Clinical Research.
With increased longevity and growth in the number of older adults comes rising rates of individuals with cognitive impairment and dementia. The expansion of this population has important implications for research on aging and dementia syndromes, namely increased enrollment of older individuals in clinical research. Ethical prerogatives, as well as historical underrepresentation of persons with dementia in research studies due to the perceived burden of traditional decisional capacity evaluations, necessitates the development of pragmatic approaches to ascertain decisional abilities in research settings. We outline a protocol used in the Wisconsin Alzheimer's Disease Research Center (ADRC) that adopts a stepped approach to the evaluation of decisional capacity meant to maximize study visit efficiency while preserving participant safety and autonomy. The protocol specifies the structure of the consent process and incorporates a brief semi-structured interview based on Appelbaum & Grisso's theoretical model for evaluating a patient's decisional capacity to provide informed consent to participate in research. This protocol is easily implemented in a research study visit and is designed to minimize participant burden and ensure reliable assessment of decisional capacity in older adults across a wide range of research protocols. The protocol emphasizes capacity optimization, using memory aids and other compensatory strategies to preserve participant autonomy while protecting welfare.


Gender and binegativity: men's and women's attitudes toward male and female bisexuals.
This study assessed the influence of gender on attitudes about bisexuals. A total of 164 heterosexual female and 89 heterosexual male undergraduates completed the Biphobia Scale (Mulick & Wright, 2002), rewritten to refer to bisexual men and bisexual women and thus re-named the Gender-Specific Binegativity Scale. A mixed-design ANOVA revealed an interaction between rater's sex and target's sex: women equally accepted bisexual men and bisexual women, but men were less accepting of bisexual men than bisexual women. A mediation analysis indicated the relationship between rater's sex and greater acceptance of bisexual women was partially explained by eroticization of female same-sex sexuality. Finally, participants also responded to two open-ended items, which provided additional information about the content of binegativity: participants described male bisexuals negatively, as gender-nonconforming, and labeled them "really gay," whereas participants described female bisexuals positively, as sexy, and labeled them "really heterosexual." These findings suggest multiple underlying beliefs about bisexuals that contribute to binegativity, particularly against bisexual men. Results also confirm the importance of considering gender (of both the target and the rater) when assessing sexual prejudice.