[Clinical significance of the measurement of serum neuron-specific enolase levels in patients with lung cancer].
Subjects were comprised of 100 healthy adults, 85 patients with primary lung cancer, 20 with benign lung disease and 4 with metastatic lung cancer. Serum neuron-specific enolase (NSE) levels were estimated by means of an NSE RIA kit produced by Eiken Radiopharmaceutical Co., Ltd. The normal range of serum NSE level was between 4.5 and 10.30 (mean: 6.81) ng/ml in the 100 healthy adults. The serum NSE level in patients with small cell carcinoma was significantly higher than the mean in patients with other histological types. Positive rates of serum NSE levels were 80% in patients with small cell carcinoma, 54% in patients with adenocarcinoma, 52% in patients with squamous cell carcinoma and 1% in healthy adults, respectively. According to the progress of staging in lung cancer patients, serum NSE levels became increased. Serum NSE level seems to be specific marker in patients with small cell lung cancer and to be useful for diagnosis and the monitoring of cancer treatment.


Validity and reliability of telephone administration of the patient-specific functional scale for the assessment of recovery from snakebite envenomation.
Although more than 1.8 million people survive snakebite envenomation each year, their recovery is understudied. Obtaining long-term follow-up is challenging in both high- and low-resource settings. The Patient-Specific Functional Scale (PSFS) is an easily administered, well-accepted patient-reported outcome that is validated for assessing limb recovery from snakebite envenomation. We studied whether the PSFS is valid and reliable when administered by telephone. This is a secondary analysis of data from a randomized clinical trial. We analyzed the results of PSFS collected in-person on days 3, 7, 14, 21, and 28 and by telephone on days 10, 17, and 24. We assessed the following scale psychometric properties: (a) content validity (ceiling and floor effects), (b) internal structure and consistency (Cronbach's alpha), and (c) temporal and external validity using Intraclass Correlation Coefficient (ICC). Temporal stability was assessed using Spearman's correlation coefficient and agreement between adjacent in-person and telephonic assessments with Cohen's kappa. Bland Altman analysis was used to assess differential bias in low and high score results. Data from 74 patients were available for analysis. Floor effects were seen in the early post-injury time points (median: 3 (IQR: 0, 5) at 3 days post-enrollment) and ceiling effects in the late time points (median: 9 (IQR: 8, 10). Internal consistency was good to excellent with both in-person (Cronbach α: 0.91 (95%CI 0.88, 0.95)) and telephone administration (0.81 (0.73, 0.89). Temporal stability was also good (ICC: 0.83 (0.72, 0.89) in-person, 0.80 (0.68, 0.88) telephone). A strong linear correlation was found between in-person and telephone administration (Spearman's ρ: 0.83 (CI: 0.78, 0.84), consistency was assessed as excellent (Cohen's κ 0.81 (CI: 0.78, 0.84), and Bland Altman analysis showed no systematic bias. Telephone administration of the PSFS provides valid, reliable, and consistent data for the assessment of recovery from snakebite envenomation.


A microfluidic device for dry sample preservation in remote settings.
This paper describes a microfluidic device for dry preservation of biological specimens at room temperature that incorporates chemical stabilization matrices. Long-term stabilization of samples is crucial for remote medical analysis, biosurveillance, and archiving, but the current paradigm for transporting remotely obtained samples relies on the costly "cold chain" to preserve analytes within biospecimens. We propose an alternative approach that involves the use of microfluidics to preserve samples in the dry state with stabilization matrices, developed by others, that are based on self-preservation chemistries found in nature. We describe a SlipChip-based device that allows minimally trained users to preserve samples with the three simple steps of placing a sample at an inlet, closing a lid, and slipping one layer of the device. The device fills automatically, and a pre-loaded desiccant dries the samples. Later, specimens can be rehydrated and recovered for analysis in a laboratory. This device is portable, compact, and self-contained, so it can be transported and operated by untrained users even in limited-resource settings. Features such as dead-end and sequential filling, combined with a "pumping lid" mechanism, enable precise quantification of the original sample's volume while avoiding overfilling. In addition, we demonstrated that the device can be integrated with a plasma filtration module, and we validated device operations and capabilities by testing the stability of purified RNA solutions. These features and the modularity of this platform (which facilitates integration and simplifies operation) would be applicable to other microfluidic devices beyond this application. We envision that as the field of stabilization matrices develops, microfluidic devices will be useful for cost-effectively facilitating remote analysis and biosurveillance while also opening new opportunities for diagnostics, drug development, and other medical fields.


Design and Implementation of a Community Health Worker HIV Treatment and Prevention Intervention in an HIV Hot Spot Fishing Community in Rakai, Uganda.
Innovative approaches are needed to increase engagement in HIV treatment and prevention services, particularly in HIV hot spots. Here, we detail our design, training approach, and early implementation experiences of a community-based HIV intervention called "health scouts." The intervention, utilizing a novel, theory-based approach, trained 10 community residents in an HIV hot spot fishing community to use motivational interviewing strategies and a mobile phone-based counseling application. During the first 3 months, 771 residents (median 82/health scout, range 27-160) were counseled. A directly observed Motivational Interviewing Treatment Integrity scale-based evaluation found adequate performance (median score 20/25, range 11-23). The health scout intervention was feasible to implement in a high HIV-prevalence fishing community, and its impact on HIV care outcomes will be evaluated in an ongoing cluster randomized trial. If found to be effective, it may be an important strategy for responding to HIV in high-burden settings.


Neural mechanism for stochastic behaviour during a competitive game.
Previous studies have shown that non-human primates can generate highly stochastic choice behaviour, especially when this is required during a competitive interaction with another agent. To understand the neural mechanism of such dynamic choice behaviour, we propose a biologically plausible model of decision making endowed with synaptic plasticity that follows a reward-dependent stochastic Hebbian learning rule. This model constitutes a biophysical implementation of reinforcement learning, and it reproduces salient features of behavioural data from an experiment with monkeys playing a matching pennies game. Due to interaction with an opponent and learning dynamics, the model generates quasi-random behaviour robustly in spite of intrinsic biases. Furthermore, non-random choice behaviour can also emerge when the model plays against a non-interactive opponent, as observed in the monkey experiment. Finally, when combined with a meta-learning algorithm, our model accounts for the slow drift in the animal's strategy based on a process of reward maximization.


Serum antibodies from a subset of horses positive for Babesia caballi by competitive enzyme-linked immunosorbent assay demonstrate a protein recognition pattern that is not consistent with infection.
Tick-borne pathogens that cause persistent infection are of major concern to the livestock industry because of transmission risk from persistently infected animals and the potential economic losses they pose. The recent reemergence of Theileria equi in the United States prompted a widespread national survey resulting in identification of limited distribution of equine piroplasmosis (EP) in the U.S. horse population. This program identified Babesia caballi-seropositive horses using rhoptry-associated protein 1 (RAP-1)-competitive enzyme-linked immunosorbent assay (cELISA), despite B. caballi being considered nonendemic on the U.S. mainland. The purpose of the present study was to evaluate the suitability of RAP-1-cELISA as a single serological test to determine the infection status of B. caballi in U.S. horses. Immunoblotting indicated that sera from U.S. horses reacted with B. caballi lysate and purified B. caballi RAP-1 protein. Antibody reactivity to B. caballi lysate was exclusively directed against a single ∼50-kDa band corresponding to a native B. caballi RAP-1 protein. In contrast, sera from experimentally and naturally infected horses from regions where B. caballi is endemic bound multiple proteins ranging from 30 to 50 kDa. Dilutions of sera from U.S. horses positive by cELISA revealed low levels of antibodies, while sera from horses experimentally infected with B. caballi and from areas where B. caballi is endemic had comparatively high antibody levels. Finally, blood transfer from seropositive U.S. horses into naive horses demonstrated no evidence of B. caballi transmission, confirming that antibody reactivity in cELISA-positive U.S. horses was not consistent with infection. Therefore, we conclude that a combination of cELISA and immunoblotting is required for the accurate serodiagnosis of B. caballi.


SU-E-I-86: Image Fusion Verification Using a Vendor-Independent Phantom.
To evaluate the image fusion accuracy of a hybrid PET/CT or SPECT/CT system using a recently developed vendor-independent phantom. The basic design of the fusion verification phantom is a 10 cm urethane cube with three 1 mm diameter channels each fitted with standard Luer connection designed to be filled with a radioactive solution. The channels also have a 0.4 mm diameter steel wire inserted in each channel. There are two versions of this cube phantom with different orientations of the wire/liquid filled channels. There is the perpendicular cube with three channels each parallel to the x, y and z axes. The second cube orientation has two opposing angled channels and one that is perpendicular to the cube base. When imaged with either a PET/CT or SPECT/CT device the wire yields a high contrast image against a high signal target of the radioisotope filled channel. Both phantoms are scanned on various vendor and model hybrid systems. Three plane reconstructed data of the perpendicular fusion phantom generates images with point source like targets of the emission and transmission data for quick visual evaluation of registration accuracy for x, y and z shifts. A series of axial reconstructed images can be used to evaluate alignment when using the opposing ramp fusion phantom. The unique utility of the opposing ramps allows for verification of a z-axis offset from the single axial image data. Alignment data are presented from a number of PET/CT and SPECT/CT systems. The use of either the perpendicular or opposing ramp fusion phantom provides a convenient QC vendor independent tool for evaluation of image alignment accuracy of hybrid imaging systems. The design supports a simple 3D processing with a straightforward visual interpretation of alignment.


Laser induced periodic surface structure formation in germanium by strong field mid IR laser solid interaction at oblique incidence.
Laser induced periodic surface structures (LIPSS or ripples) were generated on single crystal germanium after irradiation with multiple 3 µm femtosecond laser pulses at a 45° angle of incidence. High and low spatial frequency LIPSS (HSFL and LSFL, respectively) were observed for both s- and p-polarized light. The measured LSFL period for p-polarized light was consistent with the currently established LIPSS origination model of coupling between surface plasmon polaritons (SPP) and the incident laser pulses. A vector model of SPP coupling is introduced to explain the formation of s-polarized LSFL away from the center of the damage spot. Additionally, a new method is proposed to determine the SPP propagation length from the decay in ripple depth. This is used along with the measured LSFL period to estimate the average electron density and Drude collision time of the laser-excited surface. Finally, full-wave electromagnetic simulations are used to corroborate these results while simultaneously offering insight into the nature of LSFL formation.


Pulmonary embolism in patients attending the accident and emergency department with pleuritic chest pain.
A series of 92 patients presenting to an accident and emergency department with pleuritic chest pain is described. Only one of the patients had a diagnosis of pulmonary embolus. All the patients were followed up over a period of 3 months. During this time none of them suffered from mortality or morbidity which could be related to pulmonary embolism. No evidence was obtained during this study that a more aggressive approach to such patients is required in order to achieve the diagnosis.


The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth.
Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe-S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe-S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe-S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe-S cluster - and of other ROS-sensitive enzymes - could inhibit parasite development.


Malignant eccrine poroma. Case report and review of the literature.
A case of malignant eccrine poroma with lymph node metastases is described. The patient had a nodular growth of the right thigh 2 years before its first excision. Local recurrence in the scar occurred in 6 months, and by 8 months a right groin lymph node was involved. Subsequent skin nodules of the right thigh occurred over the next 12 months, associated with recurrent lymphedema of the leg. During several follow-up visits, associated malignancies were found including villous adenoma of the ascending colon and renal cell carcinoma of the right kidney, both typical histologically and unrelated to the cutaneous tumor. Subsequently, left inguinal lymph node disease histologically identical to the skin tumor was found. Clinical and histologic findings were similar to the 31 previous cases reviewed. Electron microscopic examination confirmed the presence of a ductal structure consistent with eccrine duct and a crystalline membrane-bound granule which may represent a specific marker for this rare tumor. The histologic features of this tumor are important to separate from other differential diagnostic possibilities which may have a quite different prognosis.


MacSyFinder: a program to mine genomes for molecular systems with an application to CRISPR-Cas systems.
Biologists often wish to use their knowledge on a few experimental models of a given molecular system to identify homologs in genomic data. We developed a generic tool for this purpose. Macromolecular System Finder (MacSyFinder) provides a flexible framework to model the properties of molecular systems (cellular machinery or pathway) including their components, evolutionary associations with other systems and genetic architecture. Modelled features also include functional analogs, and the multiple uses of a same component by different systems. Models are used to search for molecular systems in complete genomes or in unstructured data like metagenomes. The components of the systems are searched by sequence similarity using Hidden Markov model (HMM) protein profiles. The assignment of hits to a given system is decided based on compliance with the content and organization of the system model. A graphical interface, MacSyView, facilitates the analysis of the results by showing overviews of component content and genomic context. To exemplify the use of MacSyFinder we built models to detect and class CRISPR-Cas systems following a previously established classification. We show that MacSyFinder allows to easily define an accurate "Cas-finder" using publicly available protein profiles. MacSyFinder is a standalone application implemented in Python. It requires Python 2.7, Hmmer and makeblastdb (version 2.2.28 or higher). It is freely available with its source code under a GPLv3 license at https://github.com/gem-pasteur/macsyfinder. It is compatible with all platforms supporting Python and Hmmer/makeblastdb. The "Cas-finder" (models and HMM profiles) is distributed as a compressed tarball archive as Supporting Information.


Tissue-specific expression and developmental regulation of cytochrome b561 genes in Arabidopsis thaliana and Raphanus sativus.
Ascorbate (Asc) is an essential molecule in many aspects of development and stress responses in plants and animals. Cytochromes b561 (cyts b561) are tightly coupled to Asc homeostasis. These proteins are found in mammalian tissues, where they are involved in the regeneration of Asc, serving the synthesis of catecholamine neurotransmitters, and in intestinal iron reduction. Plant genomes encode homologous membrane-associated, Asc-reducible cyts b561. The expression of these proteins in plants, however, has so far not been studied. We have now examined the expression of two Arabidopsis thaliana cyt b561-encoding genes-Artb561-1 and Artb561-2-using relative-quantitative RT-PCR and in situ hybridization (ISH) techniques. The genes show overlapping and distinct tissue- and organ-specific expression patterns. Transcripts of both genes are found in leaf epidermal cells, and expression seems to correlate with leaf maturation and cessation of cell elongation. Both genes are also expressed in the epidermal cell layer of stems and roots in the L1 layer of the shoot apex, in the vascular system of leaves, stems and roots, and in the root pericycle. In addition, Artb561-1 is expressed in the root cap, whereas Artb561-2 mRNA is found in the epidermis of lateral roots, in the root meristem, and in unfertilized ovules. These observations provide important information for the elucidation of the physiological function of cyts b561 in plants.


Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder.
Generalized anxiety disorder (GAD) and panic disorder (PD) are most common anxiety disorders with high lifetime prevalence while the pathophysiology and disease-specific alterations still remain largely unclear. Few studies have taken a whole-brain perspective in the functional connectivity (FC) analysis of these two disorders in resting state. It limits the ability to identify regionally and psychopathologically specific network abnormalities with their subsequent use as diagnostic marker and novel treatment strategy. The whole brain FC using a novel FC metric was compared, that is, scaled correlation, which they demonstrated to be a reliable FC statistics, but have higher statistical power in two-sample t-test of whole brain FC analysis. About 21 GAD and 18 PD patients were compared with 22 matched control subjects during resting-state, respectively. It was found that GAD patients demonstrated increased FC between hippocampus/parahippocampus and fusiform gyrus among the most significantly changed FC, while PD was mainly associated with greater FC between somatosensory cortex and thalamus. Besides such regional specificity, it was observed that psychopathological specificity in that the disrupted FC pattern in PD and GAD correlated with their respective symptom severity. The findings suggested that the increased FC between hippocampus/parahippocampus and fusiform gyrus in GAD were mainly associated with a fear generalization related neural circuit, while the greater FC between somatosensory cortex and thalamus in PD were more likely linked to interoceptive processing. Due to the observed regional and psychopathological specificity, their findings bear important clinical implications for the potential treatment strategy.


Cooking-related PM2.5 and acrolein measured in grocery stores and comparison with other retail types.
We measured particulate matter (PM), acrolein, and other indoor air contaminants in eight visits to grocery stores in California. Retail stores of other types (hardware, furniture, and apparel) were also sampled on additional visits. Based on tracer gas decay data, most stores had adequate ventilation according to minimum ventilation rate standards. Grocery stores had significantly higher concentrations of acrolein, fine and ultrafine PM, compared to other retail stores, likely attributable to cooking. Indoor concentrations of PM2.5 and acrolein exceeded health guidelines in all tested grocery stores. Acrolein emission rates to indoors in grocery stores had a mean estimate about 30 times higher than in other retail store types. About 80% of the indoor PM2.5 measured in grocery stores was emitted indoors, compared to only 20% for the other retail store types. Calculations suggest a substantial increase in outdoor air ventilation rate by a factor of three from current level is needed to reduce indoor acrolein concentrations. Alternatively, acrolein emission to indoors needs to be reduced 70% by better capturing of cooking exhaust. To maintain indoor PM2.5 below the California annual ambient standard of 12 μg/m(3) , grocery stores need to use air filters with an efficiency rating higher than the MERV 8 air filters commonly used today.


Guillain-Barré syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases.
The pathology of the Guillain-Barré syndrome remains controversial, and autopsied cases available for study by contemporary techniques are uncommon. Large numbers of cases clinically diagnosed as Guillain-Barré syndrome occur in northern China. In this study we examined the neuropathological changes in 12 autopsied cases from Hebei Province, China. Eleven died early in the course of their disease. In all cases tissue was specially handled and fixed for electron microscopy and for immunocytochemistry. Three of these 12 cases had typical acute inflammatory demyelinating polyneuropathy (AIDP) with lymphocytic infiltration and macrophage-mediated demyelination, reproducing the pathological picture most often reported in Guillain-Barré syndrome in North America, Europe, and Australia. Six cases had predominantly axonal involvement, characterized by Wallerian-like degeneration of nerve fibres, with only minimal demyelination and with minimal inflammation in five. Three cases, even though paralysed at the time of death, had only very mild changes in the spinal roots and sciatic nerves. Within the group of six predominantly axonal cases, there were important differences both in the severity of the abnormalities and in the classes of fibres involved. Three cases had extensive Wallerian-like degeneration of sensory as well as motor fibres [acute motor-sensory axonal neuropathy (AMSAN)], while in the other three cases the fibre degeneration affected the motor nerve fibres almost exclusively. These latter cases establish a structural basis for the clinical and electrophysiological picture termed the acute motor axonal neuropathy (AMAN) pattern. In both the AMAN and the AMSAN patterns, a prominent feature was the presence of macrophages within the periaxonal space, surrounding or displacing the axon, and surrounded by an intact myelin sheath. These studies show that the early pathological changes in cases clinically diagnosed as the Guillain-Barré syndrome are diverse and not restricted to the well-known pattern of AIDP, and that the predominant pathological patterns may differ in different parts of the world. The differences in pathological findings between acute inflammatory demyelinating polyneuropathy and the axonal patterns are likely to reflect differences in the pathogenetic mechanisms. The periaxonal macrophages in the axonal patterns suggest that an important epitope may be localized to the axolemma or periaxonal space. The mild cases indicate that severe paralysis can occur early in Guillain-Barré syndrome without prominent structural changes along the nerve, suggesting that physiological block or nerve terminal changes may be implicated.


An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response.
Polymorphisms in the region of the interleukin (IL)-28B gene on chromosome 19 have been associated with peginterferon-alfa-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotype 2 or 3 HCV. We evaluated the effects of IL-28B polymorphisms on response to treatment with peginterferon and ribavirin in a well-characterized cohort of genotype 2/3 patients. DNA was analyzed from 268 patients (Caucasian: genotype 2, 213; genotype 3, 55). Patients were randomly assigned to groups that received standard duration (24 wk; n = 68) or variable durations of therapy. Patients who received variable durations (VD) and had a rapid virologic response (RVR) were treated for 12 weeks (VD12; n = 122); those without an RVR were treated for 24 weeks (VD24; n = 78). IL-28B genotypes (rs12979860) were analyzed for association with treatment response. The frequencies of the IL-28B genotypes were as follows: CC, 37%; CT, 48%; and TT, 15%; 82% of patients with the CC genotype achieved a sustained virologic response (SVR), compared with 75% with the CT and 58% with the TT genotypes (P = .0046). Differences between IL-28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC, 87%; CT, 67%; and TT, 29%; P = .0002). Among patients with RVRs (61%), the IL-28B genotype was not associated with SVR (>70% for all IL-28B genotypes). In a multivariable logistic regression model, IL-28B genotype predicted SVR (odds ratio, 1.76; 95% confidence interval, 1.16-2.7). An IL-28B polymorphism was associated with an SVR in patients infected with genotype 2/3 HCV who did not achieve a RVR. Analysis of IL-28B genotype might be used to guide treatment for these patients.


Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia.
Activation of the Wnt/beta-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/beta-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of beta-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2'-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).


The intervening sequence RNA of Tetrahymena is an enzyme.
A shortened form of the self-splicing ribosomal RNA (rRNA) intervening sequence of Tetrahymena thermophila acts as an enzyme in vitro. The enzyme catalyzes the cleavage and rejoining of oligonucleotide substrates in a sequence-dependent manner with Km = 42 microM and kcat = 2 min-1. The reaction mechanism resembles that of rRNA precursor self-splicing. With pentacytidylic acid as the substrate, successive cleavage and rejoining reactions lead to the synthesis of polycytidylic acid. Thus, the RNA molecule can act as an RNA polymerase, differing from the protein enzyme in that it uses an internal rather than an external template. At pH 9, the same RNA enzyme has activity as a sequence-specific ribonuclease.


A possible neural mechanism for photosensitivity in chronic pain.
Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but it cannot be attributed to a general increase in cortical sensory processing. Here, we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of pain-modulating systems in the brain. These individuals expressed discomfort at light levels substantially lower than that of healthy control subjects. Complementary studies in lightly anesthetized rat demonstrated that a subset of identified pain-modulating neurons in the rostral ventromedial medulla unexpectedly responds to light. Approximately half of the pain-facilitating "ON-cells" and pain-inhibiting "OFF-cells" sampled exhibited a change in firing with light exposure, shifting the system to a pronociceptive state with the activation of ON-cells and suppression of OFF-cell firing. The change in neuronal firing did not require a trigeminal or posterior thalamic relay, but it was blocked by the inactivation of the olivary pretectal nucleus. Light exposure also resulted in a measurable but modest decrease in the threshold for heat-evoked paw withdrawal, as would be expected with engagement of this pain-modulating circuitry. These data demonstrate integration of information about light intensity with somatic input at the level of single pain-modulating neurons in the brain stem of the rat under basal conditions. Taken together, our findings in rodents and humans provide a novel mechanism for abnormal photosensitivity and suggest that light has the potential to engage pain-modulating systems such that normally innocuous inputs are perceived as aversive or even painful.


A smart home application to eldercare: current status and lessons learned.
To address an aging population, we have been investigating sensor networks for monitoring older adults in their homes. In this paper, we report ongoing work in which passive sensor networks have been installed in 17 apartments in an aging in place eldercare facility. The network under development includes simple motion sensors, video sensors, and a bed sensor that captures sleep restlessness and pulse and respiration levels. Data collection has been ongoing for over two years in some apartments. This longevity in sensor data collection is allowing us to study the data and develop algorithms for identifying alert conditions such as falls, as well as extracting typical daily activity patterns for an individual. The goal is to capture patterns representing physical and cognitive health conditions and then recognize when activity patterns begin to deviate from the norm. In doing so, we strive to provide early detection of potential problems which may lead to serious health events if left unattended. We describe the components of the network and show examples of logged sensor data with correlated references to health events. A summary is also included on the challenges encountered and the lessons learned as a result of our experiences in monitoring aging adults in their homes.


Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections.
A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects. Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression. CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm. Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.


Factors affecting prepubertal growth in homozygous sickle cell disease.
To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.


Quantitative Monte Carlo-based 90Y SPECT reconstruction.
The evaluation of radiation absorbed doses in tumorous and healthy tissues is of increasing interest for (90)Y microsphere radioembolization of liver malignancies. The objectives of this work were to introduce and validate a new reconstruction method for quantitative (90)Y bremsstrahlung SPECT to improve posttreatment dosimetry. A fast Monte Carlo simulator was adapted for (90)Y and incorporated into a statistical reconstruction algorithm (SPECT-MC). Photon scatter and attenuation for all photons sampled from the full (90)Y energy spectrum were modeled during reconstruction by Monte Carlo simulations. The energy- and distance-dependent collimator-detector response was modeled with precalculated convolution kernels. The National Electrical Manufacturers Association 2007/International Electrotechnical Commission 2008 image quality phantom was used to quantitatively evaluate the performance of SPECT-MC in comparison with those of state-of-the-art clinical SPECT reconstruction and PET. The liver radiation absorbed doses estimated by SPECT, PET, and SPECT-MC were evaluated in 5 patients consecutively treated with radioembolization. In comparison with state-of-the-art clinical (90)Y SPECT reconstruction, SPECT-MC substantially improved image contrast (e.g., from 25% to 88% for the 37-mm sphere) and decreased the mean residual count error in the lung insert (from 73% to 15%) at the cost of higher image noise. Image noise and the mean count error were lower for SPECT-MC than for PET. Image contrast was higher in the larger spheres (diameter of ≥28 mm) but lower in the smaller spheres (≤22 mm) for SPECT-MC than for PET. In the clinical study, mean absorbed dose estimates in liver regions with high absorbed doses were consistently higher for SPECT-MC than for SPECT (P = 0.0625) and consistently higher for SPECT-MC than for PET (P = 0.0625). The quantitative accuracy of (90)Y bremsstrahlung SPECT is substantially improved by Monte Carlo-based modeling of the image-degrading factors. Consequently, (90)Y bremsstrahlung SPECT may be used as an alternative to (90)Y PET.


Low IQ has become less important as a risk factor for early disability pension. A longitudinal population-based study across two decades among Swedish men.
Low IQ has been shown to be an important risk factor for disability pension (DP) but whether the importance has changed over time remains unclear. It can be hypothesised that IQ has become more important for DP over time in parallel with a more demanding working life. The aim of this study was to investigate the relative risk of low IQ on the risk of DP before age 30 between 1971 and 2006. This study covered the entire Swedish male population born between 1951 and 1976, eligible for military conscription. Information about the study subjects was obtained by linkage of national registers. Associations between IQ and DP over time were analysed by descriptive measures (mean values, proportions, etc) and by Cox proportional hazards regressions. Analyses were adjusted for educational level. The cohort consisted of 1 229 346 men. The proportion that received DP before the age of 30 increased over time, from 0.68% in the cohort born between 1951 and 1955 to 0.95% in the cohort born between 1971 and 1976. The relative risk of low IQ (adjusted for education) in relation to high IQ decreased from 5.68 (95% CI 4.71 to 6.85) in the cohort born between 1951 and 1955 to 2.62 (95% CI 2.25 to 3.05) in the cohort born between 1971 and 1976. Our results gave no support to the idea that the importance of low IQ for the risk of DP has increased in parallel with increasing demands in working life. In fact, low IQ has become less important as a risk factor for DP compared with high IQ between the early 1970s and 1990s. An increased educational level over the same time period is likely to be part of the explanation.


Interaction between glucocorticoids and glucagon in the hormonal modification of calcium retention by isolated rat liver mitochondria.
1. The administration of dexamethasone to intact fed rats by intraperitoneal injection for 3h was associated with a 6-fold increase in the time for which mitochondria subsequently isolated from the liver retain a given load of exogenous Ca2+. This effect was blocked by the co-administration of cycloheximide with dexamethasone, and partially blocked by the co-administration of puromycin. Daily administration of dexamethasone for periods of 4--7 days resulted in liver mitochondria that exhibited a decreased ability to retain exogenous Ca2+. 2. When glucagon was administered to fed adrenalectomized rats, the increase in mitochondrial Ca2+-retention time that results from the action of this hormone was reduced by 50% when compared with its effect on intact animals. The administration of dexamethasone to adrenalectomized rats partially restored the full effect of glucagon. 3. Dexamethasone did not enhance the effect of glucagon on mitochondrial Ca2+-retention time when administered to intact fed rats. 4. It is concluded that these data support the hypothesis that the hormone-induced modification of liver mitochondria, which results in an increase in the time for which exogenous Ca2+ is retained, involves a step in which new protein is synthesized.


Mating in a viscous universe: the race is to the agile, not to the swift.
Charles Darwin's theory of natural selection has at its focal point the mating success of organisms. Among male animals, large body size is widely seen as the principal determinant of mating success. However, where mating takes place in a three-dimensional arena such as water, the arboreal habitat or air, small size with its concomitant aerobatic advantages might be advantageous. Despite considerable interest, the relationship between aerobatic ability and mating success has not yet been demonstrated in a single animal species. Here, we test the hypothesis that the known mating success of small male midges is due to their greater aerobatic ability. To do this, male midges collected from leks in the wild were flown and their flight paths in free flight were recorded on high-speed cameras in the laboratory. Four flight parameters that would seem relevant to male mate acquisition in flight, i.e. acceleration, maximum speed, tortuosity and turn-rate, were analysed with respect to body size. We show that, while in terms of maximum speed there was no detectable difference between small and large males, small males outperformed larger ones with respect to acceleration, tortuosity and turn-rate. We conclude that the hypothesis that small males gain their mating advantage through aerobatic superiority is consistent with the observations reported here.


Model predictive control of a robotically actuated delivery sheath for beating heart compensation.
Minimally invasive surgery (MIS) during cardiovascular interventions reduces trauma and enables the treatment of high-risk patients who were initially denied surgery. However, restricted access, reduced visibility and control of the instrument at the treatment locations limits the performance and capabilities of such interventions during MIS. Therefore, the demand for technology such as steerable sheaths or catheters that assist the clinician during the procedure is increasing. In this study, we present and evaluate a robotically actuated delivery sheath (RADS) capable of autonomously and accurately compensating for beating heart motions by using a model-predictive control (MPC) strategy. We develop kinematic models and present online ultrasound segmentation of the RADS that are integrated with the MPC strategy. As a case study, we use pre-operative ultrasound images from a patient to extract motion profiles of the aortic heart valve (AHV). This allows the MPC strategy to anticipate for AHV motions. Further, mechanical hysteresis in the steering mechanism is compensated for in order to improve tip positioning accuracy. The novel integrated system is capable of controlling the articulating tip of the RADS to assist the clinician during cardiovascular surgery. Experiments demonstrate that the RADS follows the AHV motion with a mean positioning error of 1.68 mm. The presented modelling, imaging and control framework could be adapted and applied to a range of continuum-style robots and catheters for various cardiovascular interventions.


Cooperativity between hydrogen- and halogen bonds: the case of selenourea.
A combined experimental/computational study of cooperativity between halogen-(XB) and hydrogen bonding (HB) is presented. Selenourea (SeU) has been chosen due to its ability to act at the same time as an XB acceptor toward I(CF2)5CF3 (I1) through the two lone pairs on the selenium atom, and as a HB donor to the benzoate anion through its two amino moieties. All equilibrium constants have been estimated using either diffusion NMR and NMR titration techniques. Experimental results demonstrate that the -NH2anion interaction strongly enhances the SeI one of about one order of magnitude (in terms of formation constant of the adduct), whereas DFT results rationalize such results revealing that the presence of a HB between the benzoate and SeU strongly polarizes the latter, enhancing the negative partial charge on selenium and, consequently, its Lewis basicity and its XB acceptor properties.


Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials.
Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium. Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies. The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06). Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.


HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the Lipoprotein Investigators Collaborative.
High-density lipoprotein (HDL) is highly heterogeneous and the link of its subclasses to prognosis remains controversial. We aimed to rigorously examine the associations of HDL subclasses with prognosis in secondary prevention. We collaboratively analysed data from two, complementary prospective cohorts: the TRIUMPH study of 2465 acute myocardial infarction patients, and the IHCS study of 2414 patients who underwent coronary angiography. All patients had baseline HDL subclassification by vertical-spin density gradient ultracentrifugation. Given non-linearity, we stratified by tertiles of HDL-C and its two major subclasses (HDL2-C, HDL3-C), then compared multivariable-adjusted hazard ratios for mortality and mortality/myocardial infarction. Patients were middle-aged to elderly (TRIUMPH: 58.2 ± 12.2 years; IHCS: 62.6 ± 12.6 years), and the majority were men (TRIUMPH: 68.0%; IHCS: 65.5%). IHCS had lower mean HDL-C levels (34.6 ± 10.1 mg/dL) compared with TRIUMPH (40 ± 10.6 mg/dL). HDL3-C accounted for >3/4 of HDL-C (mean HDL3-C/HDL-C 0.78 ± 0.05 in both cohorts). During 2 years of follow-up in TRIUMPH, 226 (9.2%) deaths occurred, while death/myocardial infarction occurred in 401 (16.6%) IHCS patients over 5 years. No independent associations with outcomes were observed for HDL-C or HDL2-C. In contrast, the lowest tertile of HDL3-C was independently associated with >50% higher risk in each cohort (TRIUMPH: with middle tertile as reference, fully adjusted HR for mortality of HDL3-C, 1.57; 95% CI, 1.13-2.18; IHCS: fully adjusted HR for mortality/myocardial infarction, 1.55; 95% CI, 1.20-2.00). In secondary prevention, increased risk for long-term hard clinical events is associated with low HDL3-C, but not HDL2-C or HDL-C, highlighting the potential value of subclassifying HDL-C.


Enhanced Therapeutic Efficacy in Cancer Patients by Short-term Fasting: The Autophagy Connection.
Preclinical studies suggest that fasting prior to chemotherapy may be an effective strategy to protect patients against the adverse effects of chemo-toxicity. Fasting may also sensitize cancer cells to chemotherapy. It is further suggested that fasting may similarly augment the efficacy of oncolytic viral therapy. The primary mechanism mediating these beneficial effects is thought to relate to the fact that fasting results in a decrease of circulating growth factors. In turn, such fasting cues would prompt normal cells to redirect energy toward cell maintenance and repair processes, rather than growth and proliferation. However, fasting is also known to upregulate autophagy, an evolutionarily conserved catabolic process that is upregulated in response to various cell stressors. Here, we review a number of mechanisms by which fasting-induced autophagy may have an impact on both chemo-tolerance and chemo-sensitization. First, fasting may exert a protective effect by mobilizing autophagic components prior to chemo-induction. In turn, the autophagic apparatus can be repurposed for removing cellular components damaged by chemotherapy. Autophagy also plays a key role in epitope expression as well as in modulating inflammation. Chemo-sensitization resulting from fasting may in fact be an effect of enhanced immune surveillance as a result of better autophagy-dependent epitope processing. Finally, autophagy is involved in host defense against viruses, and aspects of the autophagic process are also often targets for viral subversion. Consequently, altering autophagic flux by fasting may alter viral infectivity. These observations suggest that fasting-induced autophagy may have an impact on therapeutic efficacy in various oncological contexts.


Mass-Specific Metabolic Rate Influences Sperm Performance through Energy Production in Mammals.
Mass-specific metabolic rate, the rate at which organisms consume energy per gram of body weight, is negatively associated with body size in metazoans. As a consequence, small species have higher cellular metabolic rates and are able to process resources at a faster rate than large species. Since mass-specific metabolic rate has been shown to constrain evolution of sperm traits, and most of the metabolic activity of sperm cells relates to ATP production for sperm motility, we hypothesized that mass-specific metabolic rate could influence sperm energetic metabolism at the cellular level if sperm cells maintain the metabolic rate of organisms that generate them. We compared data on sperm straight-line velocity, mass-specific metabolic rate, and sperm ATP content from 40 mammalian species and found that the mass-specific metabolic rate positively influences sperm swimming velocity by (a) an indirect effect of sperm as the result of an increased sperm length, and (b) a direct effect independent of sperm length. In addition, our analyses show that species with higher mass-specific metabolic rate have higher ATP content per sperm and higher concentration of ATP per μm of sperm length, which are positively associated with sperm velocity. In conclusion, our results suggest that species with high mass-specific metabolic rate have been able to evolve both long and fast sperm. Moreover, independently of its effect on the production of larger sperm, the mass-specific metabolic rate is able to influence sperm velocity by increasing sperm ATP content in mammals.


Leukoaraiosis and risk of intracranial hemorrhage and outcome after stroke thrombolysis.
The impact of leukoaraiosis on the risk of symptomatic intracerebral hemorrhage (SICH) after stroke thrombolysis is conflicting, and the data on Asian populations are lacking. Therefore, in this study, we assessed the association between leukoaraiosis and SICH, and the association between leukoaraiosis and the 90-day functional outcome in the Asian population. Data were collected from a two-center prospective registry of acute ischemic stroke patients given intravenous tissue plasminogen activator between 2006 and 2014. A total of 614 pretreatment brain CT and 455 posttreatment MRI were retrospectively assessed using two different rating scales for the presence of leukoaraiosis. Outcome measures were the occurrence of SICH with three definitions and any hemorrhage after thrombolysis and functional outcome at 3 months. Of the 614 patients assessed, 30.3% showed severe leukoaraiosis on the baseline brain CT. The SICH rate was 4.6% - 7.2% based on different definitions, and overall, 24.9% of patients showed any post-tPA hemorrhage. No association was observed between the severity of leukoaraiosis and SICH, regardless of having used different leukoaraiosis rating scales or as assessment using different imaging modalities. However, severe leukoaraiosis was independently associated with poor functional outcome at 3 months (OR 1.96, 95% C1 1.24-3.11, P = 0.004) after adjustment for confounders. Our results showed no association between leukoaraiosis and the risk of SICH. Although the presence of severe leukoaraiosis predicted a poor functional outcome after stroke, IV thrombolysis might not be withheld in acute ischemic stroke patients solely based on the presence of severe leukoaraiosis on pre-thrombolytic CT scans.


Inflammation-induced colon cancer in uPA-deficient mice is associated with a deregulated expression of Notch signaling pathway components.
Notch is an evolutionarily conserved signaling pathway with an important role in development and cell fate determination. Deregulation of Notch signaling has been associated with several pathological conditions, including cancer. Acting as an oncogene in some types of cancers and as a tumor suppressor in other, Notch effects seem to be highly context-dependent in solid tumors. In the present study, we aimed to investigate gene expression levels of Notch pathway constituents, including ligands, receptors, and target genes, during the early stages of inflammation-associated intestinal carcinogenesis. To achieve so, we used our recently developed mouse model, in which colon cancer arises in the absence of urokinase-type plasminogen activator (uPA) due to colitis induced by dextran sodium sulfate (DSS) treatment. Among the cell surface components, ligands Jag1/Jag2 and receptors Notch1/Notch2 were found to be significantly upregulated in the uPA-deficient protumorigenic inflammatory microenvironment. Moreover, several intracellular Notch modulators, i.e. Hes1, Hey1, and Klf4, were also shown to be deregulated with inflammation, yet irrespective of uPA status. Sox9 transcription factor, however, was significantly downregulated in the uPA-deficient/DSS-treated mice that developed colon adenomas as compared to the wild-type/DSS-treated group with no neoplasia identified. The latter finding supports a tumor suppressive role of Sox9 in intestinal carcinogenesis. Our results point towards an early activation of Notch signaling pathway at the receptor-ligand level in inflammation-associated colon neoplasmatogenesis developed in the absence of uPA. Interestingly, such activation may not be accompanied by deregulation of downstream Notch-target genes, possibly due to the effects of other inter-related signaling pathways.


Editor's Choice - Recommendations for Registry Data Collection for Revascularisations of Acute Limb Ischaemia: A Delphi Consensus from the International Consortium of Vascular Registries.
To develop a minimum core data set for evaluation of acute limb ischaemia (ALI) revascularisation treatment and outcomes that would enable collaboration among international registries. A modified Delphi approach was used to achieve consensus among international multidisciplinary vascular specialists and registry members of the International Consortium of Vascular Registries (ICVR). Variables identified in the literature or suggested by the expert panel, and variables, including definitions, currently used in 15 countries in the ICVR, were assessed to define both a minimum core and an optimum data set to register ALI treatment. Clinical relevance and practicability were both assessed, and consensus was defined as ≥ 80% agreement among participants. Of 40 invited experts, 37 completed a preliminary survey and 31 completed the two subsequent Delphi rounds via internet exchange and face to face discussions. In total, 117 different items were generated from the various registry data forms, an extensive review of the literature, and additional suggestions from the experts, for potential inclusion in the data set. Ultimately, 35 items were recommended for inclusion in the minimum core data set, including 23 core items important for all registries, and an additional 12 more specific items for registries capable of capturing more detail. These 35 items supplement previous data elements recommended for registering chronic peripheral arterial occlusive disease treatment. A modified Delphi study allowed 37 international vascular registry experts to achieve a consensus recommendation for a minimum core and an optimum data set for registries covering patients who undergo ALI revascularisation. Continued global harmonisation of registry infrastructure and definition of items allows international comparisons and global quality improvement. Furthermore, it can help to define and monitor standards of care and enable international research collaboration.


Carbon adsorption onto Fe oxyhydroxide stalks produced by a lithotrophic iron-oxidizing bacteria.
Iron (Fe)-oxidizing bacteria have the potential to produce morphologically unique structures that may be used as biosignatures in geological deposits. One particular example is Mariprofundus ferrooxydans, which produces extracellular twisted ribbon-like stalks consisting of ferrihydrite, co-located with organic and inorganic elements. It is currently thought that M. ferrooxydans excrete and co-precipitate polysaccharides and Fe simultaneously; however, the cellular production of these polysaccharides has yet to be confirmed. Here, we report on a time-series study that used scanning transmission X-ray microscopy and C 1s and Ca 2p near-edge X-ray adsorption fine structure spectroscopy to investigate production of polysaccharides over the growth cycle of M. ferrooxydans. The production and morphology of twisted iron stalks were consistent with previous observations, but unexpectedly, in the log phase, the carbon content of the stalks was extremely low. It was not until stationary growth phase that a significant component of carbon was detected on the stalks. During the log phase, low levels of carbon, only detectable when the stalks were thin, suggested that M. ferrooxydans produce an extracellular polysaccharide template onto which the Fe precipitates. By stationary phase, the increased carbon association with the stalks was a result of adsorption of organic compounds that were released during osmotic shock post-stalk production. In the environment, elevated concentrations of DOC could adsorb onto the Fe stalks as well as a number of other elements, for example, Si, P, Ca, which, by preventing chemical interactions between the Fe nanoparticles, will prevent structural deformation during recrystallization and preserve the structure of these filaments in the rock record.


Using routinely collected laboratory data to identify high rifampicin-resistant tuberculosis burden communities in the Western Cape Province, South Africa: A retrospective spatiotemporal analysis.
South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data. We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing (n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location (n = 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage by clinic, and estimated average size and direction of change was mapped. We identified 799,779 individuals who had specimens submitted from mappable clinics for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27-44), and 10,255 (4.6%, 95% CI: 4.6-4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among these individuals was 11.4% (95% CI: 10.7-12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm. Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions.


2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity.
We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1-1.0 μM) over HDAC1 (IC50 = 0.9-6 μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.


PFAPA syndrome: a rare cause of periodic fever.
PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenopathy) is characterized by abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis and cervical adenopathy. The age of onset of the disease is four years, with a range of 6 months to 7 years. The syndrome is sporadic and nonhereditary. Long-term sequelae do not develop. A nine- year-old boy presented with sore throat, fever and oral aphthae. After taking a throat culture, he was prescribed oral antipyretic and was called for a follow-up visit the next day. As the culture result was negative, he was given a single dose prednisolone with the suspected diagnosis of PFAPA. Twenty-four hours later his temperature was 36.8 degrees C, with all his complaints regressed. Twenty-two days later the patient was again admitted to our hospital with the same complaints. Again, single dose oral prednisolone was given after a throat culture. On the next day the patient was free of all symptoms and the culture was again normal. To our knowledge this is the first PFAPA case report from Turkey in the literature.


Protective effects of Helicobacter pylori membrane vesicles against stress and antimicrobial agents.
Outer-membrane vesicles (OMVs) produced by Helicobacter pylori deliver bacterial components to host cells, provide a mechanism for stabilization of secreted components and may allow the bacteria to exert 'long-range' effects in the gastric niche, promoting persistence. In addition to their well-characterized host cell interactions, membrane vesicles improve stress survival in other bacterial species, and are constitutively produced by both pathogenic and non-pathogenic bacteria. We aimed to determine whether OMVs could improve H. pylori survival of a range of stressors. The effects of purified OMVs on the resistance of H. pylori to a range of environmental and antimicrobial stresses were determined using growth curves and survival assays. Addition of purified OMVs to H. pylori cultures provided dose-dependent protection against hydrogen peroxide-mediated killing. Supplementation with OMVs also partially protected H. pylori against the bactericidal effects of the antibiotics clarithromycin and levofloxacin, but not against amoxicillin nor metronidazole. Addition of purified OMVs allowed H. pylori to grow in the presence of inhibitory concentrations of the antimicrobial peptide LL-37. In the presence of 50 µg OMVs ml-1, significantly enhanced H. pylori growth was observed at higher LL-37 concentrations compared with lower LL-37 concentrations, suggesting that OMV-LL-37 interactions might facilitate release of growth-promoting nutrients. Taken together, these data indicate that production of membrane vesicles could help H. pylori to survive exposure to antibiotics and host antimicrobial defences during infection.


Identification of an Arabidopsis thaliana ribulose-1,5-bisphosphate carboxylase/oxygenase activase (RCA) minimal promoter regulated by light and the circadian clock.
Transcription of the Arabidopsis thaliana gene encoding ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activase (RCA) is organ-specific, light-responsive, and regulated by the circadian clock. RCA is transcribed throughout the green parts of the plant, but not in roots and petals. Responses elicited by short pulses of light indicate that the light response is mediated, at least in part, by phytochrome. Analysis of transgenic tobacco and Arabidopsis carrying RCA 5' untranscribed regions fused to reporter genes (uidA, encoding beta-glucuronidase, or cat, encoding chloramphenicol acetyltransferase) indicate that elements sufficient to confer organ-specific, light-responsive, and clock-regulated transcription are localized within 317 base pairs upstream of the site of transcription initiation. A clock-responsive element sufficient to confer a low-amplitude (approximately 2-fold) circadian oscillation lies within 317 base pairs of the trascription start, but other elements necessary for high-amplitude (approximately 10-fold) circadian oscillation lie upstream of -317 and are removed by deletion from -970 to -317.


Leptin regulates CD16 expression on human monocytes in a sex-specific manner.
Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic-sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16-positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16-positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14(++)16(++) monocytes, which are primary producers of TNFα, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin × sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose-related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin × sex interaction). There were no sex-related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14(+)16(++) monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima-media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = -0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16-positive monocyte populations in a sex-specific manner and that these subpopulations are associated with diminished vascular function.


Inhibitory Effects of α-Lipoic Acid on Oxidative Stress-Induced Adipogenesis in Orbital Fibroblasts From Patients With Graves Ophthalmopathy.
A choice of the optimal treatment for Graves ophthalmopathy (GO) is a challenge due to the complexity of the pathogenesis. Alpha-lipoic acid (ALA) is well known as a multifunctional antioxidant, helping to protect cells against oxidative stress and inflammatory damage.The aim of this study was to investigate the effects of ALA on intracellular production of reactive oxygen species (ROS), inflammation, and adipogenesis using primary cultured orbital fibroblasts from patients with GO.Intracellular ROS levels and mRNA expressions of proinflammatory cytokines and chemokines including intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T cell expressed and presumably secreted (RANTES) were measured. After adipogenesis, the expressions of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT-enhancer-binding proteins (C/EBP)α and β, and heme oxygenase-1 (HO-1) were investigated.H2O2 dose-dependently stimulated ROS production and HO-1 expression. Addition of ALA strongly attenuated ROS production and further increased HO-1 expression. However, by pretreatment of zinc protoporphyrin (ZnPP), HO-1 inhibitor, ALA inhibition of ROS generation by H2O2 was abolished. Tumor necrosis factor (TNF)α-induced mRNA expressions of ICAM-1, IL-6, MCP-1, and RANTES were inhibited by ALA treatment. In this context, TNFα-induced phosphorylation of P65 was also inhibited. In addition, ALA dose-dependently inhibited H2O2-induced intracellular accumulation of lipid droplets. The expression of adipogenic transcription factors, including PPARγ, C/EBPα, and β, was also inhibited.ALA is a potential therapeutic agent for GO because of the inhibitory effects on ROS production and gene expression of proinflammatory cytokines and chemokines, resulting in prevention of adipose-tissue expansion.


[Socioeconomic and contextual determinants of reproductive activity among adolescent women in Colombia].
To contribute to a better understanding of the problems of pregnancy among adolescent women, including proximate and socioeconomic determining factors, in two large, culturally different cities in Colombia: Santa Fe de Bogotá and Cali. This longitudinal study combined quantitative and qualitative research methods, using information generated by a survey of adolescents conducted in 2003. The survey included 550 adolescents in Bogotá and 550 adolescents in Cali, from all socioeconomic strata. To analyze the determinants, discrete-time proportional hazards models were used. For the qualitative study, 72 in-depth interviews and four focus groups were done. With the information organized by subjects and categories that were defined in relation to the purposes of the study, categories were identified that arose from the patterns and recurrences in the data, in order to see sociocultural trends by sex, stratum, and city. The patterns of sexual activity, union (married or unmarried relationship), and maternity differ considerably among the socioeconomic strata, in both of the cities. The adolescent women in the low stratum begin having sexual relations, form unions, and become mothers earlier in life and with greater frequency than do adolescent women in the medium or high strata. The main determinant of the reproductive behavior of adolescent women is the set of contextual and socioeconomic factors in the home, mainly the family context (environment and supervision) and the educational climate (the average number of years of formal education of the family members over the age of 15). Sex education has been provided in the schools in Colombia since 1993, but our results clearly indicate that it has had only a limited impact on the reproductive behavior of adolescent women.


In vivo assembly of overproduced DNA polymerase III. Overproduction, purification, and characterization of the alpha, alpha-epsilon, and alpha-epsilon-theta subunits.
The genes for the polymerase core (alphaepsilontheta) of the DNA polymerase III holoenzyme map to widely separated loci on the Escherichia coli chromosome. To enable efficient overproduction and in vivo assembly of DNA polymerase III core, artificial operons containing the three structural genes, dnaE, dnaQ, and holE, were placed in an expression plasmid. The proteins alpha, alphaepsilon and alphaepsilontheta were overexpressed and assembled in E. coli and purified to homogeneity. The three purified polymerases had a similar specific activity of about 6.0 x 10(6) units/mg in a gap-filling assay. Kinetics studies showed that neither epsilon nor theta influenced the Km of alpha for deoxynucleotide triphosphate and only slightly decreased the Km of alpha for DNA, although epsilon was absolutely required for maximal DNA synthesis. The rate of DNA synthesis by alpha-reconstituted holoenzyme using tau complex was about 5-fold less than that of alphaepsilon or alphaepsilontheta-reconstituted holoenzyme as determined by a gel analysis. The processivity of alpha-reconstituted holoenzyme was very similar to that of alphaepsilontheta-reconstituted holoenzyme when tau complex was used as a clamp loader.


Implementation of tuberculosis infection prevention and control in Mozambican health care facilities.
District and urban health care facilities in three provinces (Manica, Sofala, Tete) in central Mozambique. To assess the level of implementation of selected tuberculosis infection prevention and control (TB-IPC) measures. In a cross-sectional study of TB-IPC implementation in 29 health care facilities, we assessed TB clinics, laboratories, out-patient departments and medical and TB wards. Assessment included selected managerial, administrative and environmental measures and the availability and use of respiratory protective equipment (N95 respirators). Guidelines for diagnosis and treatment of (presumptive) TB patients were not present in all facilities. Staff instructed patients on sputum collection in 91%, but only 4% observed it. Using a pragmatic '20% rule', 52% of the rooms assessed had adequate ventilation. Potentially, this could be increased to 76%. Three quarters of the health care workers had N95 respirators. Only 36% knew how to use it correctly. Implementation of TB-IPC measures showed wide variations within health care facilities. Relatively simple measures to improve TB-IPC include the availability of guidelines, opening doors and windows to improve ventilation, and training and support on correct N95 respirator use. However, even relatively simple measures are challenging to implement, and require careful attention in and evaluation of the implementation process.


Acid-base balance in acute gastrointestinal bleeding.
Acid-base balance has been studied in 21 patients with acute upper gastrointestinal bleeding. A low plasma bicarbonate concentration was found in nine patients, accompanied in each case by a base deficit of more than 3 mEq/litre, indicating a metabolic acidosis. Three patients had a low blood pH. Hyperlactataemia appeared to be a major cause of the acidosis. This was not accompanied by a raised blood pyruvate concentration. The hyperlactataemia could not be accounted for on the basis of hyperventilation, intravenous infusion of dextrose, or arterial hypoxaemia. Before blood transfusion it was most pronounced in patients who were clinically shocked, suggesting that it may have resulted from poor tissue perfusion and anaerobic glycolysis. Blood transfusion resulted in a rise in lactate concentration in seven patients who were not clinically shocked, and failed to reverse a severe uncompensated acidosis in a patient who was clinically shocked. These effects of blood transfusion are probably due to the fact that red blood cells in stored bank blood, with added acid-citrate-dextrose solution, metabolize the dextrose anaerobically to lactic acid. Monitoring of acid-base balance is recommended in patients with acute gastrointestinal bleeding who are clinically shocked. A metabolic acidosis can then be corrected with intravenous sodium bicarbonate.


Intracellular adhesion molecule 1 plays a key role in acquired immunity to salmonellosis.
This study investigated the role of intracellular adhesion molecule 1 (ICAM-1) during Salmonella enterica serovar Typhimurium infection of mice. We show that ICAM-1 is expressed in and around granulomas on day 4 of infection in wild-type mice. However, when naive ICAM-1(-/-) mice were challenged with a sublethal dose of serovar Typhimurium, there were no detectable differences in systemic bacterial burden over the first 9 days of infection compared to wild-type control mice. When mice were immunized with the S. enterica serovar Typhimurium vaccine strain SL2361 and then challenged with the virulent S. enterica serovar Typhimurium strain C5, 100% of the ICAM-1(-/-) mice succumbed to infection, compared to 30% of wild-type mice. T-cell responses, as measured by activation via interleukin-2 production, as well as antibody responses were comparable in the ICAM-1(-/-) and wild-type mice. Following challenge, counts in organs were significantly higher in the ICAM-1(-/-) mice, and histological examination of organs showed pathological differences. Strain SL3261-immunized wild-type mice had cellular infiltrate and normal granuloma formation in the liver and spleen on days 5 and 10 after challenge with strain C5. ICAM-1(-/-) mice had a similar infiltrate on day 5, whereas on day 10 the infiltrate was more widespread and there were fewer macrophages associated with the granulomas. High circulating levels of tumor necrosis factor alpha and gamma interferon, as well as a high burden of strain C5 in the blood, accompanied the differences in histopathology. In this study we show that ICAM-1 plays a critical role during rechallenge of immunized mice with virulent S. enterica serovar Typhimurium.


Using the Extended Parallel Process Model to create and evaluate the effectiveness of brochures to reduce the risk for noise-induced hearing loss in college students.
Brochures containing messages developed according to the Extended Parallel Process Model were deployed to increase intentions to use hearing protection for college students. These brochures were presented to one-half of a college student sample, after which a questionnaire was administered to assess perceptions of threat, efficacy, and behavioral intentions. The other half of the sample completed the questionnaire and then received brochures. Results indicated that people receiving the brochure before the questionnaire reported greater perceptions of hearing loss threat and efficacy to use ear plugs when in loud environments, however, intentions to use ear plugs were unchanged. Distribution of the brochure also resulted in greater perceptions of hearing loss threat and efficacy to use over-the-ear headphones when using devices such as MP3 players. In this case, however, intentions to use over-the-ear headphones increased. Results are discussed in terms of future research and practical applications.


Epidemiology and correlation of the clinicopathological features in oral epithelial dysplasia: analysis of 173 cases.
Oral epithelial dysplasias (OEDs) are potentially malignant disorders characterized by diverse degrees of cellular atypia. The early and careful diagnosis has extreme importance, allowing prevention of the progression to the oral squamous cell carcinoma. This study aimed to determine the epidemiology and then correlate it with the clinicopathological features of OED. One hundred seventy-three cases of oral lesions retrieved from the files of a Service of Pathological Anatomy, covering a 38-year period, were submitted to descriptive statistical analysis through the Pearson χ(2) test. The majority of cases were from affected females (57.9%), with a peak of occurrence in the age group of 41 and 55 years (37.3%), white patients (64.8%), and those with lesions located on the gingiva/alveolar ridge (25.1%). The lesions predominantly presented with white color (56.8%) and were described as nodules (27.4%), with a rough surface (76.7%), an exophytic growth (79.1%), and a sessile base (95.6%). The majority of the lesions with degree of mild (34.6%) and moderate (34.9%) OED had clinical diagnosis of leukoplakia, whereas 33.3% of the lesions with degree of severe had clinical diagnosis of squamous cell carcinoma (P < .05). Tobacco use was the risk habit more related with OED (42.6%) (P > .05). The knowledge of OED epidemiology and clinical features provide a better understanding of the factors that possibly are associated with the malignant transformation of OED. Furthermore, these results contribute to supporting a prompt and accurate recognition of these lesions in clinical practice.


Curcumin protects against methylmercury-induced cytotoxicity in primary rat astrocytes by activating the Nrf2/ARE pathway independently of PKCδ.
Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31-8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.


Genotyping by sequencing resolves shallow population structure to inform conservation of Chinook salmon (Oncorhynchus tshawytscha).
Recent advances in population genomics have made it possible to detect previously unidentified structure, obtain more accurate estimates of demographic parameters, and explore adaptive divergence, potentially revolutionizing the way genetic data are used to manage wild populations. Here, we identified 10 944 single-nucleotide polymorphisms using restriction-site-associated DNA (RAD) sequencing to explore population structure, demography, and adaptive divergence in five populations of Chinook salmon (Oncorhynchus tshawytscha) from western Alaska. Patterns of population structure were similar to those of past studies, but our ability to assign individuals back to their region of origin was greatly improved (>90% accuracy for all populations). We also calculated effective size with and without removing physically linked loci identified from a linkage map, a novel method for nonmodel organisms. Estimates of effective size were generally above 1000 and were biased downward when physically linked loci were not removed. Outlier tests based on genetic differentiation identified 733 loci and three genomic regions under putative selection. These markers and genomic regions are excellent candidates for future research and can be used to create high-resolution panels for genetic monitoring and population assignment. This work demonstrates the utility of genomic data to inform conservation in highly exploited species with shallow population structure.


Hepatic tyrosine aminotransferase from the rainbow lizard Agama agama: purification and some properties.
Tyrosine aminotransferase, induced by dexamethasone in the liver of the rainbow lizard, Agama agama, was extracted under optimal conditions which yield the native undegraded enzyme; purified by heat treatment at 65 degrees C, ammonium sulfate precipitation, chromatography on DEAE-Sephacel and Sephadex G-150-120 and then characterized. The enzyme was purified over 2000-fold to a specific activity of 2653 units/mg of protein. It had an optimum pH of 7.6 in potassium phosphate buffer, KmTyr: 1.0 mM; K alpha-KGm: 0.32 mM; Vmax: 1.33 nmol/min and a molecular weight of about 130,000. It was inhibited by L-glutamate (competitively, Ki, 2.5 mM), and by metal ions Ca2+, Mn2+, Zn2+, Hg2+ and Ag2+, but was unaffected by chelating agents and other divalent cations. Lizard hepatic cytosolic tyrosine aminotransferase was specific for L-tyrosine and alpha-ketoglutarate as substrates sensitive to sulfhydryl inactivation and to protection from thermal lability by alpha-ketoglutarate and pyridoxal phosphate.


Hematopoiesis and its disorders: a systems biology approach.
Scientists have traditionally studied complex biologic systems by reducing them to simple building blocks. Genome sequencing, high-throughput screening, and proteomics have, however, generated large datasets, revealing a high level of complexity in components and interactions. Systems biology embraces this complexity with a combination of mathematical, engineering, and computational tools for constructing and validating models of biologic phenomena. The validity of mathematical modeling in hematopoiesis was established early by the pioneering work of Till and McCulloch. In reviewing more recent papers, we highlight deterministic, stochastic, statistical, and network-based models that have been used to better understand a range of topics in hematopoiesis, including blood cell production, the periodicity of cyclical neutropenia, stem cell production in response to cytokine administration, and the emergence of imatinib resistance in chronic myeloid leukemia. Future advances require technologic improvements in computing power, imaging, and proteomics as well as greater collaboration between experimentalists and modelers. Altogether, systems biology will improve our understanding of normal and abnormal hematopoiesis, better define stem cells and their daughter cells, and potentially lead to more effective therapies.


SU-E-J-89: Deformable Registration Method Using B-TPS in Radiotherapy.
A novel deformable registration method for four-dimensional computed tomography (4DCT) images is developed in radiation therapy. The proposed method combines the thin plate spline (TPS) and B-spline together to achieve high accuracy and high efficiency. The method consists of two steps. First, TPS is used as a global registration method to deform large unfit regions in the moving image to match counterpart in the reference image. Then B-spline is used for local registration, the previous deformed moving image is further deformed to match the reference image more accurately. Two clinical CT image sets, including one pair of lung and one pair of liver, are simulated using the proposed algorithm, which results in a tremendous improvement in both run-time and registration quality, compared with the conventional methods solely using either TPS or B-spline. The proposed method can combine the efficiency of TPS and the accuracy of B-spline, performing good adaptively and robust in registration of clinical 4DCT image.


Molecular characterization of the apical organ of the anthozoan Nematostella vectensis.
Apical organs are sensory structures present in many marine invertebrate larvae where they are considered to be involved in their settlement, metamorphosis and locomotion. In bilaterians they are characterised by a tuft of long cilia and receptor cells and they are associated with groups of neurons, but their relatively low morphological complexity and dispersed phylogenetic distribution have left their evolutionary relationship unresolved. Moreover, since apical organs are not present in the standard model organisms, their development and function are not well understood. To provide a foundation for a better understanding of this structure we have characterised the molecular composition of the apical organ of the sea anemone Nematostella vectensis. In a microarray-based comparison of the gene expression profiles of planulae with either a wildtype or an experimentally expanded apical organ, we identified 78 evolutionarily conserved genes, which are predominantly or specifically expressed in the apical organ of Nematostella. This gene set comprises signalling molecules, transcription factors, structural and metabolic genes. The majority of these genes, including several conserved, but previously uncharacterized ones, are potentially involved in different aspects of the development or function of the long cilia of the apical organ. To demonstrate the utility of this gene set for comparative analyses, we further analysed the expression of a subset of previously uncharacterized putative orthologs in sea urchin larvae and detected expression for twelve out of eighteen of them in the apical domain. Our study provides a molecular characterization of the apical organ of Nematostella and represents an informative tool for future studies addressing the development, function and evolutionary history of apical organ cells.


Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo-controlled study.
The relative benefits of selegeline hydrochloride (2 x 5 mg, 2 x 10 mg selegeline) were studied in 30 narcoleptic patients using a randomized, double-blind, placebo-controlled design. Patients were randomly assigned to three groups (placebo and 2 x 5 mg and 2 x 10 mg selegeline). After a 2-week washout period for previous anticataplectic and stimulant medication, the study started with a 2-day period of placebo intake for each group, continued by 14 days of medication, ending with a 2-day placebo period. Outcome was measured by comparison of four polysomnographies and four multiple sleep latency tests (MSLTs) performed during the initial and the final placebo and medication period. Each MSLT day included acoustic and visual vigilance tests. Blood pressure and pulse rate were monitored daily. Patients reported daily about mood, concentration, subjective sleep time, nocturnal awakenings, nocturnal wake times, number of naps, and occurrence of symptoms of the narcoleptic tetrad. Selegeline caused dose-dependent REM suppression during nighttime sleep and naps and increase of sleep and REM latency. Under selegeline, daytime sleepiness improved significantly and the number of sleep attacks and naps as well as the frequency of cataplexy were reduced. Selegeline at a dose of a least 20 mg/day is a potent drug for the treatment of all narcoleptic symptoms.


Electronic structure of Fe1.08Te bulk crystals and epitaxial FeTe thin films on Bi2Te3.
The electronic structure of thin films of FeTe grown on Bi2Te3 is investigated using angle-resolved photoemission spectroscopy, scanning tunneling microscopy and first principles calculations. As a comparison, data from cleaved bulk Fe1.08Te taken under the same experimental conditions is also presented. Due to the substrate and thin film symmetry, FeTe thin films grow on Bi2Te3 in three domains, rotated by 0°, 120°, and 240°. This results in a superposition of photoemission intensity from the domains, complicating the analysis. However, by combining bulk and thin film data, it is possible to partly disentangle the contributions from three domains. We find a close similarity between thin film and bulk electronic structure and an overall good agreement with first principles calculations, assuming a p-doping shift of 65 meV for the bulk and a renormalization factor of around two. By tracking the change of substrate electronic structure upon film growth, we find indications of an electron transfer from the FeTe film to the substrate. No significant change of the film's electronic structure or doping is observed when alkali atoms are dosed onto the surface. This is ascribed to the film's high density of states at the Fermi energy. This behavior is also supported by the ab initio calculations.


Synthesis of MgO-coated corncob biochar and its application in lead stabilization in a soil washing residue.
In this study, a magnesium oxide (MgO) coated corncob biochar (MCB) was synthesized by pyrolyzing MgCl2 pretreated corncob, for a better performance in lead immobilization in a contaminated soil compared with corncob biochar (CB). The properties and microstructures of CB and MCB were investigated. It was observed that MgO particles ranging from 1 to 2 μm were well coated on MCB, and the MgO content in MCB was calculated at 29.90% in w/w. The surface area of the biochar was significantly enhanced from 0.07 to 26.56 m2/g after the MgO coating. The MgO coating also significantly facilitated the lead removal percentage from 23% to 74% in aqueous solution by biochar. CB failed to immobilize lead in a soil washing residue and could not reduce its environmental risks in a laboratory incubation study. In contrast, MCB was applied to the soil and resulted in a significant reduction in TCLP leached lead from 10.63 to 5.24 mg/L (reduced by 50.71%). The comparison between MCB and other amendments suggests that the biochar component of MCB adsorbed lead onto its surface through cation-π interaction and increased surface adsorption due to higher surface area, and then the MgO coated on MCB's surface further enhanced the adsorption through precipitation. The synergistic roles of biochar-mineral composites make them a promising candidate for soil remediation.


The growth of the central region by acquisition of counterrotating gas in star-forming galaxies.
Galaxies grow through both internal and external processes. In about 10% of nearby red galaxies with little star formation, gas and stars are counter-rotating, demonstrating the importance of external gas acquisition in these galaxies. However, systematic studies of such phenomena in blue, star-forming galaxies are rare, leaving uncertain the role of external gas acquisition in driving evolution of blue galaxies. Here, based on new measurements with integral field spectroscopy of a large representative galaxy sample, we find an appreciable fraction of counter-rotators among blue galaxies (9 out of 489 galaxies). The central regions of blue counter-rotators show younger stellar populations and more intense, ongoing star formation than their outer parts, indicating ongoing growth of the central regions. The result offers observational evidence that the acquisition of external gas in blue galaxies is possible; the interaction with pre-existing gas funnels the gas into nuclear regions (<1 kpc) to form new stars.